Chimeric fibroblast growth factor 21 proteins and methods of use

FIELD OF THE INVENTION

The present invention relates to chimeric fibroblast growth factor ("FGF") proteins and uses thereof.

BACKGROUND OF THE INVENTION

Type 2 diabetes is a chronic progressive disorder, which results from end-organ resistance to the action of insulin in combination with insufficient insulin secretion from the pancreas. The metabolic abnormalities associated with insulin resistance and secretory defects, in particular the hyperglycemia, lead over the course of years to extensive irreversible damage to multiple organs including heart, blood vessels, kidney, and eye. Currently, nearly 200 million or 2.9% of the world population have type 2 diabetes (World Health Organization, Diabetes Fact Sheet N.degree. 312, January 2011; Wild et al., "Global Prevalence of Diabetes: Estimates for the Year 2000 and Projections for 2030," Diabetes Care 27(5):1047-1053 (2004)), and its prevalence is rising at an alarmingly fast pace in parallel with the rise in the prevalence of overweight and obesity (World Health Organization, Obesity and Overweight Fact Sheet N.degree. 311, January 2011). Until the end of the 20.sup.th century, type 2 diabetes was observed only in adults but what was once known as "adult-onset diabetes" is now also diagnosed in children and adolescents, and this growing incidence can be related to the increase in overweight and obesity among children and adolescents. The prevalence of pre-diabetes, an intermediate metabolic stage between normal glucose homeostasis and diabetes, is even greater than that of type 2 diabetes. Currently, nearly 80 million or 26% of the population in the United States alone have pre-diabetes (Center for Disease Control and Prevention, National Diabetes Fact Sheet 2011), and as such are at high risk for progressing to type 2 diabetes. Type 2 diabetes ranks among the ten leading causes of death worldwide, and the World Health Organization projects that mortality from diabetes (90% of which is type 2) will more than double within the next decade (World Health Organization, Diabetes Fact Sheet N.degree. 312, January 2011). Type 2 diabetes also is a major cause of disability. As a consequence of diabetic retinopathy, about 10% of all patients with diabetes in the world develop severe visual impairment and 2% become blind 15 years into the disease (World Health Organization, Diabetes Fact Sheet N.degree. 312, January 2011). Diabetic neuropathy, which affects up to half of all patients with diabetes worldwide (World Health Organization, Diabetes Fact Sheet N.degree. 312, January 2011), accounts for the majority of nontraumatic lower-limb amputations. Indeed, in its recently published first worldwide report on non-infectious diseases, the World Health Organization considers diabetes, together with other chronic non-infectious diseases like cancer and heart disease, a global economic and social burden, which exceeds that imposed by infectious diseases such as HIV/AIDS.

The current drug therapy for type 2 diabetes is focused on correcting the hyperglycemia in the patients. Although a number of small molecules and biologics with different mechanisms of anti-hyperglycemic action are available for use as mono-therapy or combination therapy, most, if not all of these have limited efficacy, limited tolerability, and significant adverse effects (Moller, "New Drug Targets for Type 2 Diabetes and the Metabolic Syndrome," Nature 414(6865):821-827 (2001)). For example, treatment with sulfonylureas, glinides, thiazolidinediones, or insulin has been associated with weight gain, which is an undesired effect since overweight is considered a driving force in the pathogenesis of type 2 diabetes. Some of these treatments have also been associated with increased risk of hypoglycemia. A limitation specific to the thiazolidinediones is the potential for adverse cardiovascular effects (DeSouza et al., "Therapeutic Targets to Reduce Cardiovascular Disease in Type 2 Diabetes," Nat Rev Drug Discov 8(5):361-367 (2009)). A meta-analysis of clinical data on the thiazolidinedione rosiglitazone (Avandia.RTM.), which was widely used for the treatment of type 2 diabetes, found that the drug increased the risk of myocardial infarction in patients with type 2 diabetes (Nissen et al., "Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes," N Engl J Med 356(24):2457-2471 (2007)). Of all diabetic complications, cardiovascular disease is the main cause of morbidity and mortality in patients with diabetes (World Health Organization, Diabetes Fact Sheet N.degree. 312, January 2011; Center for Disease Control and Prevention, National Diabetes Fact Sheet 2011), and hence an aggravation of cardiovascular risk by drug treatment is absolutely unacceptable. In the wake of the debate about the cardiovascular safety of thiazolidinediones, the FDA issued a guidance on evaluating cardiovascular risk in new anti-diabetic therapies to treat type 2 diabetes (Opar A, "Diabetes Drugs Pass Cardiovascular Risk Check," Nat Rev Drug Discov 8(5):343-344 (2009)). Meanwhile, thiazolidinediones lost their popularity. Even for glucagon-like peptide-1 agonists, one of the latest class of drugs introduced for the treatment of type 2 diabetes, concerns about safety have been raised, namely the potential for carcinogenicity (Opar A, "Diabetes Drugs Pass Cardiovascular Risk Check," Nat Rev Drug Discov 8(5):343-344 (2009)). Therefore, novel therapies that are more effective and safer than existing drugs are needed. Since the currently available drugs do not directly target complications of advanced diabetic disease, especially cardiovascular disease, therapies that are not only effective in lowering blood glucose but also reduce cardiovascular risk factors such as dyslipidemia are particularly desired.

A search conducted by Eli Lilly & Co. for potential novel biotherapeutics to treat type 2 diabetes led to the discovery of fibroblast growth factor (FGF) 21 as a protein that stimulates glucose uptake into adipocytes in an insulin-independent fashion (Kharitonenkov et al., "FGF-21 as a Novel Metabolic Regulator," J Clin Invest 115(6): 1627-1635 (2005)). FGF21 has since emerged as a key endocrine regulator not only of glucose metabolism but also of lipid metabolism, and has become one of the most promising drug candidates for the treatment of type 2 diabetes, obesity, and metabolic syndrome. In mouse models of diabetes and obesity, pharmacologic doses of FGF21 lower plasma glucose and increase insulin sensitivity (Kharitonenkov et al., "FGF-21 as a Novel Metabolic Regulator," J Clin Invest 115(6):1627-1635 (2005); Coskun et al., "Fibroblast growth factor 21 corrects obesity in mice," Endocrinology 149(12):6018-6027 (2008)). Concurrently, FGF21 lowers plasma triglyceride and cholesterol, enhances lipolysis and suppresses lipogenesis, and accelerates energy expenditure (Kharitonenkov et al., "FGF-21 as a Novel Metabolic Regulator," J Clin Invest 115(6):1627-1635 (2005); Coskun et al., "Fibroblast growth factor 21 corrects obesity in mice," Endocrinology 149(12):6018-6027 (2008)). In obese mice, FGF21 causes weight loss, in lean mice, it is weight neutral (Kharitonenkov et al., "FGF-21 as a Novel Metabolic Regulator," J Clin Invest 115(6):1627-1635 (2005); Coskun et al., "Fibroblast growth factor 21 corrects obesity in mice," Endocrinology 149(12):6018-6027 (2008)). Thus, FGF21 has some of the most desired characteristics of a drug for the treatment of type 2 diabetes; not only does it improve glycemic control, but also directly affects cardiovascular risk factors, such as hypertriglyceridemia, and reduces obesity, which is considered the single most important promoter of type 2 diabetes. Importantly, FGF21 does not induce hypoglycemia (Kharitonenkov et al., "FGF-21 as a Novel Metabolic Regulator," J Clin Invest 115(6): 1627-1635 (2005)), a side effect that can occur with several of the current anti-diabetic therapies, including insulin. Moreover, FGF21 does not exhibit any mitogenic activity in mice (Kharitonenkov et al., "FGF-21 as a Novel Metabolic Regulator," J Clin Invest 115(6): 1627-1635 (2005)), ruling out the possibility of a carcinogenic risk. The findings on FGF21 therapy in mouse models of diabetes have been reproduced in diabetic rhesus monkeys (Kharitonenkov et al., "The Metabolic State of Diabetic Monkeys is Regulated by Fibroblast Growth Factor-21," Endocrinology 148(2):774-781 (2007)), and are currently followed up with clinical trials in humans (Kharitonenkov et al., "FGF21 Reloaded: Challenges of a Rapidly Growing Field," Trends Endocrinol Metab 22(3):81-86 (2011)). However, there is a need for more effective FGF21 therapeutics.

The present invention overcomes these and other deficiencies in the art.

SUMMARY OF THE INVENTION

One aspect of the present invention relates to a chimeric protein. The chimeric protein includes an N-terminus coupled to a C-terminus, where the N-terminus includes a portion of a paracrine fibroblast growth factor ("FGF") and the C-terminus includes a C-terminal portion of an FGF21 molecule. The portion of the paracrine FGF is modified to decrease binding affinity for heparin and/or heparan sulfate compared to the portion without the modification.

Another aspect of the present invention relates to a method for treating a subject suffering from a disorder. This method involves selecting a subject suffering from the disorder and providing a chimeric FGF protein, where the chimeric FGF protein includes an N-terminus coupled to a C-terminus. The N-terminus includes a portion of a paracrine FGF and the C-terminus includes a C-terminal portion of FGF21. The portion of the paracrine FGF is modified to decrease binding affinity for heparin and/or heparan sulfate compared to the portion without the modification. This method also involves administering a therapeutically effective amount of the chimeric FGF protein to the selected subject under conditions effective to treat the disorder.

Another aspect of the present invention relates to a method of making a chimeric FGF protein possessing enhanced endocrine activity. This method involves introducing one or more modifications to an FGF protein, where the modification decreases the affinity of the FGF protein for heparin and/or heparan sulfate and coupling a Klotho co-receptor binding domain to the modified FGF protein's C-terminus, whereby a chimeric FGF protein possessing enhanced endocrine activity is made.

Yet another aspect of the present invention relates to a method of facilitating fibroblast growth factor receptor ("FGFR")-.beta.Klotho co-receptor complex formation. This method involves providing a cell that includes a .beta.Klotho co-receptor and an FGFR and providing a chimeric FGF protein. The chimeric FGF protein includes a C-terminal portion of FGF21 and a portion of a paracrine FGF, where the portion of the paracrine FGF is modified to decrease binding affinity for heparin and/or heparan sulfate compared to the portion without the modification. This method also involves contacting the cell and the chimeric FGF protein under conditions effective to cause FGFR-.beta.Klotho co-receptor complex formation.

Yet a further aspect of the present invention relates to a method of screening for agents capable of facilitating FGFR-.beta.Klotho complex formation in the treatment of a disorder. This method involves providing a chimeric FGF that includes an N-terminus coupled to a C-terminus, where the N-terminus includes a portion of a paracrine FGF and the C-terminus includes a C-terminal portion of FGF21. The portion of the paracrine FGF is modified to decrease binding affinity for heparin and/or heparan sulfate compared to the portion without the modification. This method also involves providing a binary .beta.Klotho-FGFR complex and providing one or more candidate agents. This method further involves combining the chimeric FGF, the binary .beta.Klotho-FGFR complex, and the one or more candidate agents under conditions permitting the formation of a ternary complex between the chimeric FGF and the binary .beta.Klotho-FGFR complex in the absence of the one or more candidate agents. This method also involves identifying the one or more candidate agents that decrease ternary complex formation between the chimeric FGF and the binary .beta.Klotho-FGFR complex compared to the ternary complex formation in the absence of the one or more candidate agents as suitable for treating the disorder.

Fibroblast growth factors (FGFs) 19, 21, and 23 are hormones that regulate in a Klotho co-receptor-dependent fashion major metabolic processes such as glucose and lipid metabolism (FGF21) and phosphate and vitamin D homeostasis (FGF23). The role of heparan sulfate glycosaminoglycan in the formation of the cell surface signaling complex of endocrine FGFs has remained unclear. To decipher the role of HS in endocrine FGF signaling, we generated FGF19 and FGF23 mutant ligands devoid of HS binding and compared their signaling capacity with that of wild-type ligands. The data presented herein show that the mutated ligands retain full metabolic activity demonstrating that HS does not participate in the formation of the endocrine FGF signaling complex. Here it is shown that heparan sulfate is not a component of the signal transduction unit of FGF19 and FGF23. A paracrine FGF is converted into an endocrine ligand by diminishing heparan sulfate binding affinity of the paracrine FGF and substituting its C-terminal tail for that of an endocrine FGF containing the Klotho co-receptor binding site in order to home the ligand into the target tissue. The ligand conversion provides a novel strategy for engineering endocrine FGF-like molecules for the treatment of metabolic disorders, including global epidemics such as type 2 diabetes and obesity.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1D are schematic diagrams showing side-by-side comparison of the HS-binding site of FGF2, FGF19, and FGF23, and two working models for the endocrine FGF signaling complex. FIG. 1A shows interactions of FGF2 (schematic representation) with a heparin hexasaccharide (shown as sticks) as observed in the crystal structure of the 2:2 FGF2-FGFR1c dimer (PDB ID: 1FQ9; (Schlessinger et al., Mol. Cell 6:743-750 (2000), which is hereby incorporated by reference in its entirety)). The heparin hexasaccharide consists of three disaccharide units of 1.fwdarw.4 linked N-sulfated-6-O-sulfated D-glucosamine and 2-O-sulfated L-iduronic acid. Note that the heparin hexasaccharide interacts with both side chain and backbone atoms of residues in the HS-binding site of FGF2. Dashed lines denote hydrogen bonds. K128, R129, and K134, which make the majority of hydrogen bonds with the heparin hexasaccharide, are boxed. The .beta.-strand nomenclature follows the original FGF1 and FGF2 crystal structures (Ago et al., J. Biochem. 110:360-363 (1991); Eriksson et al., Proc. Nat'l. Acad. Sci. U.S.A. 88:3441-3445 (1991); Zhang et al., Proc. Nat'l. Acad. Sci. U.S.A. 88:3446-3450 (1991); Zhu et al., Science 251:90-93 (1991), which are hereby incorporated by reference in their entirety). Please note that compared to the prototypical .beta.-trefoil fold seen in soybean trypsin inhibitor (PDB ID: 1TIE; (Onesti et al., J. Mol. Biol. 217:153-176 (1991), which is hereby incorporated by reference in its entirety)) and interleukin 1.beta. (PDB ID: 1I1B; (Finzel et al., J. Mol. Biol. 209:779-791 (1989), which is hereby incorporated by reference in its entirety)), the .beta.10-.beta.11 strand pairing in FGF2 and other paracrine FGFs is less well defined. FIGS. 1B and 1C show cartoon representation of the crystal structures of FGF19 (PDB ID: 2P23; (Goetz et al., Mol. Cell Biol. 27:3417-3428 (2007), which is hereby incorporated by reference in its entirety)) (FIG. 1B) and FGF23 (PDB ID: 2P39; (Goetz et al., Mol. Cell Biol. 27:3417-3428 (2007), which is hereby incorporated by reference in its entirety)) (FIG. 1C) shown in the same orientation as the FGF2 structure in FIG. 1A. Side chains of residues that map to the corresponding HS-binding sites of these ligands are shown as sticks. Residues selected for mutagenesis to knock out residual HS binding in FGF19 and FGF23 are boxed. NT and CT indicate N- and C-termini of the FGFs. FIG. 1D is a schematic of two working models for the endocrine FGF-FGFR-Klotho coreceptor signal transduction unit. A recent study on the ternary complex formation between FGF21, FGFR1c, and .beta.Klotho supports the 1:2:1 model rather than the 2:2:2 model (Ming et al., J. Biol. Chem. 287:19997-20006 (2012), which is hereby incorporated by reference in its entirety). For comparison, a schematic of the paracrine FGF-FGFR-HS signaling unit is shown, which was made based on the crystal structure of the 2:2:2 FGF2-FGFR1c-HS complex (PDB ID: 1FQ9; (Schlessinger et al., Mol. Cell 6:743-750 (2000), which is hereby incorporated by reference in its entirety)). HS engages both paracrine FGF and receptor to enhance binding of FGF to its primary and secondary receptors thus promoting receptor dimerization. A question mark denotes whether or not HS is also a component of the endocrine FGF signaling complex.

FIG. 2 shows a sequence alignment of the endocrine FGFs, FGF1 and FGF2. The amino acid sequences of the mature human FGF19, FGF21, and FGF23 ligands are aligned. Also included in the alignment are the human sequences of FGF1 and FGF2, prototypical paracrine FGFs, which were used in the experiments described herein, in which FGF1 and FGF2 were converted into endocrine FGF ligands. Residue numbers corresponding to the human sequence of FGF1 (SEQ ID NO:1) (GenBank Accession No. AAH32697, which is hereby incorporated by reference in its entirety), FGF2 (SEQ ID NO: 121) (GenBank Accession No. EAX05222, which is hereby incorporated by reference in its entirety), FGF19 (SEQ ID NO: 337) (GenBank Accession No. NP_005108, which is hereby incorporated by reference in its entirety), FGF21 (SEQ ID NO: 233) (GenBank Accession No. NP_061986, which is hereby incorporated by reference in its entirety), and FGF23 (SEQ ID NO:351) (GenBank accession no. AAG09917, which is hereby incorporated by reference in its entirety) are in parenthesis to the left of the alignment. Secondary structure elements are labeled, and residues containing these elements for known secondary structures are boxed. Gaps (dashes) were introduced to optimize the sequence alignment. The .beta.-trefoil core domain for known FGF crystal structures is shaded gray. Blue bars on top of the alignment indicate the location of the HS-binding regions. HS-binding residues selected for mutagenesis are shaded blue.

FIGS. 3A-3G show Surface plasmon resonance ("SPR") results relating to knockout of residual heparin binding in FGF19 and FGF23 by site-directed mutagenesis. FIG. 3A shows an overlay of SPR sensorgrams illustrating heparin binding of FGF2, FGF19, FGF21, and FGF23 (left panel) and an exploded view of the binding responses for FGF19-, FGF21-, and FGF23-heparin interactions (right panel). Heparin was immobilized on a biosensor chip, and 400 nM of FGF2, FGF19, FGF21, or FGF23 were passed over the chip. Note that FGF19, FGF21, and FGF23 exhibit measurable, residual heparin binding and that differences in heparin binding exist between these three endocrine FGFs. FIGS. 3B-3D show overlays of SPR sensorgrams illustrating binding of FGF19 to heparin (FIG. 3B) and lack of interaction between the FGF19.sup.K149A mutant and heparin (FIG. 3C) and between the FGF19.sup.K149A, R157A mutant and heparin (FIG. 3D). Heparin was immobilized on a biosensor chip, and increasing concentrations of FGF19 were passed over the chip. Thereafter, FGF19.sup.K149A or FGF19.sup.K149A, R157A was injected over the heparin chip at the highest concentration tested for the wild-type ligand. FIGS. 3E-3G show overlays of SPR sensorgrams illustrating binding of FGF23 to heparin (FIG. 3E), poor interaction between the FGF23.sup.R48A, N49A mutant and heparin (FIG. 3F), and lack of interaction between the FGF23.sup.R140A, R143A mutant and heparin (FIG. 3G). Heparin was immobilized on a biosensor chip, and increasing concentrations of FGF23 were passed over the chip. FGF23.sup.R48A, N49A or FGF23.sup.R140A, R143A was then injected over the heparin chip at the highest concentration tested for the wild-type ligand.

FIGS. 4A-4D show results demonstrating that HS is dispensable for the metabolic activity of FGF19 and FGF23. FIG. 4A shows results of an immunoblot analysis of phosphorylation of FRS2.alpha. (pFRS2.alpha.) and 44/42 MAP kinase (p44/42 MAPK) in H4IIE hepatoma cells following stimulation with the FGF19.sup.K149A mutant, the FGF19.sup.K149A, R157A mutant, or wild-type FGF19. Numbers above the lanes give the amounts of protein added in ng ml.sup.-1. Total 44/42 MAPK protein expression was used as a loading control. FIG. 4B shows results of an immunoblot analysis of phosphorylation of FRS2.alpha. (pFRS2.alpha.) and 44/42 MAP kinase (p44/42 MAPK) in a HEK293-.alpha.Klotho cell line following stimulation with the FGF23.sup.R48A, N49A mutant, the FGF23.sup.R140A, R143A mutant, or wild-type FGF23. Numbers above the lanes give the amounts of protein added in ng ml.sup.-1. Total 44/42 MAPK and .alpha.Klotho protein expression were used as loading controls. FIG. 4C shows graphical results of a quantitative analysis of CYP7A1 and CYP8B1 mRNA expression in liver tissue from mice treated with FGF19.sup.K149A, FGF19.sup.K149A, R157A, FGF19, or vehicle. 1 mg of protein per kg of body weight was given. Data are presented as mean.+-.SEM; ***, P<0.001 by Student's t test. FIG. 4D shows graphical results of analysis of serum phosphate concentrations (serum P.sub.i) in mice before and 8 h after intraperitoneal injection of FGF23.sup.R48A, N49A, FGF23.sup.R140A, R143A, FGF23, or vehicle. Wild-type mice were given a single dose of protein (0.29 mg kg body weight.sup.-1), whereas Fgf23 knockout mice received two doses of 0.71 mg kg body weight.sup.-1 each. Data are presented as mean.+-.SEM; *, P<0.05, and **, P<0.01 by ANOVA.

FIGS. 5A-5G show design and results relating to the conversion of FGF2 into an endocrine ligand. FIG. 5A is a schematic of human FGF2, FGF19, FGF21, FGF23, and engineered FGF2-FGF19, FGF2-FGF21, and FGF2-FGF23 chimeras. Amino acid boundaries of each ligand and of each component of the chimeras are labeled with residue letter and number. The .beta.-trefoil core domain for the known ligand crystal structures is shaded gray. HS-binding residues mutated in the FGF2 portion of chimeras are labeled with residue letter and number. Also labeled are the arginine residues of the proteolytic cleavage site in the C-terminal region of FGF23 that were mutated to glutamine in both FGF23 and the FGF2-FGF23 chimeras. FIGS. 5B and 5C show overlays of SPR sensorgrams illustrating binding of FGF2.sup.WTcore-FGF21.sup.C-tail (FIG. 5B) and FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail (FIG. 5C) to heparin, and fitted saturation binding curves. Heparin was immobilized on a biosensor chip, and increasing concentrations of FGF2.sup.WTcore-FGF21.sup.C-tail or FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail were passed over the chip. Dissociation constants (K.sub.Ds) were derived from the saturation binding curves. FIGS. 5D and 5E show overlays of SPR sensorgrams illustrating binding of FGF2.sup.WTcore-FGF23.sup.C-tail (FIG. 5D) and FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail (FIG. 5E) to heparin. Increasing concentrations of FGF2.sup.WTcore-FGF23.sup.C-tail or FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail were passed over a chip containing immobilized heparin. FIGS. 5F and 5G show results of immunoblot analysis for Egr1 expression in HEK293 cells following stimulation with chimeras or native FGFs as denoted. Numbers above the lanes give the amounts of protein added in nanomolar. GAPDH protein expression was used as a loading control.

FIG. 6 is a schematic illustrating the conversion of FGF1 into an endocrine ligand. Shown are schematic drawings of human FGF1, FGF19, FGF21, FGF23, and exemplary FGF1-FGF19, FGF1-FGF21, and FGF1-FGF23 chimeras according to the present invention. Amino acid boundaries of each ligand and of each component of the chimeras are labeled with residue letter and number. The .beta.-trefoil core domain for the known ligand crystal structures is shaded gray. HS-binding residues mutated in the FGF1 portion of chimeras are labeled with residue letter and number. Also labeled are the arginine residues of the proteolytic cleavage site in the C-terminal region of FGF23 that were mutated to glutamine in both FGF23 and the FGF1-FGF23 chimeras.

FIGS. 7A-7G show results demonstrating that the FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail chimera exhibits FGF23-like activity. FIGS. 7A and 7B show overlays of SPR sensorgrams illustrating inhibition by FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail (FIG. 7A) or FGF23 (FIG. 7B) of .alpha.Klotho-FGFR1c binding to FGF23 immobilized on a biosensor chip. Increasing concentrations of FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail or FGF23 were mixed with a fixed concentration of .alpha.Klotho-FGFR1c complex, and the mixtures were passed over a FGF23 chip. FIG. 7C shows an overlay of SPR sensorgrams illustrating failure of FGF2 to inhibit .alpha.Klotho-FGFR1c binding to FGF23. FGF2 and .alpha.Klotho-FGFR1c complex were mixed at a molar ratio of 15:1, and the mixture was passed over a biosensor chip containing immobilized FGF23. FIGS. 7D and 7E show overlays of SPR sensorgrams illustrating no inhibition by FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail (FIG. 7D) or FGF23 (FIG. 7E) of .beta.Klotho-FGFR1c binding to FGF21. FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail or FGF23 were mixed with .beta.Klotho-FGFR1c complex at a molar ratio of 10:1, and the mixtures were passed over a biosensor chip containing immobilized FGF21. FIG. 7F shows analysis of serum phosphate concentrations (serum P.sub.i) in mice before and 8 h after intraperitoneal injection of FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail, FGF2.sup.WTcore-FGF23.sup.C-tail, FGF23, or vehicle. Wild-type mice and .alpha.Klotho knockout mice were given 0.21 mg and 0.51 mg of protein, respectively, per kg of body weight. Data are presented as mean.+-.SEM; **, P<0.01; ***, P<0.001 by ANOVA. FIG. 7G shows quantitative analysis of CYP27B1 mRNA expression in renal tissue from mice injected with FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail, FGF2.sup.WTcore-FGF23.sup.C-tail, FGF23, or vehicle. 0.21 mg of protein per kg of body weight were injected. Data are presented as mean.+-.SEM; ***, P<0.001 by ANOVA.

FIGS. 8A-8G show results demonstrating that the FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail chimera exhibits FGF21-like activity. FIGS. 8A-8B show overlays of SPR sensorgrams illustrating inhibition by FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail (FIG. 8A) or FGF21 (FIG. 8B) of .beta.Klotho-FGFR1c binding to FGF21 immobilized on a biosensor chip. Increasing concentrations of FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail or FGF21 were mixed with a fixed concentration of .beta.Klotho-FGFR1c complex, and the mixtures were passed over a FGF21 chip. FIG. 8C shows an overlay of SPR sensorgrams illustrating failure of FGF2 to inhibit .beta.Klotho-FGFR1c binding to FGF21. FGF2 and .beta.Klotho-FGFR1c complex were mixed at a molar ratio of 15:1, and the mixture was passed over a biosensor chip containing immobilized FGF21. FIGS. 8D-8E show overlays of SPR sensorgrams illustrating no inhibition by FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail (FIG. 8D) or FGF21 (FIG. 8E) of .alpha.Klotho-FGFR1c binding to FGF23. FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail or FGF21 were mixed with .alpha.Klotho-FGFR1c complex at a molar ratio of 10:1, and the mixtures were passed over a biosensor chip containing immobilized FGF23. FIG. 8F shows results of immunoblot analysis for Egr1 expression in HEK293-.beta.Klotho cells stimulated with FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail or FGF21. Numbers above the lanes give the amounts of protein added in ng ml.sup.-1. GAPDH protein expression was used as a loading control. Note that the FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail chimera is more potent than native FGF21 at inducing Egr1 expression suggesting that the chimera has agonistic property. This is expected since the core domain of FGF2 has inherently greater binding affinity for FGFR than the core domain of FGF21 (see FIGS. 10A and 10C). FIG. 8G shows graphical results of analysis of blood glucose concentrations in mice before and at the indicated time points after intraperitoneal injection of insulin alone, insulin plus FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail chimera, insulin plus FGF21, or vehicle alone. 0.5 units of insulin per kg of body weight and 0.3 mg of FGF21 ligand per kg of body weight were injected. Blood glucose concentrations are expressed as percent of pre-injection values. Data are presented as mean.+-.SEM.

FIGS. 9A-9C show the glucose-lowering effects in ob/ob mice of FGF1 variants according to the present invention. FIG. 9A shows graphical results of analysis of blood glucose concentrations in ob/ob mice before and at the indicated time points after subcutaneous injection of FGF1 or FGF21. FIG. 9B shows graphical results of analysis of blood glucose concentrations in ob/ob mice before and at the indicated time points after subcutaneous injection of FGF1, FGF1.sup..DELTA.NT, or FGF1.sup..DELTA.HBS. FIG. 9C shows graphical results of analysis of blood glucose concentrations in ob/ob mice before and at the indicated time points after subcutaneous injection of FGF1 or FGF1.sup..DELTA.HBScore-FGF21.sup.C-tail chimera. For the experiments shown in FIGS. 9A-9C, ob/ob mice were injected with a bolus of 0.5 mg of FGF protein per kg of body weight. Data are presented as mean.+-.SD.

FIGS. 10A-10F show results demonstrating that endocrine FGFs have low binding affinity for FGFR1c compared to FGF2. FIGS. 10A-10D show overlays of SPR sensorgrams illustrating binding of FGFR1c to FGF2 (FIG. 10A), FGF19 (FIG. 10B), FGF21 (FIG. 10C), and FGF23 (FIG. 10D), and fitted saturation binding curves. Increasing concentrations of FGFR1c ligand-binding domain were passed over a biosensor chip containing immobilized FGF2, FGF19, FGF21, or FGF23. FIG. 10E shows an overlay of SPR sensorgrams illustrating binding of .alpha.Klotho-FGFR1c complex to FGF23. Increasing concentrations of .alpha.Klotho-FGFR1c complex were passed over a biosensor chip containing immobilized FGF23. FIG. 10F shows an overlay of SPR sensorgrams showing lack of interaction between the C-terminal tail peptide of FGF23 and FGFR1c. FGF2.sup.3C-tail was immobilized on a biosensor chip and increasing concentrations of FGFR1c ligand-binding domain were passed over the chip. Dissociation constants (.sub.KDs) given in FIGS. 10A-10E were derived from the saturation binding curves.

FIG. 11 shows an alignment of the C-terminal tail sequences of human FGF19 (SEQ ID NO: 337) (GenBank Accession No. NP_005108, which is hereby incorporated by reference in its entirety), FGF21 (SEQ ID NO:233) (GenBank Accession No. NP_061986, which is hereby incorporated by reference in its entirety), and FGF23 (SEQ ID NO:351) (GenBank accession no. AAG09917, which is hereby incorporated by reference in its entirety). Residue numbers are in parenthesis to the left of the alignment. Gaps (dashes) were introduced to optimize the alignment. Residues that are identical between FGF19 and FGF21 are shaded gray. Note that 40% of these residues map to the most C-terminal sequence.

FIG. 12 shows an alignment of the C-terminal tail sequences of human FGF21 (SEQ ID NO:233) (GenBank Accession No. NP_061986, which is hereby incorporated by reference in its entirety), FGF19 (SEQ ID NO: 337) (GenBank Accession No. NP_005108, which is hereby incorporated by reference in its entirety), and variants of FGF21 harboring a single amino acid substitution or insertion for a residue unique to FGF19. Residue numbers for the sequences of native FGF21 and FGF19 are in parenthesis to the left of the alignment. Gaps (dashes) were introduced to optimize the alignment. In the sequence of native FGF19, residues unique to FGF19 are bold and boxed, and in the sequences of the variants of the FGF21 C-terminal tail, introduced FGF19 residues are highlighted in the same manner.

FIG. 13 shows an alignment of the C-terminal tail sequences of human FGF21 (SEQ ID NO:233) (GenBank Accession No. NP_061986, which is hereby incorporated by reference in its entirety), FGF19 (SEQ ID NO: 337) (GenBank Accession No. NP_005108, which is hereby incorporated by reference in its entirety), and variants of FGF21 in which residues unique to FGF19 progressively replace the corresponding residues of FGF21 or are inserted into the FGF21 sequence. Residue numbers for the sequences of native FGF21 and FGF19 are in parenthesis to the left of the alignment. Gaps (dashes) were introduced to optimize the alignment. In the sequence of native FGF19, residues unique to FGF19 are bold and boxed, and in the sequences of variants of the FGF21 C-terminal tail, introduced FGF19 residues are highlighted in the same manner.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the present invention relates to a chimeric protein. The chimeric protein includes an N-terminus coupled to a C-terminus, where the N-terminus includes a portion of a paracrine fibroblast growth factor ("FGF") and the C-terminus includes a C-terminal portion of an FGF21 molecule. The portion of the paracrine FGF is modified to decrease binding affinity for heparin and/or heparan sulfate compared to the portion without the modification.

As described by Goetz et al. (Goetz et al., "Molecular Insights into the Klotho-Dependent, Endocrine Mode of Action of Fibroblast Growth Factor 19 Subfamily Members," Mol Cell Biol 3417-3428 (2007), which is hereby incorporated by reference in its entirety), the mammalian fibroblast growth factor (FGF) family comprises 18 polypeptides (FGF1 to FGF10 and FGF16 to FGF23), which participate in a myriad of biological processes during embryogenesis, including but not limited to gastrulation, body plan formation, somitogenesis, and morphogenesis of essentially every tissue/organ such as limb, lung, brain, and kidney (Bottcher et al., "Fibroblast Growth Factor Signaling During Early Vertebrate Development," Endocr Rev 26:63-77 (2005), and Thisse et al., "Functions and Regulations of Fibroblast Growth Factor Signaling During Embryonic Development," Dev Biol 287:390-402 (2005), which are hereby incorporated by reference in their entirety).

FGFs execute their biological actions by binding to, dimerizing, and activating FGFR tyrosine kinases, which are encoded by four distinct genes (Fgfr1 to Fgfr4). Prototypical FGFRs consist of an extracellular domain composed of three immunoglobulin-like domains, a single-pass transmembrane domain, and an intracellular domain responsible for the tyrosine kinase activity (Mohammadi et al., "Structural Basis for Fibroblast Growth Factor Receptor Activation," Cytokine Growth Factor Rev 16:107-137 (2005), which is hereby incorporated by reference in its entirety).

The number of principal FGFRs is increased from four to seven due to a major tissue-specific alternative splicing event in the second half of the immunoglobulin-like domain 3 of FGFR1 to FGFR3, which creates epithelial lineage-specific "b" and mesenchymal lineage-specific "c" isoforms (Mohammadi et al., "Structural Basis for Fibroblast Growth Factor Receptor Activation," Cytokine Growth Factor Rev 16:107-137 (2005) and Ornitz et al., "Fibroblast Growth Factors," Genome Biol 2(3):reviews3005.1-reviews3005.12 (2001), which are hereby incorporated by reference in their entirety). Generally, the receptor-binding specificity of FGFs is divided along this major alternative splicing of receptors whereby FGFRb-interacting FGFs are produced by epithelial cells and FGFRc-interacting FGFs are produced by mesenchymal cells (Ornitz et al., "Fibroblast Growth Factors," Genome Biol 2(3):reviews3005.1-reviews3005.12 (2001), which is hereby incorporated by reference in its entirety). These reciprocal expression patterns of FGFs and FGFRs result in the establishment of specific paracrine FGF signaling loops between the epithelium and the mesenchyme, which is essential for proper organogenesis and patterning during embryonic development as well as tissue homeostasis in the adult organism.

Based on sequence homology and phylogenetic and structural considerations, the eighteen mammalian FGFs are grouped into six subfamilies (Itoh et al., "Fibroblast growth factors: from molecular evolution to roles in development, metabolism, and disease," J Biochem 149:121-130 (2011); Mohammadi et al., "Structural basis for fibroblast growth factor receptor activation," Cytokine Growth Factor Rev 16:107-137 (2005), which are hereby incorporated by reference in its entirety). The FGF core homology domain (approximately 120 amino acids long) is flanked by N- and C-terminal sequences that are highly variable in both length and primary sequence, particularly among different FGF subfamilies. The core region of FGF19 shares the highest sequence identity with FGF21 (38%) and FGF23 (36%), and therefore, these ligands are considered to form a subfamily.

Based on mode of action, the eighteen mammalian FGFs are grouped into paracrine-acting ligands (five FGF subfamilies) and endocrine-acting ligands (one FGF subfamily) comprising FGF19, FGF21 and FGF23 (Itoh and Ornitz, "Fibroblast Growth Factors: From Molecular Evolution to Roles in Development, Metabolism and Disease," J. Biochem. 149:121-130 (2011); Mohammadi et al., "Structural Basis for Fibroblast Growth Factor Receptor Activation," Cytokine Growth Factor Rev. 16:107-137 (2005), which are hereby incorporated by reference in their entirety).

Paracrine FGFs direct multiple processes during embryogenesis, including gastrulation, somitogenesis, organogenesis, and tissue patterning (Itoh and Ornitz, "Fibroblast Growth Factors: From Molecular Evolution to Roles in Development, Metabolism and Disease," J. Biochem. 149:121-130 (2011); Bottcher and Niehrs, "Fibroblast Growth Factor Signaling During Early Vertebrate Development," Endocr. Rev. 26:63-77 (2005); Thisse et al., "Functions and Regulations of Fibroblast Growth Factor Signaling During Embryonic Development," Dev. Biol. 287:390-402 (2005), which are hereby incorporated by reference in their entirety), and also regulate tissue homeostasis in the adult (Hart et al., "Attenuation of FGF Signalling in Mouse Beta-cells Leads to Diabetes," Nature 408:864-868 (2000); Jonker et al., "A PPAR.gamma.-FGF1 Axis is Required for Adaptive Adipose Remodelling and Metabolic Homeostasis," Nature 485:391-394 (2012), which is hereby incorporated by reference in its entirety).

Endocrine FGFs control major metabolic processes such as bile acid homeostasis (Inagaki et al., "Fibroblast Growth Factor 15 Functions as an Enterohepatic Signal to Regulate Bile Acid Homeostasis," Cell Metab. 2:217-225 (2005), which is hereby incorporated by reference in its entirety), and hepatic glucose and protein metabolism (Kir et al., "FGF19 as a Postprandial, Insulin-Independent Activator of Hepatic Protein and Glycogen Synthesis," Science 331:1621-1624 (2011); Potthoff et al., "FGF15/19 Regulates Hepatic Glucose Metabolism by Inhibiting the CREB-PGC-1.alpha. Pathway," Cell Metab. 13:729-738 (2011), which are hereby incorporated by reference in their entirety) (FGF19), glucose and lipid metabolism (Badman et al., "Hepatic Fibroblast Growth Factor 21 Is Regulated by PPAR.alpha. and Is a Key Mediator of Hepatic Lipid Metabolism in Ketotic States," Cell Metab. 5:426-437 (2007); Inagaki et al., "Endocrine Regulation of the Fasting Response by PPARalpha-mediated Induction of Fibroblast Growth Factor 21," Cell Metab. 5:415-425 (2007); Kharitonenkov et al., "FGF-21 as a Novel Metabolic Regulator," J. Clin. Invest. 115:1627-1635 (2005); Potthoff et al., "FGF21 Induces PGC-1alpha and Regulates Carbohydrate and Fatty Acid Metabolism During the Adaptive Starvation Response," Proc. Nat'l. Acad. Sci. U.S.A. 106:10853-10858 (2009), which are hereby incorporated by reference in their entirety) (FGF21), and phosphate and vitamin D homeostasis (White et al., "Autosomal Dominant Hypophosphataemic Rickets is Associated with Mutations in FGF23," Nat. Genet. 26:345-348 (2000); Shimada et al., "Targeted Ablation of Fgf23 Demonstrates an Essential Physiological Role of FGF23 in Phosphate and Vitamin D Metabolism," J. Clin. Invest. 113:561-568 (2004), which are hereby incorporated by reference in their entirety) (FGF23). Thus, these ligands have attracted much attention as potential drugs for the treatment of various inherited or acquired metabolic disorders (Beenken and Mohammadi, "The FGF Family: Biology, Pathophysiology and Therapy," Nat. Rev. Drug Discov. 8:235-253 (2009); Beenken and Mohammadi, "The Structural Biology of the FGF19 Subfamily," in Endocrine FGFs and Klothos (Kuro-o, M. ed.), Landes Bioscience. pp 1-24 (2012), which are hereby incorporated by reference in their entirety).

FGFs share a core homology region of about one hundred and twenty amino acids that fold into a .beta.-trefoil (Ago et al., J. Biochem. 110:360-363 (1991); Eriksson et al., Proc. Nat'l. Acad. Sci. U.S.A. 88:3441-3445 (1991); Zhang et al., Proc. Nat'l. Acad. Sci. U.S.A. 88:3446-3450 (1991); Zhu et al., Science 251:90-93 (1991), which are hereby incorporated by reference in their entirety) consisting of twelve .beta. strands in paracrine FGFs ((.beta.1-.beta.12) and eleven .beta. strands in endocrine FGFs ((.beta.1-.beta.10 and .beta.12) (Mohammadi et al., "Structural Basis for Fibroblast Growth Factor Receptor Activation," Cytokine Growth Factor Rev. 16:107-137 (2005); Goetz et al., Mol. Cell Biol. 27:3417-3428 (2007), which are hereby incorporated by reference in their entirety). The conserved core region is flanked by divergent N- and C-termini, which play a critical role in conferring distinct biological activity on FGFs (Mohammadi et al., "Structural Basis for Fibroblast Growth Factor Receptor Activation," Cytokine Growth Factor Rev. 16:107-137 (2005); Olsen et al., Genes Dev. 20:185-198 (2006), which are hereby incorporated by reference in their entirety).

All FGFs interact with pericellular heparan sulfate (HS) glycosaminoglycans albeit with different affinities (Asada et al., Biochim. Biophys. Acta. 1790:40-48 (2009), which is hereby incorporated by reference in its entirety). The HS-binding site of FGFs is comprised of the .beta.1-.beta.2 loop and the region between .beta.10 and .beta.12 strands (Mohammadi et al., "Structural Basis for Fibroblast Growth Factor Receptor Activation," Cytokine Growth Factor Rev. 16:107-137 (2005), which is hereby incorporated by reference in its entirety). HS interacts with both side chain and main chain atoms of the HS-binding site in paracrine FGFs (Schlessinger et al., Mol. Cell 6:743-750 (2000), which is hereby incorporated by reference in its entirety). The HS-binding site of endocrine FGFs deviates from the common conformation adopted by paracrine FGFs such that interaction of HS with backbone atoms of the HS-binding site is precluded (Goetz et al., Mol. Cell Biol. 27:3417-3428 (2007), which is hereby incorporated by reference in its entirety). As a result, compared to paracrine FGFs, endocrine FGFs exhibit poor affinity for HS (Beenken and Mohammadi, "The FGF Family: Biology, Pathophysiology and Therapy," Nat. Rev. Drug Discov. 8:235-253 (2009); Asada et al., Biochim. Biophys. Acta. 1790:40-48 (2009), which are hereby incorporated by reference in their entirety). The poor HS affinity enables these ligands to diffuse freely away from the site of their secretion and enter the blood circulation to reach their distant target organs (Goetz et al., Mol. Cell Biol. 27:3417-3428 (2007); Asada et al., Biochim. Biophys. Acta. 1790:40-48 (2009), which are hereby incorporated by reference in their entirety).

By contrast, owing to their high HS affinity (Asada et al., Biochim. Biophys. Acta. 1790:40-48 (2009), which is hereby incorporated by reference in its entirety), paracrine FGFs are mostly immobilized in the vicinity of the cells secreting these ligands, and hence can only act within the same organ. There is emerging evidence that differences in HS-binding affinity among paracrine FGFs translate into the formation of ligand-specific gradients in the pericellular matrix (Kalinina et al., Mol. Cell Biol. 29:4663-4678 (2009); Makarenkova et al., Sci. Signal 2:ra55 (2009), which are hereby incorporated by reference in their entirety), which contribute to the distinct functions of these ligands (Beenken and Mohammadi, "The FGF Family: Biology, Pathophysiology and Therapy," Nat. Rev. Drug Discov. 8:235-253 (2009); Itoh and Ornitz, "Fibroblast Growth Factors: From Molecular Evolution to Roles in Development, Metabolism and Disease," J. Biochem. 149:121-130 (2011), which are hereby incorporated by reference in their entirety).

Besides controlling ligand diffusion in the extracellular space, HS promotes the formation of the 2:2 paracrine FGF-FGFR signal transduction unit (Schlessinger et al., Mol. Cell 6:743-750 (2000); Mohammadi et al., Curr. Opin. Struct. Biol. 15:506-516 (2005), which are hereby incorporated by reference in their entirety). HS engages both ligand and receptor to enhance the binding affinity of FGF for receptor and promote dimerization of ligand-bound receptors. Owing to their poor HS-binding affinity, endocrine FGFs rely on Klotho co-receptors to bind their cognate FGFR (Kurosu et al., J. Biol. Chem. 282:26687-26695 (2007); Kurosu et al., J. Biol. Chem. 281:6120-6123 (2006); Ogawa et al., Proc. Nat'l. Acad. Sci. U.S.A. 104:7432-7437 (2007); Urakawa et al., Nature 444:770-774 (2006), which are hereby incorporated by reference in their entirety). Klotho co-receptors are single-pass transmembrane proteins with an extracellular domain composed of two type I .beta.-glycosidase domains (Ito et al., Mech. Dev. 98:115-119 (2000); Kuro-o et al., Nature 390:45-51 (1997), which are hereby incorporated by reference in their entirety). Klotho co-receptors constitutively associate with FGFRs to enhance the binding affinity of endocrine FGFs for their cognate FGFRs in target tissues (Kurosu et al., J. Biol. Chem. 282:26687-26695 (2007); Kurosu et al., J. Biol. Chem. 281:6120-6123 (2006); Ogawa et al., Proc. Nat'l. Acad. Sci. U.S.A. 104:7432-7437 (2007); Urakawa et al., Nature 444:770-774 (2006), which are hereby incorporated by reference in their entirety). .alpha.Klotho is the co-receptor for FGF23 (Kurosu et al., J. Biol. Chem. 281:6120-6123 (2006); Urakawa et al., Nature 444:770-774 (2006), which are hereby incorporated by reference in their entirety), and .beta.Klotho is the co-receptor for both FGF19 and FGF21 (Kurosu et al., J. Biol. Chem. 282:26687-26695 (2007); Ogawa et al., Proc. Nat'l. Acad. Sci. U.S.A. 104:7432-7437 (2007), which are hereby incorporated by reference in their entirety). The C-terminal region of endocrine FGFs mediates binding of these ligands to the FGFR-.alpha./.beta.Klotho co-receptor complex (Goetz et al., Mol. Cell Biol. 27:3417-3428 (2007); Goetz et al., Proc. Nat'l. Acad. Sci. U.S.A. 107:407-412 (2010); Micanovic et al., J. Cell Physiol. 219:227-234 (2009); Wu et al., J. Biol. Chem. 283:33304-33309 (2008); Yie et al., FEBS Lett, 583:19-24 (2009); Goetz et al., Mol. Cell Biol. 32:1944-1954 (2012), which are hereby incorporated by reference in their entirety).

.beta.Klotho promotes binding of FGF21 to its cognate FGFR by engaging ligand and receptor simultaneously through two distinct binding sites (Goetz et al., "Klotho Coreceptors Inhibit Signaling by Paracrine Fibroblast Growth Factor 8 Subfamily Ligands," Mol Cell Biol 32:1944-1954 (2012), which is hereby incorporated by reference in its entirety). .beta.Klotho plays the same role in promoting binding of FGF19 to its cognate FGFR (Goetz et al., "Klotho Coreceptors Inhibit Signaling by Paracrine Fibroblast Growth Factor 8 Subfamily Ligands," Mol Cell Biol 32:1944-1954 (2012), which is hereby incorporated by reference in its entirety). The binding site for .beta.Klotho was mapped on FGF21 and FGF19 to the C-terminal region of each ligand that follows the .beta.-trefoil core domain (Goetz et al., "Klotho Coreceptors Inhibit Signaling by Paracrine Fibroblast Growth Factor 8 Subfamily Ligands," Mol Cell Biol 32:1944-1954 (2012), which is hereby incorporated by reference in its entirety). In the course of these studies, it was found that the C-terminal tail peptides of FGF21 and FGF19 share a common binding site on .beta.Klotho, and that the C-terminal tail of FGF19 binds tighter than the C-terminal tail of FGF21 to this site (Goetz et al., "Klotho Coreceptors Inhibit Signaling by Paracrine Fibroblast Growth Factor 8 Subfamily Ligands," Mol Cell Biol 32:1944-1954 (2012), which is hereby incorporated by reference in its entirety).

Endocrine FGFs still possess residual HS-binding affinity, and moreover, there are differences in this residual binding affinity among the endocrine FGFs (Goetz et al., Mol. Cell Biol. 27:3417-3428 (2007), which is hereby incorporated by reference in its entirety). These observations raise the possibility that HS may play a role in endocrine FGF signaling. Indeed, there are several reports showing that HS can promote endocrine FGF signaling in the presence as well as in the absence of Klotho co-receptor. It has been shown that HS augments the mitogenic signal elicited by endocrine FGFs in BaF3 cells over-expressing FGFR and Klotho co-receptor by at least two-fold (Suzuki et al., Mol. Endocrinol. 22:1006-1014 (2008), which is hereby incorporated by reference in its entirety). In addition, even in the absence of Klotho co-receptor, HS enables endocrine FGFs to induce proliferation of BaF3 cells over-expressing FGFR (Yu et al., Endocrinology 146:4647-4656 (2005); Zhang et al., J. Biol. Chem. 281:15694-15700 (2006), which are hereby incorporated by reference in their entirety). Compared to paracrine FGFs, however, significantly higher concentrations of both ligand and HS are needed, and the proliferative response of cells to endocrine FGFs still lags behind that of paracrine FGFs by about one order of magnitude (Zhang et al., J. Biol. Chem. 281:15694-15700 (2006), which is hereby incorporated by reference in its entirety).

As used herein, the terms "chimeric polypeptide" and "chimeric protein" encompass a polypeptide having a sequence that includes at least a portion of a full-length sequence of first polypeptide sequence and at least a portion of a full-length sequence of a second polypeptide sequence, where the first and second polypeptides are different polypeptides. A chimeric polypeptide also encompasses polypeptides that include two or more non-contiguous portions derived from the same polypeptide. A chimeric polypeptide or protein also encompasses polypeptides having at least one substitution, wherein the chimeric polypeptide includes a first polypeptide sequence in which a portion of the first polypeptide sequence has been substituted by a portion of a second polypeptide sequence.

As used herein, the term "N-terminal portion" of a given polypeptide sequence is a contiguous stretch of amino acids of the given polypeptide sequence that begins at or near the N-terminal residue of the given polypeptide sequence. An N-terminal portion of the given polypeptide can be defined by a contiguous stretch of amino acids (e.g., a number of amino acid residues). Similarly, the term "C-terminal portion" of a given polypeptide sequence is a contiguous length of the given polypeptide sequence that ends at or near the C-terminal residue of the given polypeptide sequence. A C-terminal portion of the given polypeptide can be defined by a contiguous stretch of amino acids (e.g., a number of amino acid residues).

The term "portion," when used herein with respect to a given polypeptide sequence, refers to a contiguous stretch of amino acids of the given polypeptide's sequence that is shorter than the given polypeptide's full-length sequence. A portion of a given polypeptide may be defined by its first position and its final position, in which the first and final positions each correspond to a position in the sequence of the given full-length polypeptide. The sequence position corresponding to the first position is situated N-terminal to the sequence position corresponding to the final position. The sequence of the portion is the contiguous amino acid sequence or stretch of amino acids in the given polypeptide that begins at the sequence position corresponding to the first position and ending at the sequence position corresponding to the final position. A portion may also be defined by reference to a position in the given polypeptide sequence and a length of residues relative to the referenced position, whereby the sequence of the portion is a contiguous amino acid sequence in the given full-length polypeptide that has the defined length and that is located in the given polypeptide in reference to the defined position.

As noted above, a chimeric protein according to the present invention may include an N-terminus coupled to a C-terminus. N-terminus and C-terminus are used herein to refer to the N-terminal region or portion and the C-terminal region or portion, respectively, of the chimeric protein of the present invention. In some embodiments of the present invention, the C-terminal portion and the N-terminal portion of the chimeric protein of the present invention are contiguously joined. In alternative embodiments, the C-terminal portion and the N-terminal portion of the chimeric protein of the present invention are coupled by an intervening spacer. In one embodiment, the spacer may be a polypeptide sequence of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acid residues. In some embodiments, the C-terminal portion and/or the N-terminal portion of the chimeric protein of the present invention may include additional portion(s) coupled to the C-terminal residue and/or the N-terminal residue of the chimeric protein of the present invention, respectively. In some embodiments, the additional portion(s) may be a polypeptide sequence of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more amino acid residues. In some embodiments, the N-terminal portion and/or the C-terminal portion having such additional portion(s) will maintain the activity of the corresponding naturally occurring N-terminal portion and/or C-terminal portion, respectively. In some embodiments, the N-terminal portion and/or the C-terminal portion having such additional portion(s) will have enhanced and/or prolonged activity compared to the corresponding naturally occurring N-terminal portion and/or C-terminal portion, respectively. In other embodiments, the C-terminal portion and/or the N-terminal portion of the chimeric protein of the present invention do not include any additional portion(s) coupled to the C-terminal residue and/or the N-terminal residue of the chimeric protein of the present invention, respectively.

The portion of the paracrine FGF may be derived from any suitable paracrine FGF. Suitable paracrine FGFs in accordance with the present invention include FGF1, FGF2, and ligands of the FGF4 and FGF9 subfamilies. Certain embodiments of the present invention may include a full-length amino acid sequence of a paracrine FGF, rather than a portion of a paracrine FGF.

In one embodiment, the portion of the paracrine FGF is derived from a mammalian FGF. In one embodiment, the portion of the paracrine FGF is derived from a vertebrate FGF. In one embodiment, the portion of the paracrine FGF is derived from a human FGF. In one embodiment, the paracrine FGF is derived from a non-human mammalian FGF. In one embodiment, the portion of the paracrine FGF is derived from a non-human vertebrate FGF. In one embodiment, the paracrine FGF is derived from an ortholog of human FGF, or a polypeptide or protein obtained from one species that is the functional counterpart of a polypeptide or protein from a different species.

In one embodiment according to the present invention, the portion of the paracrine FGF of the chimeric protein includes an N-terminal portion of the paracrine FGF.

In one embodiment, the paracrine FGF is FGF1. In one embodiment, the portion of the FGF1 is from human FGF1 having the following amino acid sequence (GenBank Accession No. AAH32697, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 1):

TABLE-US-00001 1 MAEGEITTFT ALTEKFNLPP GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESVGEVY IKSTETGQYL AMDTDGLLYG SQTPNEECLF LERLEENHYN TYISKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD

In one embodiment, the portion of the paracrine FGF includes an amino acid sequence beginning at any one of residues 1 to 25 and ending at any one of residues 150 to 155 of SEQ ID NO: 1 (human FGF1). In one embodiment, the portion of the paracrine FGF includes amino acid residues 1-150, 1-151, 1-152, 1-153, 1-154, 1-155, 2-150, 2-151, 2-152, 2-153, 2-154, 2-155, 3-150, 3-151, 3-152, 3-153, 3-154, 3-155, 4-150, 4-151, 4-152, 4-153, 4-154, 4-155, 5-150, 5-151, 5-152, 5-153, 5-154, 5-155, 6-150, 6-151, 6-152, 6-153, 6-154, 6-155, 7-150, 7-151, 7-152, 7-153, 7-154, 7-155, 8-150, 8-151, 8-152, 8-153, 8-154, 8-155, 9-150, 9-151, 9-152, 9-153, 9-154, 9-155, 10-150, 10-151, 10-152, 10-153, 10-154, 10-155, 11-150, 11-151, 11-152, 11-153, 11-154, 11-155, 12-150, 12-151, 12-152, 12-153, 12-154, 12-155, 13-150, 13-151, 13-152, 13-153, 13-154, 13-155, 14-150, 14-151, 14-152, 14-153, 14-154, 14-155, 15-150, 15-151, 15-152, 15-153, 15-154, 15-155, 16-150, 16-151, 16-152, 16-153, 16-154, 16-155, 17-150, 17-151, 17-152, 17-153, 17-154, 17-155, 18-150, 18-151, 18-152, 18-153, 18-154, 18-155, 19-150, 19-151, 19-152, 19-153, 19-154, 19-155, 20-150, 20-151, 20-152, 20-153, 20-154, 20-155, 21-150, 21-151, 21-152, 21-153, 21-154, 21-155, 22-150, 22-151, 22-152, 22-153, 22-154, 22-155, 23-150, 23-151, 23-152, 23-153, 23-154, 23-155, 24-150, 24-151, 24-152, 24-153, 24-154, 24-155, 25-150, 25-151, 25-152, 25-153, 25-154, or 25-155 of FGF1 (SEQ ID NO: 1). In one embodiment, the portion of the paracrine FGF includes amino acid residues 1-150 or 25-150 of SEQ ID NO: 1.

In one embodiment, the portion of the paracrine FGF includes an amino acid sequence that has at least 80%, at least 85%, at least 90%, at least 95%, at least 97% or at least 99% amino acid sequence identity to an amino acid sequence beginning at any one of residues 1 to 25 and ending at any one of residues 150 to 155 of SEQ ID NO: 1 (human FGF1). In one embodiment, the portion of the paracrine FGF includes an amino acid sequence that has at least 80%, at least 85%, at least 90%, at least 95%, at least 97% or at least 99% amino acid sequence homology to an amino acid sequence beginning at any one of residues 1 to 25 and ending at any one of residues 150 to 155 of SEQ ID NO: 1 (human FGF1).

Percent (%) amino acid sequence identity with respect to a given polypeptide sequence identified herein is defined as the percentage of amino acid residues in a candidate sequence that are identical to the amino acid residues in the reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Percent (%) amino acid sequence homology with respect to a given polypeptide sequence identified herein is the percentage of amino acid residues in a candidate sequence that are identical to or strongly similar to the amino acid residues in the reference sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence homology. Strongly similar amino acid residues may include, for example, conservative amino acid substitutions known in the art. Alignment for purposes of determining percent amino acid sequence identity and/or homology can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software such as BLAST, BLAST-2, ALIGN, ALIGN-2 or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full-length of the sequences being compared.

In one embodiment of the present invention, the portion of the paracrine FGF of the chimeric protein is derived from an ortholog of human FGF1. In one embodiment, the portion of FGF1 is derived from Papio Anubis, Pongo abelii, Callithrix jacchus, Equus caballus, Pan troglodytes, Loxodonta Africana, Canis lupus familiaris, Ailuropoda melanoleuca, Saimiri boliviensis boliviensis, Sus scrofa, Otolemur garnettii, Rhinolophus ferrumequinum, Sorex araneus, Oryctolagus cuniculus, Cricetulus griseus, Sarcophilus harrisii, Mus musculus, Cavia porcellus, Monodelphis domestica, Desmodus rotundus, Bos taurus, Ornithorhynchus anatinus, Taeniopygia guttata, Dasypus novemcinctus, Xenopus Silurana tropicalis, Heterocephalus glaber, Pteropus alecto, Tupaia chinensis, Columba livia, Ovis aries, Gallus gallus, Vicugna pacos, Anolis carolinensis, Otolemur garnettii, Felis catus, Pelodiscus sinensis, Latimeria chalumnae, Tursiops truncates, Mustela putorius furo, Nomascus leucogenys, Gorilla gorilla, Erinaceus europaeus, Procavia capensis, Dipodomys ordii, Petromyzon marinus, Echinops telfairi, Macaca mulatta, Pteropus vampyrus, Myotis lucifugus, Microcebus murinus, Ochotona princeps, Rattus norvegicus, Choloepus hoffmanni, Ictidomys tridecemlineatus, Tarsius syrichta, Tupaia belangeri, Meleagris gallopavo, Macropus eugenii, or Danio rerio. The portions of an ortholog of human paracrine FGF1 include portions corresponding to the above-identified amino acid sequences of human FGF1. Corresponding portions may be determined by, for example, sequence analysis and structural analysis.

In one embodiment, the portion of the FGF1 of the chimeric protein of the present invention is derived from an ortholog of human FGF1 having the amino acid sequence shown in Table 1.

TABLE-US-00002 TABLE 1 Amino acid sequence of human FGF1 (SEQ ID NO: 1)(GenBank accession no. AAH32697, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTEKFNLPP GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESVGEVY IKSTETGQYL AMDTDGLLYG SQTPNEECLF LERLEENHYN TYISKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Papio anubis (olive baboon) FGF1(SEQ ID NO: 2) (GenBank accession no. NP_001162557, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTEKFNLPP ANYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESVGEVY IKSTETGQYL AMDTDGLLYG SQTPNEECLF LERLEENHYN TYISKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Pongo abelii (Sumatran orangutan) FGF1 (SEQ ID NO: 3) (GenBank accession no. NP_001127073, which is hereby incorporated by reference in its entirety) 60 M 61 AEGEITTFTA LTEKFNLPPG NYKKPKLLYC SNGGHFLRIL PDGTVDGTRD RSDQHIQLQL 121 SAESVGEVYI KSTETGQYLA MDTDGLLYGS QTPNEECLFL ERLEENHYNT YISKKHAEKN 181 WFVGLKKNGS CKRGPRTHYG QKAILFLPLP VSSD Amino acid sequence of Callithrix jacchus (white-tufted-ear marmoset) FGF1(SEQ ID NO: 4) (GenBank accession no. XP_002744341, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTEKFDLPP GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESVGEVY IKSTETGQYL AMDTDGLLYG SQTPNEECLF LERLEENHYN TYISKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Equus caballus (horse) FGF1(SEQ ID NO: 5) (GenBank accession no. NP_001157358, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTEKFNLPP GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESVGEVY IKSTETGQYL AMDTDGLLYG SQTPNEECLF LERLEENHYN TYTSKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Pan troglodytes (chimpanzee) FGF1(SEQ ID NO: 6) (GenBank accession no. JAA29511, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTEKFNLPS GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESVGEVY IKSTETGQYL AMDTDGLLYG SQTPNEECLF LERLEENHYN TYISKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Loxodonta africana (elephant) FGF1(SEQ ID NO: 7) (GenBank accession no. XP_003404621, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTEKFNLPP GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESVGEVY IKGTETGQYL AMDTDGLLYG SQTPNEECLF LERLEENHYN TYTSKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Canis lupus familiaris (dog) FGF1(SEQ ID NO: 8) (GenBank accession no. XP_849274, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTEKFNLPP GNYMKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESVGEVY IKSTETGQYL AMDTDGLLYG SQTPNEECLF LERLEENHYN TYTSKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Ailuropoda melanoleuca (giant panda) FGF1(SEQ ID NO: 9) (GenBank accession no. XP_002912581, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTEKFNLPA GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESVGEVY IKSTETGQYL AMDTDGLLYG SQTPNEECLF LERLEENHYN TYTSKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Saimiri boliviensis boliviensis (Bolivian squirrel monkey) FGF1(SEQ ID NO: 10) (GenBank accession no. XP_003920596, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTEKFDLPP GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDLHIQLQ 61 LSAESVGEVY IKSTETGQYL AMDTDGLLYG SQTPNEECLF LERLEENHYN TYISKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Sus scrofa (pig) FGF1(SEQ ID NO: 11) (GenBank accession no. XP_003124058, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTEKFNLPP GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESVGEVY IKSTETGQYL AMDTSGLLYG SQTPSEECLF LERLEENHYN TYTSKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Otolemur garnettii (small-eared galago) FGF1(SEQ ID NO: 12) (GenBank accession no. XP_003782135, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTEKFNLPL GNYKKPKLLY CSNGGHFLRI LPDGTVDGTQ DRSDQHIQLQ 61 LSAESVGEVY IKSTQTGQYL AMDSDGLLYG SQTPNEECLF LERLEENHYN TYVSKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Rhinolophus ferrumequinum (greater horseshoe bat) FGF1(SEQ ID NO: 13) (GenBank accession no. ACC62496, which is hereby incorporated by reference in its entirety): 1 MAEGEVTTFT ALTEKFNLPT GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DKSDQHIQLQ 61 LSAESVGEVY IKSTESGQYL AMDSDGLLYG SQTPNEECLF LERLEENHYN TYTSKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Sorex araneus (European shrew) FGF1(SEQ ID NO: 14) (GenBank accession no. ACE75805, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFG ALMEKFNLPP GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESVGEVY IKSTETGHYL AMDTDGLLYG SQTPNEECLF LERLEENHYN TYTSKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Oryctolagus cuniculus (rabbit) FGF1(SEQ ID NO: 15) (GenBank accession no. NP_001164959, which is hereby incorporated by reference in its entirety): 1 MAEGEVTTFT ALTEKFNLPA GNYKLPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESVGEVY IKSTETGQYL AMDTDGLLYG SQTPSEECLF LERLEENHYN TYTSKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Cricetulus griseus (Chinese hamster) FGF1(SEQ ID NO: 16) (GenBank accession no. XP_003502469, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFS ALTERFNLPP GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESAGEVY IKGTETGQYR NMDTDGLLYG SQTPNEECLF LERLEENHYN TYTSKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Sarcophilus harrisii (Tasmanian devil) FGF1(SEQ ID NO: 17) (GenBank accession no. XP_003756738, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTERFNLPL GNYKKPKLLY CSNGGHFLRI LPDGKVDGTR DRNDQHIQLQ 61 LSAESVGEVY IKSTESGQYL AMDTDGLLYG SQTPTEECLF LERLEENHYN TYISKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSE Amino acid sequence of Mus musculus (house mouse) FGF1(SEQ ID NO: 18) (GenBank accession no. NP_034327, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFA ALTERFNLPL GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESAGEVY IKGTETGQYL AMDTEGLLYG SQTPNEECLF LERLEENHYN TYTSKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Cavia porcellus (domestic guinea pig) FGF1(SEQ ID NO: 19) (GenBank accession no. XP_003477242, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFA ALTEKFNLPP GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAEGVGEVY IQSTETGQYL AMDTDGLLYG SQTPSEECLF LERLEENHYN TYTSKKHVEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSD Amino acid sequence of Monodelphis domestica (gray short-tailed opossum) FGF1(SEQ ID NO: 20) (GenBank accession no. XP_001368921, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTERFNLPL GNYKKPKLLY CSNGGHFLRI LPDGKVDGTR DRNDQHIQLQ 61 LSTESVGEVY IKSTESGQYL AMDTDGLLYG SQTPSEECLF LERLEENHYN TYTSKKHAEK 121 NWFVGLKKNG SCKKGPRTHY GQKAILFLPL PVSSE Amino acid sequence of Desmodus rotundus (common vampire bat) FGF1(SEQ ID NO: 21) (GenBank accession no. JAA45191, which is hereby incorporated by reference in its entirety): 1 MAEGEVTTFT ALTEKFNLPL ESYKKPKLLY CSNGGHFLRI LPDGTVDGTR DKSDQHIQLQ 61 LSAESVGEVY IKSTGSGQYL AMDSAGLLYG SQTPNEECLF LERLEENHYN TYTSKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVNSD Amino acid sequence of Bos taurus (cattle) FGF1(SEQ ID NO: 22) (GenBank accession no. NP_776480, which is hereby incorporated by reference in its entirety): 1 MAEGETTTFT ALTEKFNLPL GNYKKPKLLY CSNGGYFLRI LPDGTVDGTK DRSDQHIQLQ 61 LCAESIGEVY IKSTETGQFL AMDTDGLLYG SQTPNEECLF LERLEENHYN TYISKKHAEK 121 HWFVGLKKNG RSKLGPRTHF GQKAILFLPL PVSSD Amino acid sequence of Ornithorhynchus anatinus (platypus) FGF1(SEQ ID NO: 23) (GenBank accession no. XP_001514861, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALMEKFDLPL GNYKKPRLLY CSNGGYFLRI QPDGKVDGTR DRSDQHIQLQ 61 LSAESVGEVY IKSTESGHYL AMDTEGLLYG SQAPSEDCLF LERLEENHYN TYVSKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVASD Amino acid sequence of Taeniopygia guttata (zebra finch) FGF1(SEQ ID NO: 24) (GenBank accession no. XP_002193287, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFS ALTEKFNLPP GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESVGVVH IQSTQSGQYL AMDTNGLLYG SQLPPGECLF LERLEENHYN TYVSKMHADK 121 NWFVGLKKNG TSKLGPRTHY GQKAILFLPL PVAAD Amino acid sequence of Dasypus novemcinctus (nine-banded armadillo) FGF1(SEQ ID NO: 25) (GenBank accession no. AC006224, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFM ALMEKFNLPL ENYKHPRLLY CRNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESVGEVY IKSAETGQYL AMDTDGLLYG SETPSEECLF MEKLEENNYN TYISKKHAEK 121 KWFVGLKKDG SSKRGPQTHY GQKAILFLPL PVSSD Amino acid sequence of Xenopus Silurana tropicalis (western clawed frog) FGF1(SEQ ID NO: 26) (GenBank accession no. ACJ50585, which is hereby incorporated by reference in its entirety): 1 MAEGDITTFN PIAESFSLPI GNYKKPKLLY CNNGGYFLRI LPDGVVDGTR DRDDLYITLK 61 LSAQSQGEVH IKSTETGSYL AMDSSGQLYG TLTPNEESLF LETLEENHYN TYKSKKYAEN 121 NWFVGIKKNG ASKKGSRTHY GQKAILFLPL PASPD Amino acid sequence of Heterocephalus glaber (naked mole-rat) FGF1(SEQ ID NO: 27) (GenBank accession no. EHA99379, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTEKFNLPP GNYKKPKLLY CSNGGHFLRI LPDGKVDGTR DRSDQHIQLQ 61 LSAEGVGEVY IKSTETGQYL AMDTDGLLYG SQTASEECLF LERLEENHYN TYISKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Pteropus alecto (black flying fox) FGF1(SEQ ID NO: 28) (GenBank accession no. ELK02961, which is hereby incorporated by reference in its entirety): 1 MAEGEVTTFT ALTERFNLPP GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DKSDQHIQLQ 61 LSAESVGEVY IKSTESGQYL AMDSDGLLYG SQTPDEDCLF LERLEENHYN TYTSKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Tupaia chinensis (Chinese tree shrew) FGF1(SEQ ID NO: 29) (GenBank accession no. ELW69091, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFA ALTEKFDLPP GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LTAENVGEVY IKSTETGQYL AMDADGLLYG SQTPNEECLF LERLEENHYN TYISKKHAEK 121 NWFVALKKNG SCKLGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Columba livia (rock pigeon) FGF1(SEQ ID NO: 30) (GenBank accession no. EMC79997, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTEKFNLPP GNYKKPKLLY CSNGGHFLRI LPDGKVDGTR DRSDQHIQLQ 61 LSAESVGEVY IKSTQSGQYL AMDPTGLLYG SQLLGEECLF LERIEENHYN TYVSKKHADK 121 NWFVGLKKNG NSKLGPRTHY GQKAILFLPL PVSAD Amino acid sequence of Ovis aries (sheep) FGF1(SEQ ID NO: 31) (GenBank accession no. XP_004008958, which is hereby incorporated by reference in its entirety): 1 MAEGETTTFR ALTEKFNLPL GNYKKPKLLY CSNGGYFLRI LPDGRVDGTK DRSDQHIQLQ 61 LYAESIGEVY IKSTETGQFL AMDTNGLLYG SQTPSEECLF LERLEENHYN TYISKKHAEK 121 NWFIGLKKNG SSKLGPRTHF GQKAILFLPL PVSSD Amino acid sequence of Gallus gallus (chicken) FGF1(SEQ ID NO: 32) (GenBank accession no. NP_990511, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTERFGLPL GNYKKPKLLY CSNGGHFLRI LPDGKVDGTR DRSDQHIQLQ 61 LSAEDVGEVY IKSTASGQYL AMDTNGLLYG SQLPGEECLF LERLEENHYN TYISKKHADK 121 NWFVGLKKNG NSKLGPRTHY GQKAILFLPL PVSAD Amino acid sequence of Vicugna pacos (alpaca) FGF1(SEQ ID NO: 33) (Ensembl accession no. ENSVPAP00000007810; partial sequence corresponding to human FGF1 residues 58 to 155, which is hereby incorporated by reference in its entirety): 1 QLQLSAESVG EVYIKSTETG QYLAMDTDGL LHGSQTPNEE CLFLERLEEN HYNTYTSKKH 61 AEKNWFVGLK KNGSCKRGPR THYGQKAILF LPLPVSSD Amino acid sequence of Anolis carolinensis (anole lizard) FGF1(SEQ ID NO: 34) (Ensembl accession no. ENSACAP00000013203, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTERFALPM ENYKKPKLLY CSNGGHFLRI LPDGKVDGTM DRNDSYIQLL 61 LTAEDVGVVY IKGTETGQYL AMDANGHLYG SQLPTEECLF VETLEENHYN TYTSKMHGDK 121 KWYVGLKKNG KGKLGPRTHR GQKAILFLPL PVSPD Amino acid sequence of Otolemur garnettii (bushbaby) FGF1(SEQ ID NO: 35) (Ensembl accession no. ENSOGAP00000004540, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTEKFNLPL GNYKKPKLLY CSNGGHFLRI LPDGTVDGTQ DRSDQHIQLQ 61 LSAESVGEVY IKSTQTGQYL AMDSDGLLYG SQTPNEECLF LERLEENHYN TYVSKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Felis catus (cat) FGF1(SEQ ID NO: 36) (Ensembl accession no. ENSFCAP00000008457, which is hereby incorporated by

reference in its entirety): 1 MAEGEITTFT ALTEKFNLPP GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESVGEVY IKSTETGQYL AMDTDGLLYG SQTPNEECLF LERLEENHYN TYTSKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Pelodiscus sinensis (Chinese softshell turtle) FGF1(SEQ ID NO: 37) (Ensembl accession no. ENSPSIP00000016356, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTEKFNLPL GNYKNPKLLY CSNGGYFLRI HPDGKVDGTR DRSDQHIQLQ 61 LSAESVGEVY IKSTESGQFL AMDANGLLYG SLSPSEECLF LERMEENHYN TYISKKHADK 121 NWFVGLKKNG SCKLGPRTHY GQKAVLFLPL PVSAD Amino acid sequence of Latimeria chalumnae (coelacanth) FGF1(SEQ ID NO: 38) (Ensembl accession no. ENSLACP00000015106, which is hereby incorporated by reference in its entirety): 1 MAEDKITTLK ALAEKFNLPM GNYKKAKLLY CSNGGYFLRI PPDGKVEGIR ERSDKYIQLQ 61 MNAESLGMVS IKGVEAGQYL AMNTNGLLYG SQSLTEECLF MEKMEENHYN TYRSKTHADK 121 NWYVGIRKNG SIKPGPRTHI GQKAVLFLPL PASSD Amino acid sequence of Tursiops truncatus (dolphin) FGF1(SEQ ID NO: 39) (Ensembl accession no. ENSTTRP00000004470, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTEKFNLPP GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESVGEVY IKSTETGQYL AMDTDGLLYG SQTPNEECLF LERLEENHYN TYASKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Mustela putorius furo (ferret) FGF1(SEQ ID NO: 40) (Ensembl accession no. ENSMPUP00000007888, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALMEKFNLPA GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESVGEVY IKSTETGQYL AMDTDGLLYG SQTPNEECLF LERLEENHYN TYTSKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Nomascus leucogenys (gibbon) FGF1(SEQ ID NO: 41) (Ensembl accession no. ENSNLEP00000011873, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTEKFNLPP GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESVGEVY IKSTETGQYL AMDTDGLLYG SQTPNEECLF LERLEENHYN TYISKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Gorilla gorilla (gorilla) FGF1(SEQ ID NO: 42) (Ensembl accession no. ENSGGOP00000017663, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTEKFNLPP GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESVGEVY IKSTETGQYL AMDTDGLLYG SQTPNEECLF LERLEENHYN TYISKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Erinaceus europaeus (hedgehog) FGF1(SEQ ID NO: 43) (Ensembl accession no. ENSEEUP00000005318, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTEKFNLPL GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESVGEVY IKSTETGQYL AMDTDGLLYG SQTPNEECLF LERLEENHYN TYTSKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Procavia capensis (hyrax) FGF1(SEQ ID NO: 44) (Ensembl accession no. ENSPCAP00000010969, which is hereby incorporated by reference in its entirety)(partial sequence corresponding to human FGF1 residues 1 to 91): 1 MAEGEITTFT ALTEKFNLPL ENYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESVGEVY IKGTETGQYL AMDTDGLLYG S Amino acid sequence of Dipodomys ordii (kangaroo rat) FGF1(SEQ ID NO: 45) (Ensembl accession no. ENSDORP00000006889, which is hereby incorporated by reference in its entirety) (partial sequence corresponding to human FGF1 residues 1 to 16 and 58 to 155): 1 MAEGEITTFT ALTERF---- ---------- ---------- ---------- -------QLQ 61 LSAESVGEVY IKSTETGQYL AMDADGLLYG SQTPDEECLF LERLEENHYN TYIAKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Petromyzon marinus (lamprey) FGF1(SEQ ID NO: 46) (Ensembl accession no. ENSPMAP00000010683, which is hereby incorporated by reference in its entirety)(partial sequence corresponding to human FGF1 residues 1 to 93): 1 MEVGHIGTLP VVPAGPVFPG SFKEPRRLYC RSAGHHLQIL GDGTVSGTQD ENEPHAVLQL 61 QAVRRGVVTI RGLCAERFLA MSTEGHLYGA VR Amino acid sequence of Echinops telfairi (lesser hedgehog tenrec) FGF1(SEQ ID NO: 47) (Ensembl accession no. ENSETEP00000014504, which is hereby incorporated by reference in its entirety)(partial sequence corresponding to human FGF1 residues 58 to 155) 1 QLKLVAESVG VVYIKSIKTG QYLAMNPDGL LYGSETPEEE CLFLETLEEN HYTTFKSKKH 61 VEKNWFVGLR KNGRVKIGPR THQGQKAILF LPLPVSSD Amino acid sequence of Macaca mulatta (rhesus monkey) FGF1(SEQ ID NO: 48) (Ensembl accession no. ENSMMUP00000030943, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTEKFNLPP GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESVGEVY IKSTETGQYL AMDTDGLLYG SQTPNEECLF LERLEENHYN TYTSKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Pteropus vampyrus (megabat) FGF1(SEQ ID NO: 49) (Ensembl accession no. ENSPVAP00000004349, which is hereby incorporated by reference in its entirety): 1 MAEGEVTTFT ALTERFNLPP GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DKSDQHIQLQ 61 LSAESVGEVY IKSTESGQYL AMDSDGLLYG SQTPDEDCLF LERLEENHYN TYTSKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Myotis lucifugus (microbat) FGF1(SEQ ID NO: 50) (Ensembl accession no. ENSMLUP00000006481, which is hereby incorporated by reference in its entirety): 1 MAEGEVTTFT ALTERFNLPL ENYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESVGEVY IKSTESGQYL AMDSDGLLYG SQTPNEECLF LERLEENHYN TYTSKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Microcebus murinus (mouse lemur) FGF1(SEQ ID NO: 51) (Ensembl accession no. ENSMICP00000008602, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTEKFNLPP GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESAGEVY IKSTQTGRYL AMDADGLLYG SQTPNEECLF LERLEENHYN TYVSKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Ochotona princeps (pika) FGF1(SEQ ID NO: 52) (Ensembl accession no. ENSOPRP00000011739, which is hereby incorporated by reference in its entirety): 1 MAEGEVTTFS ALTEKFNLPG GNYKLPKLLY CSNGGHFLRI LPDGTVDGTR DRSDLH---- 61 -------EVF IKSTETGQYL AMDTDGLLYG SQTPSEECLF LERLEENHYN TYTSKKHAEK 121 NWFVGIKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Rattus norvegicus (rat) FGF1(SEQ ID NO: 53) (Ensembl accession no. ENSRNOP00000018577, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFA ALTERFNLPL GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESAGEVY IKGTETGQYL AMDTEGLLYG SQTPNEECLF LERLEENHYN TYTSKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Choloepus hoffmanni (sloth) FGF1(SEQ ID NO: 54) (Ensembl accession no. ENSCHOP00000010964, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALMEKFNLPP GNYMKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDLHIQLQ 61 LSAESVGEVY IKSAETGQYL AMDTGGLLYG SQTPSEECLF LERLEENHYN TYVSKKHAEK 121 NWFVGLKKNG SSKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Ictidomys tridecemlineatus (squirrel) FGF1(SEQ ID NO: 55) (Ensembl accession no. ENSSTOP00000021782, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTEKFNLPP GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESVGEVY IKSTETGQYL AMDTDGLLYG SQTPNEECLF LERLEENHYN TYTSKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Tarsius syrichta (tarsier) FGF1(SEQ ID NO: 56) (Ensembl accession no. ENSTSYP00000006804, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTEKFNLPP GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LSAESVGEVY IKSTETGQYL AMDTDGLLYG SQTPNEECLF LERLEENHYN TYVSKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Tupaia belangeri (tree shrew) FGF1(SEQ ID NO: 57) (Ensembl accession no. ENSTBEP00000010264, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFA ALTEKFDLPP GNYKKPKLLY CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ 61 LTAENVGEVY IKSTETGQYL AMDADGLLYG SQTPNEECLF LERLEENHYN TYISKKHAEK 121 NWFVALKKNG SCKLGPRTHY GQKAILFLPL PVSSD Amino acid sequence of Meleagris gallopavo (turkey) FGF1(SEQ ID NO: 58) (Ensembl accession no. ENSMGAP00000016398; partial sequence corresponding to human FGF1 residues 1 to 56, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTERFGLPL GNYKKPKLLY CSNGGHFLRI LPDGKVDGTR DRSDQH Amino acid sequence of Macropus eugenii (wallaby) FGF1(SEQ ID NO: 59) (Ensembl accession no. ENSMEUP00000015084, which is hereby incorporated by reference in its entirety): 1 MAEGEITTFT ALTERFNLPL GNYKKPKLLY CSNGGHFLRI LPDGKVDGTR DRNDQHIQLQ 61 LSAESVGEVY IKSTESGQYL AMDTNGLLYG SQTPSEECLF LERLEENHYN TYISKKHAEK 121 NWFVGLKKNG SCKRGPRTHY GQKAILFLPL PVSSE Amino acid sequence of Danio rerio (zebrafish) FGF1(SEQ ID NO: 60) (Ensembl accession no. ENSDARP00000008825, which is hereby incorporated by reference in its entirety): 1 MTEADIAVKS SPRDYKKLTR LYCMNGGFHL QILADGTVAG AADENTYSIL RIKATSPGVV 61 VIEGSETGLY LSMNEHGKLY ASSLVTDESY FLEKMEENHY NTYQSQKHGE NWYVGIKKNG 121 KMKRGPRTHI GQKAIFFLPR QVEQEED

As noted above, the portion of the paracrine FGF may be modified to decrease binding affinity for heparin and/or heparan sulfate compared to the portion without the modification. In one embodiment, the modified portion of the paracrine FGF includes one or more substitutions, additions, or deletions.

In one embodiment, the one or more substitutions are located at one or more amino acid residues of SEQ ID NO: 1 selected from N33, K127, K128, N129, K133, R134, R137, Q142, K143, and combinations thereof. In one embodiment, the one or more substitutions are selected from N33T, K127D, K128Q, N129T, K133V, R134L, R137H, Q142M, K143T/L/I, and combinations thereof. In one embodiment, the modification is one or more substitutions which are located at one or more amino acid residues corresponding to residues of SEQ ID NO: 1 selected from N33, K127, K128, N129, K133, R134, R137, Q142, K143, and combinations thereof. In one embodiment, the modification is one or more substitutions which are located at one or more amino acid residues corresponding to residues of SEQ ID NO: 1 selected from N33, K127, K128, N129, K133, R134, R137, Q142, K143, and combinations thereof. Amino acid residues corresponding to those of SEQ ID NO: 1 may be determined by, for example, sequence analysis and structural analysis.

Also encompassed within the present invention are portions of paracrine FGFs other than FGF1 (e.g., FGF2, FGF4, FGF5, FGF6, FGF9, FGF16, and FGF20). The portions derived from paracrine FGFs other than FGF1 include portions corresponding to the above-identified amino acid sequences of FGF1. Corresponding portions may be determined by, for example, sequence analysis and structural analysis.

It will be understood that the portion of the paracrine FGF according to the present invention may be derived from a nucleotide sequence that encodes a paracrine FGF protein. For example, in one embodiment, the nucleotide sequence is the nucleotide sequence that encodes human FGF1 (GenBank Accession No. BC032697, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 61), as follows:

TABLE-US-00003 91 ATGGCTGAAG GGGAAATCAC CACCTTCACA 121 GCCCTGACCG AGAAGTTTAA TCTGCCTCCA GGGAATTACA AGAAGCCCAA ACTCCTCTAC 181 TGTAGCAACG GGGGCCACTT CCTGAGGATC CTTCCGGATG GCACAGTGGA TGGGACAAGG 241 GACAGGAGCG ACCAGCACAT TCAGCTGCAG CTCAGTGCGG AAAGCGTGGG GGAGGTGTAT 301 ATAAAGAGTA CCGAGACTGG CCAGTACTTG GCCATGGACA CCGACGGGCT TTTATACGGC 361 TCACAGACAC CAAATGAGGA ATGTTTGTTC CTGGAAAGGC TGGAGGAGAA CCATTACAAC 421 ACCTATATAT CCAAGAAGCA TGCAGAGAAG AATTGGTTTG TTGGCCTCAA GAAGAATGGG 481 AGCTGCAAAC GCGGTCCTCG GACTCACTAT GGCCAGAAAG CAATCTTGTT TCTCCCCCTG 541 CCAGTCTCTT CTGATTAA

In another embodiment of the present invention, the portion of the paracrine FGF of the chimeric protein may be derived from a nucleotide sequence that encodes an ortholog of human FGF1. Nucleotide sequences that encode FGF1 orthologs are shown in Table 2.

TABLE-US-00004 TABLE 2 Olive Baboon FGF1 gene coding sequence (1-155) (SEQ ID NO: 62) (GenBank accession no. NM_001169086, which is hereby incorporated by reference in its entirety): 1 ATGGCTGAAG GGGAAATCAC CACGTTCACA GCCCTGACCG AGAAGTTTAA TCTGCCTCCA 61 GCGAATTACA AGAAGCCCAA ACTGCTCTAC TGTAGCAACG GGGGACACTT CTTGAGGATC 121 CTTCCGGATG GCACAGTGGA TGGGACAAGG GACAGGAGCG ACCAGCACAT TCAGCTGCAG 181 CTCAGTGCGG AAAGCGTGGG GGAGGTGTAT ATAAAGAGTA CCGAGACTGG CCAGTACTTG 241 GCCATGGACA CCGACGGGCT TTTATACGGC TCACAGACAC CAAATGAGGA ATGTTTGTTC 301 CTGGAAAGGC TGGAGGAGAA CCATTACAAC ACCTACATAT CCAAGAAGCA CGCAGAGAAG 361 AATTGGTTTG TTGGCCTCAA GAAGAATGGA AGCTGCAAAC GTGGTCCTCG GACTCACTAT 421 GGCCAGAAAG CAATCTTGTT TCTTCCCCTG CCAGTCTCTT CTGATTAA Sumatran orangutan FGF1 gene coding sequence (60-214) (SEQ ID NO: 63) (GenBank accession no. NM_001133601, which is hereby incorporated by reference in its entirety): 211 ATGGCTGAAG GGGAAATCAC CACCTTCACA 241 GCCCTGACCG AGAAGTTTAA TCTGCCTCCA GGGAATTACA AGAAGCCCAA ACTCCTCTAC 301 TGTAGCAACG GGGGCCACTT CTTGAGGATC CTTCCGGATG GCACAGTGGA TGGGACAAGG 361 GACAGGAGCG ACCAGCACAT TCAGCTGCAG CTCAGTGCGG AAAGCGTGGG GGAGGTGTAT 421 ATAAAGAGTA CCGAGACTGG CCAGTACTTG GCCATGGACA CCGACGGGCT TTTATACGGC 481 TCACAGACAC CAAATGAGGA ATGTTTGTTC CTGGAAAGGC TGGAGGAGAA CCATTACAAC 541 ACCTATATAT CCAAGAAGCA TGCAGAGAAG AATTGGTTTG TTGGCCTCAA GAAGAATGGA 601 AGCTGCAAAC GCGGTCCTCG GACTCACTAT GGCCAGAAAG CAATCTTGTT TCTCCCCCTG 661 CCAGTCTCTT CCGATTAA White-tufted-ear marmoset FGF1 gene coding sequence (1-155) (SEQ ID NO: 64) (GenBank accession no. XM_002744295, which is hereby incorporated by reference in its entirety): 130 A TGGCTGAAGG GGAAATCACC ACCTTCACAG CCCTGACCGA GAAGTTTGAT 181 CTGCCTCCAG GGAATTACAA GAAGCCCAAA CTCCTCTACT GTAGCAATGG GGGCCACTTC 241 TTGAGGATCC TTCCGGATGG CACAGTGGAT GGGACAAGGG ACAGGAGCGA CCAGCACATT 301 CAGCTGCAGC TCAGTGCGGA AAGCGTGGGG GAGGTGTATA TAAAGAGTAC CGAGACTGGC 361 CAGTACTTGG CCATGGACAC CGACGGGCTT TTATACGGCT CACAGACACC AAATGAGGAA 421 TGTTTGTTCC TGGAGAGGCT GGAGGAGAAC CATTACAACA CCTATATATC CAAGAAACAT 481 GCAGAGAAGA ATTGGTTTGT CGGCCTCAAG AAGAATGGAA GCTGTAAACG TGGTCCTCGG 541 ACTCACTATG GTCAGAAAGC GATCTTGTTT CTCCCCCTGC CAGTTTCTTC TGATTAA Horse FGF1 gene coding sequence (1-155) (SEQ ID NO: 65) (GenBank accession no. NM_001163886, which is hereby incorporated by reference in its entirety): 34 ATGGCTG AAGGAGAAAT CACAACCTTC 61 ACGGCCCTGA CCGAGAAGTT TAATCTGCCT CCAGGGAATT ACAAGAAGCC CAAACTCCTC 121 TACTGTAGCA ATGGGGGCCA CTTCCTGAGG ATCCTTCCAG ATGGCACAGT GGATGGGACA 181 AGGGACAGGA GCGACCAGCA CATTCAGCTG CAGCTCAGTG CGGAAAGCGT GGGGGAGGTG 241 TATATAAAGA GTACCGAGAC TGGCCAGTAC TTGGCCATGG ACACCGACGG GCTGTTGTAC 301 GGCTCACAGA CACCAAACGA GGAATGTTTG TTCCTGGAAA GGCTGGAGGA AAACCATTAC 361 AACACCTACA CATCCAAGAA GCATGCAGAG AAGAACTGGT TCGTTGGTCT CAAGAAGAAT 421 GGGAGCTGCA AACGCGGTCC TCGGACTCAC TATGGGCAGA AAGCAATCTT GTTTCTTCCC 481 CTGCCCGTCT CCTCTGACTA A Chimpanzee FGF1 gene coding sequence (1-155) (SEQ ID NO: 66) (GenBank accession no. GABD01003589, which is hereby incorporated by reference in its entirety): 80 A TGGCTGAAGG GGAAATCACC ACCTTCACAG CCCTGACCGA 121 GAAGTTTAAT CTGCCTTCAG GGAATTACAA GAAGCCCAAA CTCCTCTACT GTAGCAACGG 181 GGGCCACTTC CTGAGGATCC TTCCGGATGG CACAGTGGAT GGGACAAGGG ACAGGAGCGA 241 CCAGCACATT CAGCTGCAGC TCAGTGCGGA AAGCGTGGGG GAGGTGTATA TAAAGAGTAC 301 CGAGACTGGC CAGTACTTGG CCATGGACAC CGACGGGCTT TTATACGGCT CACAGACACC 361 AAATGAGGAA TGTTTGTTCC TGGAACGGCT GGAGGAGAAC CATTACAACA CCTATATATC 421 CAAGAAGCAT GCAGAGAAGA ATTGGTTTGT TGGCCTCAAG AAGAATGGAA GCTGCAAACG 481 CGGTCCTCGG ACTCACTATG GCCAGAAAGC AATCTTGTTT CTCCCCCTGC CAGTCTCTTC 541 CGATTAA Elephant FGF1 gene coding sequence (1-155) (SEQ ID NO: 67) (GenBank accession no. XM_003404573, which is hereby incorporated by reference in its entirety): 1 ATGGCCGAAG GGGAAATCAC AACTTTCACA GCCCTGACAG AGAAGTTCAA CCTGCCTCCA 61 GGGAATTACA AGAAGCCCAA ACTCCTCTAC TGTAGCAATG GAGGTCACTT CTTAAGGATC 121 CTTCCAGATG GCACAGTGGA TGGCACCAGG GACAGGAGTG ACCAGCACAT TCAGCTGCAG 181 CTCAGTGCGG AAAGCGTGGG GGAGGTGTAT ATAAAGGGCA CCGAGACTGG CCAGTACTTG 241 GCCATGGACA CCGACGGGCT TTTATACGGC TCACAGACAC CAAATGAGGA ATGTTTGTTC 301 CTGGAAAGGC TGGAGGAAAA CCATTACAAC ACCTACACAT CCAAGAAGCA CGCAGAGAAG 361 AATTGGTTCG TTGGTCTCAA GAAGAATGGA AGCTGCAAAC GCGGTCCTCG GACTCACTAT 421 GGCCAGAAAG CAATCTTGTT TCTCCCCCTG CCAGTCTCCT CTGATTAA Dog FGF1 genecoding sequence (1-155) (SEQ ID NO: 68) (GenBank accession no. XM_844181, which is hereby incorporated by reference in its entirety): 164 ATGGCTG AAGGGGAAAT 181 CACAACCTTC ACTGCCCTGA CGGAGAAGTT TAATCTGCCT CCGGGGAATT ACATGAAGCC 241 CAAACTCCTC TACTGTAGCA ACGGGGGCCA CTTCCTGAGG ATCCTTCCAG ATGGCACAGT 301 GGATGGGACA AGGGACAGGA GCGACCAGCA CATTCAGCTG CAGCTCAGCG CGGAAAGCGT 361 GGGGGAGGTG TATATAAAGA GCACCGAGAC TGGCCAGTAC TTGGCCATGG ACACCGATGG 421 GCTTCTGTAC GGCTCACAGA CACCGAATGA GGAATGTTTG TTCCTGGAAA GGCTGGAGGA 481 AAACCATTAC AACACCTACA CATCCAAGAA GCATGCAGAA AAAAATTGGT TTGTTGGTCT 541 CAAGAAGAAT GGAAGCTGCA AACGCGGTCC TCGGACTCAC TATGGTCAAA AAGCAATTTT 601 GTTTCTCCCC CTGCCAGTGT CCTCTGATTA A Giant panda FGF1 gene coding sequence (1-155) (SEQ ID NO: 69) (GenBank accession no. XM_002912535, which is hereby incorporated by reference in its entirety): 146 ATGGC TGAAGGGGAG ATCACAACCT TCACCGCCCT 181 GACGGAGAAG TTTAATCTGC CTGCGGGGAA TTACAAGAAG CCCAAACTCC TCTACTGTAG 241 CAACGGGGGC CACTTCCTGA GGATCCTTCC AGATGGCACA GTGGACGGGA CGAGGGACAG 301 GAGCGACCAG CACATTCAAC TGCAGCTCAG CGCGGAAAGC GTAGGGGAGG TGTACATAAA 361 GAGCACCGAG ACCGGCCAGT ACTTGGCCAT GGACACCGAT GGGCTTCTGT ACGGCTCACA 421 GACACCAAAT GAGGAATGTT TGTTCCTGGA AAGGCTGGAG GAAAACCATT ACAACACCTA 481 CACATCCAAG AAGCACGCGG AGAAGAATTG GTTTGTTGGT CTCAAGAAGA ATGGAAGCTG 541 CAAACGTGGT CCTCGGACTC ACTATGGCCA GAAAGCAATT CTGTTTCTCC CCCTGCCAGT 601 CTCCTCTGAT TAA Bolivian squirrel monkey FGF1 gene coding sequence (1-155) (SEQ ID NO: 70) (GenBank accession no. XM_003920547, which is hereby incorporated by reference in its entirety): 130 A TGGCTGAAGG GGAAATCACC ACCTTTACAG CCCTGACCGA GAAGTTTGAT 181 CTGCCTCCAG GGAATTACAA GAAGCCCAAA CTCCTCTACT GTAGCAACGG GGGCCACTTC 241 TTGAGGATCC TTCCGGATGG CACAGTGGAT GGGACCAGGG ACAGGAGCGA TCTTCACATT 301 CAGCTGCAGC TCAGTGCGGA AAGCGTGGGG GAGGTGTATA TAAAGAGTAC CGAGACTGGC 361 CAGTACTTGG CCATGGACAC CGACGGGCTT TTATACGGCT CACAGACACC AAATGAGGAA 421 TGTTTGTTCC TGGAAAGGCT GGAGGAGAAC CATTACAACA CCTATATATC CAAGAAACAC 481 GCAGAGAAGA ATTGGTTTGT TGGCCTCAAG AAGAATGGAA GCTGCAAGCG CGGTCCTCGG 541 ACTCACTATG GCCAGAAAGC AATCTTGTTT CTCCCCCTGC CAGTCTCTTC TGATTAA Pig FGF1 gene coding sequence (1-155) (SEQ ID NO: 71) (GenBank accession no. XM_003124010, which is hereby incorporated by reference in its entirety): 35 ATGGCT GAAGGCGAAA TCACAACCTT 61 CACGGCCCTG ACCGAGAAGT TTAATCTGCC TCCAGGAAAT TACAAGAAGC CCAAGCTCCT 121 CTACTGCAGC AACGGGGGCC ATTTCCTCAG GATCCTTCCA GATGGCACAG TGGATGGGAC 181 CAGGGACAGG AGCGACCAGC ACATTCAGCT GCAGCTCAGT GCGGAAAGCG TGGGGGAGGT 241 GTATATAAAG AGTACGGAGA CTGGCCAGTA CTTGGCCATG GACACCAGCG GGCTTTTGTA 301 CGGCTCACAG ACACCCAGTG AGGAGTGTTT GTTCCTGGAG AGGCTGGAGG AAAACCATTA 361 CAATACCTAC ACATCCAAGA AGCACGCAGA GAAGAACTGG TTCGTTGGCC TCAAGAAGAA 421 TGGAAGCTGC AAACGCGGTC CTCGGACTCA CTATGGCCAG AAAGCCATCC TGTTTCTCCC 481 CCTGCCAGTA TCCTCGGATT AA Small-eared galago FGF1 gene coding sequence (1-155) (SEQ ID NO: 72) (GenBank accession no. XM_003782087, which is hereby incorporated by reference in its entirety): 28 ATG GCTGAAGGGG AAATCACAAC CTTCACAGCC 61 CTCACAGAGA AGTTTAATCT GCCTCTAGGA AATTACAAGA AGCCCAAGCT CCTCTACTGT 121 AGCAACGGGG GTCACTTTCT GAGGATCCTG CCGGATGGCA CCGTGGATGG GACACAAGAC 181 AGGAGCGACC AGCACATTCA GCTGCAGCTC AGTGCGGAAA GCGTGGGGGA GGTGTATATA 241 AAGAGTACCC AGACTGGCCA GTACTTGGCC ATGGACTCCG ACGGGCTTTT ATACGGCTCA 301 CAAACACCAA ATGAGGAATG CCTGTTCCTG GAACGGCTGG AGGAAAACCA TTACAACACC 361 TATGTGTCCA AGAAGCACGC CGAGAAGAAT TGGTTTGTCG GTCTCAAGAA GAACGGAAGT 421 TGCAAACGTG GTCCTCGGAC TCACTACGGC CAGAAAGCAA TCTTGTTTCT CCCCCTGCCA 481 GTCTCCTCTG ATTAA Greater horseshoe bat FGF1 gene coding sequence (1-155) (SEQ ID NO: 73) (GenBank accession no. DP000705, which is hereby incorporated by reference in its entirety): 190120 T TAATCAGAGG AGACTGGCAG 190141 GGGGAGAAAC AGGATTGCTT TCTGGCCATA GTGAGTCCGA GGACCGCGCT TGCAGCTTCC 190201 ATTCTTCTTG AGCCCAACGA ACCAATTCTT TTCTGCGTGC TTCTTGGACG TGTAGGTGTT 190261 GTAATGGTTT TCCTCCAGCC TTTCCAGGAA CAGACATTCC TCATTTGGTG TCTG 194466 TGAGC CGTACAAAAG CCCGTCGGAG TCCATGGCCA AGTACTGGCC ACTCTCGGTG 194521 CTCTTTATAT ACACCTCCCC CACGCTTTCC GCACTGAGCT GCAGCTGAA 208114 TGTGCTG GTCACTCTTG TCCCTTGTCC 208141 CATCCACTGT GCCATCTGGA AGGATCCTCA GGAAGTGGCC CCCGTTGCTG CAGTAGAGAA 208201 GTTTGGGTTT CTTGTAATTC CCTGTAGGCA GATTAAACTT CTCAGTAAGG GCTGTGAACG 208261 TGGTGACTTC CCCTTCGGCC AT European shrew FGF1 gene coding sequence (1-155) (SEQ ID NO: 74) (GenBank accession no. DP000767, which is hereby incorporated by reference in its entirety): 138344 CTAGTCG GAGGAGACGG 138361 GCAGGGGGAG AAACAAGATC GCTTTCTGGC CGTAGTGAGT CCGGGGACCA CGCTTGCAGC 138421 TTCCGTTCTT CTTCAGACCA ACAAACCAAT TCTTCTCGGC ATGCTTCTTG GAGGTATAGG 138481 TGTTGTAATG GTTTTCCTCC AGCCTTTCCA GAAACAGACA TTCCTCATTC GGTGTTTG 143512 TGAGCCGTA 143521 TAAAAGCCCG TCGGTGTCCA TGGCCAAGTA ATGGCCAGTC TCCGTGCTCT TTATATACAC 143581 CTCCCCCACG CTTTCCGCAC TGAGCTGCAG CTGAA 157009 TG TGCTGGTCGC 157021 TGCGGTCCCT GGTCCCATCC ACTGTGCCGT CCGGGAGGAT GCGCAGGAAG TGGCCCCCGT 157081 TGCTGCAGTA CAGGAGTTTG GGCTTCTTGT AGTTCCCTGG TGGCAGGTTA AACTTCTCCA 157141 TGAGGGCCCC AAAGGTGGTG ATCTCCCCCT CGGCCAT Rabbit FGF1 gene coding sequence (1-155) (SEQ ID NO: 75) (GenBank accession no. NM_001171488, which is hereby incorporated by reference in its entirety): 1 ATGGCTGAGG GGGAGGTCAC CACCTTCACA GCCCTGACCG AGAAGTTCAA CCTGCCTGCA 61 GGGAACTACA AGTTGCCCAA ACTCCTCTAC TGCAGCAACG GGGGCCACTT CCTGAGGATC 121 CTGCCGGACG GCACTGTGGA CGGCACAAGG GACAGGAGCG ACCAGCACAT TCAGCTGCAG 181 CTGAGTGCGG AAAGCGTGGG GGAGGTGTAT ATAAAGAGTA CGGAGACCGG CCAGTACTTG 241 GCCATGGACA CCGACGGCCT TTTATACGGC TCGCAAACGC CCAGTGAGGA GTGTTTGTTC 301 CTGGAACGGC TGGAGGAGAA CCACTACAAC ACCTACACGT CCAAGAAGCA CGCCGAGAAG 361 AACTGGTTCG TGGGGCTGAA GAAAAACGGG AGCTGCAAGC GCGGTCCTCG GACTCACTAC 421 GGCCAGAAAG CCATCTTGTT CCTCCCCCTG CCGGTCTCCT CCGACTAA Chinese hamster FGF1 gene coding sequence (1-155) (SEQ ID NO: 76) (GenBank accession no. XM_003502421, which is hereby incorporated by reference in its entirety): 1 ATGGCTGAAG GAGAAATCAC CACCTTCTCA GCCCTGACAG AGAGATTTAA TCTGCCTCCA 61 GGAAACTACA AGAAGCCCAA ACTGCTCTAC TGCAGCAACG GGGGCCACTT CTTGAGGATC 121 CTTCCAGATG GCACAGTGGA TGGGACAAGG GACAGGAGTG ACCAGCACAT TCAGCTGCAG 181 CTGAGTGCGG AAAGCGCGGG CGAAGTGTAT ATAAAGGGTA CAGAGACAGG CCAGTACAGG 241 AACATGGACA CGGATGGCCT TTTATACGGC TCACAGACAC CAAATGAAGA ATGCCTGTTC 301 CTGGAAAGGC TGGAAGAAAA CCATTACAAC ACTTATACAT CCAAGAAGCA CGCAGAGAAG 361 AACTGGTTTG TGGGCCTCAA GAAAAACGGG AGCTGCAAGC GTGGTCCTCG GACTCACTAT 421 GGCCAGAAAG CAATCTTGTT TCTCCCCCTG CCTGTATCTT CTGACTAG Tasmanian devil FGF1 gene coding sequence (1-155) (SEQ ID NO: 77) (GenBank accession no. XM_003756690, which is hereby incorporated by reference in its entirety): 24 ATGGCCG AAGGGGAGAT CACAACCTTC ACAGCCCTGA 61 CCGAAAGATT TAATCTGCCA CTGGGGAATT ACAAGAAGCC CAAGCTTCTC TACTGTAGCA 121 ATGGGGGCCA CTTTTTGAGG ATTCTTCCTG ATGGTAAAGT GGATGGGACA AGGGACAGAA 181 ATGATCAACA CATTCAACTG CAACTAAGCG CGGAAAGCGT GGGTGAGGTG TATATAAAGA 241 GCACTGAGTC TGGCCAGTAT TTGGCTATGG ACACCGATGG ACTTTTATAC GGCTCACAGA 301 CACCCACTGA AGAATGCTTG TTCCTGGAGA GATTGGAGGA GAATCATTAC AACACCTACA 361 TATCAAAGAA GCATGCGGAG AAAAATTGGT TTGTGGGCCT CAAGAAAAAT GGAAGCTGCA 421 AAAGAGGTCC CAGGACTCAC TATGGCCAGA AAGCCATCCT CTTCCTTCCC CTCCCTGTGT 481 CCTCTGAGTA A House mouse FGF1 gene coding sequence (1-155) (SEQ ID NO: 78) (GenBank accession no. NM_010197, which is hereby incorporated by reference in its entirety): 188 ATG GCTGAAGGGG AGATCACAAC CTTCGCAGCC CTGACCGAGA GGTTCAACCT 241 GCCTCTAGGA AACTACAAAA AGCCCAAACT GCTCTACTGC AGCAACGGGG GCCACTTCTT 301 GAGGATCCTT CCTGATGGCA CCGTGGATGG GACAAGGGAC AGGAGCGACC AGCACATTCA 361 GCTGCAGCTC AGTGCGGAAA GTGCGGGCGA AGTGTATATA AAGGGTACGG AGACCGGCCA 421 GTACTTGGCC ATGGACACCG AAGGGCTTTT ATACGGCTCG CAGACACCAA ATGAGGAATG 481 TCTGTTCCTG GAAAGGCTGG AAGAAAACCA TTATAACACT TACACCTCCA AGAAGCATGC 541 GGAGAAGAAC TGGTTTGTGG GCCTCAAGAA GAACGGGAGC TGTAAGCGCG GTCCTCGGAC 601 TCACTATGGC CAGAAAGCCA TCTTGTTTCT GCCCCTCCCG GTGTCTTCTG ACTAG Domestic guinea pig FGF1 gene coding sequence (1-154) (SEQ ID NO: 79) (GenBank accession no. XM_003477194, which is hereby incorporated by reference in its entirety): 1 ATGGCTGAAG GAGAAATCAC AACTTTTGCA GCCCTGACTG AGAAGTTTAA TCTGCCTCCA 61 GGGAATTATA AGAAGCCCAA ACTGCTCTAC TGCAGCAATG GGGGCCACTT CCTGAGGATC 121 CTTCCAGACG GCACAGTGGA CGGCACAAGA GACAGGAGCG ACCAGCACAT TCAGCTGCAG 181 CTCAGTGCGG AAGGCGTGGG GGAGGTGTAT ATACAGAGCA CCGAGACCGG CCAGTACTTG 241 GCCATGGACA CCGACGGGCT TTTATACGGC TCACAGACAC CAAGTGAGGA ATGCTTGTTC 301 CTGGAAAGGC TGGAGGAAAA CCATTACAAC ACCTACACAT CCAAGAAGCA TGTGGAGAAG 361 AATTGGTTTG TTGGCCTCAA GAAGAACGGA AGCTGCAAGC GTGGTCCTCG GACTCACTAT 421 GGCCAGAAAG CAATCTTGTT CCTCCCCTTG CCAGTCTCTG ATTAG Gray short-tailed opossum FGF1 gene coding sequence (1-155) (SEQ ID NO: 80) (GenBank accession no. XM_001368884, which is hereby incorporated by reference in its entirety): 1 ATGGCCGAAG GGGAGATCAC AACCTTCACA GCCCTGACTG AAAGATTTAA CCTGCCACTG 61 GGGAATTACA AGAAACCCAA GCTTCTCTAC TGTAGCAATG GGGGCCATTT CTTGAGGATC 121 CTTCCTGATG GCAAAGTGGA TGGGACACGG GACAGAAATG ATCAACACAT TCAACTGCAG 181 CTGAGCACGG AAAGTGTGGG TGAGGTGTAT ATAAAGAGCA CTGAGTCTGG CCAGTATTTG 241 GCTATGGACA CCGATGGACT TTTATATGGC TCACAGACAC CCAGTGAAGA ATGCTTGTTT 301 CTGGAGAGGT TGGAGGAGAA TCATTACAAC ACCTACACAT CGAAGAAGCA TGCAGAGAAA 361 AATTGGTTTG TTGGTCTCAA GAAGAATGGA AGCTGCAAAA AGGGTCCCAG GACTCACTAC 421 GGCCAGAAAG CCATCCTGTT CCTTCCCCTC CCTGTGTCCT CTGAGTAA Common vampire bat FGF1 gene coding sequence (1-155) (SEQ ID NO: 81) (GenBank accession no. GABZ01008334, which is hereby incorporated by

reference in its entirety): 1 ATGGCTGAAG GGGAAGTCAC CACGTTCACA GCTCTGACTG AGAAGTTTAA TCTGCCTCTG 61 GAGAGTTACA AGAAGCCCAA ACTTCTCTAC TGCAGCAACG GTGGCCACTT CCTGAGGATC 121 CTTCCAGATG GTACAGTGGA TGGGACAAGG GACAAGAGCG ACCAGCACAT TCAGCTGCAG 181 CTCAGTGCGG AAAGCGTGGG GGAGGTGTAC ATAAAGAGCA CCGGGAGTGG CCAGTACTTG 241 GCCATGGACT CCGCCGGGCT TTTGTATGGC TCACAGACAC CAAATGAGGA ATGTTTGTTC 301 CTGGAAAGGC TGGAGGAAAA CCATTACAAC ACCTACACAT CCAAGAAGCA TGCAGAAAAG 361 AATTGGTTCG TGGGGCTCAA GAAGAATGGA AGCTGCAAGC GTGGCCCCCG GACTCATTAT 421 GGCCAGAAAG CAATCTTGTT TCTCCCCCTG CCAGTCAACT CTGATTAA Cattle FGF1 gene coding sequence (1-155) (SEQ ID NO: 82) (GenBank accession no. NM_174055, which is hereby incorporated by reference in its entirety): 918 ATG GCTGAAGGAG AAACCACGAC CTTCACGGCC CTGACTGAGA 961 AGTTTAACCT GCCTCTAGGC AATTACAAGA AGCCCAAGCT CCTCTACTGC AGCAACGGGG 1021 GCTACTTCCT GAGAATCCTC CCAGATGGCA CAGTGGATGG GACGAAGGAC AGGAGCGACC 1081 AGCACATTCA GCTGCAGCTC TGTGCGGAAA GCATAGGGGA GGTGTATATT AAGAGTACGG 1141 AGACTGGCCA GTTCTTGGCC ATGGACACCG ACGGGCTTTT GTACGGCTCA CAGACACCCA 1201 ATGAGGAATG TTTGTTCCTG GAAAGGTTGG AGGAAAACCA TTACAACACC TACATATCCA 1261 AGAAGCATGC AGAGAAGCAT TGGTTCGTTG GTCTCAAGAA GAACGGAAGG TCTAAACTCG 1321 GTCCTCGGAC TCACTTCGGC CAGAAAGCCA TCTTGTTTCT CCCCCTGCCA GTCTCCTCTG 1381 ATTAA Platypus FGF1 gene coding sequence (1-155) (SEQ ID NO: 83) (GenBank by reference in accession no. XM_001514811, which is hereby incorporated its entirety): 1 ATGGCGGAGG GTGAAATCAC CACGTTCACA GCCCTGATGG AGAAGTTCGA CCTACCCCTG 61 GGCAACTACA AAAAGCCTAG GCTGCTCTAC TGCAGCAATG GCGGCTACTT CCTGCGCATC 121 CAGCCAGACG GTAAAGTGGA CGGGACCAGG GATCGGAGCG ATCAGCACAT TCAACTGCAG 181 CTAAGCGCGG AAAGCGTGGG CGAGGTGTAT ATAAAGAGCA CCGAGTCTGG CCACTATTTG 241 GCTATGGACA CCGAAGGACT TTTATATGGC TCACAGGCAC CCAGTGAAGA CTGCTTGTTC 301 CTGGAGCGGC TGGAGGAGAA CCACTATAAC ACGTACGTGT CCAAGAAGCA CGCTGAGAAG 361 AATTGGTTTG TCGGTCTCAA GAAGAACGGG AGCTGCAAAC GAGGTCCCCG GACTCACTAC 421 GGCCAGAAAG CCATCCTCTT CCTCCCGCTC CCCGTGGCAT CCGACTAG Zebra finch FGF1 gene coding sequence (1-155) (SEQ ID NO: 84) (GenBank accession no. XM_002193251, which is hereby incorporated by reference in its entirety): 1 ATGGCCGAGG GGGAGATCAC CACCTTCAGC GCCCTGACGG AGAAGTTCAA CCTGCCCCCG 61 GGGAACTACA AGAAGCCCAA ACTGCTGTAC TGCAGCAACG GGGGGCATTT CCTGCGCATC 121 CTCCCGGACG GCACCGTGGA TGGCACCAGG GACCGCAGCG ACCAGCACAT TCAGCTCCAG 181 CTGAGTGCAG AGAGCGTGGG GGTGGTGCAC ATCCAGAGCA CCCAGTCGGG GCAGTACCTG 241 GCCATGGACA CCAACGGGCT GCTCTACGGC TCGCAGCTGC CACCCGGTGA GTGTCTGTTC 301 CTGGAAAGGC TGGAGGAGAA CCATTACAAC ACCTACGTCT CCAAAATGCA CGCGGACAAG 361 AACTGGTTTG TGGGGCTGAA GAAGAACGGG ACAAGCAAGC TGGGCCCGCG GACTCACTAC 421 GGCCAGAAGG CGATCCTGTT CCTGCCGCTG CCCGTGGCGG CCGACTGA Nine-banded armadillo FGF1 gene coding sequence (1-155) (SEQ ID NO: 85) (GenBank accession no. DP001080, which is hereby incorporated by reference in its entirety): 178389 TT AATCAGAGGA GACTGGCAGG GGAAGAAACA AGATAGCTTT CTGGCCATAG 178441 TGAGTCTGAG GACCACGTTT GCTGCTTCCG TCCTTCTTGA GACCAACAAA CCATTTCTTC 178501 TCTGCATGCT TCTTGGATAT GTAGGTGTTG TAATTGTTTT CTTCCAGCTT TTCCATGAAC 178561 AAGCATTCCT CACTTGGTGT CTC 182873 TGAGCCAT 182881 ATAAAAGCCC GTCGGTGTCC ATGGCTAAGT ACTGGCCGGT CTCTGCACTC TTTATATACA 182941 CCTCCCCCAC GCTTTCCGCA CTGAGCTGCA GCTGAA 197786 TGTGT TGGTCGCTCC TGTCCCTTGT CCCATCCACC 197821 GTGCCATCTG GAAGGATCCT CAAGAAGTGG CCCCCGTTTC TGCAGTAGAG GAGTCTGGGG 197881 TGCTTGTAAT TTTCTAGGGG CAGGTTGAAC TTCTCCATCA GGGCCATGAA GGTTGTGATC 197941 TCCCCTTCAG CCAT Xenopus Silurana tropicalis FGF1 gene coding sequence (1-155) (SEQ ID NO: 86) (GenBank accession no. FJ428265, which is hereby incorporated by reference in its entirety): 1 ATGGCAGAGG GAGACATCAC AACATTCAAC CCCATTGCAG AGTCCTTCAG TCTTCCAATT 61 GGCAACTACA AGAAACCAAA ACTTCTGTAC TGTAATAATG GAGGGTATTT TTTGCGCATC 121 CTCCCAGATG GGGTTGTGGA TGGAACAAGA GACAGAGATG ACCTTTACAT TACACTGAAG 181 TTAAGCGCAC AAAGCCAAGG GGAGGTGCAT ATCAAAAGCA CAGAGACAGG GAGTTACTTA 241 GCCATGGACT CCAGTGGACA GTTGTATGGA ACTCTCACAC CAAATGAAGA AAGCCTGTTT 301 CTGGAGACAT TAGAAGAGAA TCACTATAAC ACATACAAGT CAAAGAAGTA TGCAGAAAAT 361 AACTGGTTTG TGGGGATAAA GAAGAACGGG GCAAGCAAAA AGGGATCAAG GACTCACTAT 421 GGACAAAAAG CCATCCTTTT TCTGCCGCTG CCAGCATCAC CTGACTAG Heterocephalus glaber FGF1 gene coding sequence (1-155) (SEQ ID NO: 87) (generated using SMS Reverse Translate tool on the ExPASy Bioinformatics Resource website (www.expasy.org): 1 ATGGCGGAAG GCGAAATTAC CACCTTTACC GCGCTGACCG AAAAATTTAA CCTGCCGCCG 61 GGCAACTATA AAAAACCGAA ACTGCTGTAT TGCAGCAACG GCGGCCATTT TCTGCGCATT 121 CTGCCGGATG GCAAAGTGGA TGGCACCCGC GATCGCAGCG ATCAGCATAT TCAGCTGCAG 181 CTGAGCGCGG AAGGCGTGGG CGAAGTGTAT ATTAAAAGCA CCGAAACCGG CCAGTATCTG 241 GCGATGGATA CCGATGGCCT GCTGTATGGC AGCCAGACCG CGAGCGAAGA ATGCCTGTTT 301 CTGGAACGCC TGGAAGAAAA CCATTATAAC ACCTATATTA GCAAAAAACA TGCGGAAAAA 361 AACTGGTTTG TGGGCCTGAA AAAAAACGGC AGCTGCAAAC GCGGCCCGCG CACCCATTAT 421 GGCCAGAAAG CGATTCTGTT TCTGCCGCTG CCGGTGAGCA GCGAT Black flying fox FGF1 gene coding sequence (1-155) (SEQ ID NO: 88) (generated using SMS Reverse Translate tool on the ExPASy Bioinformatics Resource website (www.expasy.org): 1 ATGGCGGAAG GCGAAGTGAC CACCTTTACC GCGCTGACCG AACGCTTTAA CCTGCCGCCG 61 GGCAACTATA AAAAACCGAA ACTGCTGTAT TGCAGCAACG GCGGCCATTT TCTGCGCATT 121 CTGCCGGATG GCACCGTGGA TGGCACCCGC GATAAAAGCG ATCAGCATAT TCAGCTGCAG 181 CTGAGCGCGG AAAGCGTGGG CGAAGTGTAT ATTAAAAGCA CCGAAAGCGG CCAGTATCTG 241 GCGATGGATA GCGATGGCCT GCTGTATGGC AGCCAGACCC CGGATGAAGA TTGCCTGTTT 301 CTGGAACGCC TGGAAGAAAA CCATTATAAC ACCTATACCA GCAAAAAACA TGCGGAAAAA 361 AACTGGTTTG TGGGCCTGAA AAAAAACGGC AGCTGCAAAC GCGGCCCGCG CACCCATTAT 421 GGCCAGAAAG CGATTCTGTT TCTGCCGCTG CCGGTGAGCA GCGAT Chinese tree shrew FGF1 gene coding sequence (1-155) (SEQ ID NO: 89) (generated using SMS Reverse Translate tool on the ExPASy Bioinformatics Resource website (www.expasy.org): 1 ATGGCGGAAG GCGAAATTAC CACCTTTGCG GCGCTGACCG AAAAATTTGA TCTGCCGCCG 61 GGCAACTATA AAAAACCGAA ACTGCTGTAT TGCAGCAACG GCGGCCATTT TCTGCGCATT 121 CTGCCGGATG GCACCGTGGA TGGCACCCGC GATCGCAGCG ATCAGCATAT TCAGCTGCAG 181 CTGACCGCGG AAAACGTGGG CGAAGTGTAT ATTAAAAGCA CCGAAACCGG CCAGTATCTG 241 GCGATGGATG CGGATGGCCT GCTGTATGGC AGCCAGACCC CGAACGAAGA ATGCCTGTTT 301 CTGGAACGCC TGGAAGAAAA CCATTATAAC ACCTATATTA GCAAAAAACA TGCGGAAAAA 361 AACTGGTTTG TGGCGCTGAA AAAAAACGGC AGCTGCAAAC TGGGCCCGCG CACCCATTAT 421 GGCCAGAAAG CGATTCTGTT TCTGCCGCTG CCGGTGAGCA GCGAT Rock pigeon FGF1 gene coding sequence (1-155) (SEQ ID NO: 90) (generated using SMS Reverse Translate tool on the ExPASy Bioinformatics Resource website (www.expasy.org): 1 ATGGCGGAAG GCGAAATTAC CACCTTTACC GCGCTGACCG AAAAATTTAA CCTGCCGCCG 61 GGCAACTATA AAAAACCGAA ACTGCTGTAT TGCAGCAACG GCGGCCATTT TCTGCGCATT 121 CTGCCGGATG GCAAAGTGGA TGGCACCCGC GATCGCAGCG ATCAGCATAT TCAGCTGCAG 181 CTGAGCGCGG AAAGCGTGGG CGAAGTGTAT ATTAAAAGCA CCCAGAGCGG CCAGTATCTG 241 GCGATGGATC CGACCGGCCT GCTGTATGGC AGCCAGCTGC TGGGCGAAGA ATGCCTGTTT 301 CTGGAACGCA TTGAAGAAAA CCATTATAAC ACCTATGTGA GCAAAAAACA TGCGGATAAA 361 AACTGGTTTG TGGGCCTGAA AAAAAACGGC AACAGCAAAC TGGGCCCGCG CACCCATTAT 421 GGCCAGAAAG CGATTCTGTT TCTGCCGCTG CCGGTGAGCG CGGAT Sheep FGF1 gene coding sequence (1-155) (SEQ ID NO: 91) (GenBank accession no. XM_004008909, which is hereby incorporated by reference in its entirety): 361 ATGGCTGAAG GAGAAACCAC AACCTTCAGG GCCCTGACTG AGAAGTTTAA CCTGCCTCTA 421 GGCAATTACA AGAAGCCCAA GCTCCTCTAT TGCAGCAACG GGGGCTACTT CCTGAGAATC 481 CTCCCAGATG GCAGAGTGGA TGGGACGAAG GACAGGAGCG ACCAGCACAT TCAGCTGCAG 541 CTCTATGCGG AAAGCATAGG GGAGGTGTAT ATTAAGAGTA CGGAGACTGG CCAGTTCTTG 601 GCCATGGACA CCAACGGGCT TTTGTACGGC TCACAAACAC CCAGTGAGGA ATGTTTGTTC 661 CTGGAAAGGC TGGAGGAAAA CCATTATAAC ACCTACATAT CCAAGAAGCA TGCAGAGAAG 721 AATTGGTTCA TTGGTCTCAA GAAGAACGGA AGCTCCAAAC TCGGTCCTCG GACTCACTTC 781 GGCCAGAAAG CCATCTTGTT TCTCCCCCTG CCAGTTTCCT CTGATTAA Chicken FGF1 gene coding sequence (1-155) (SEQ ID NO: 92) (GenBank accession no. NM_205180, which is hereby incorporated by reference in its entirety): 52 ATGGCCGAG 61 GGGGAGATAA CCACCTTCAC CGCCCTGACC GAGCGCTTCG GCCTGCCGCT GGGCAACTAC 121 AAGAAGCCCA AACTCCTGTA CTGCAGCAAC GGGGGCCACT TCCTACGGAT CCTGCCGGAC 181 GGCAAGGTGG ACGGGACGCG GGACCGGAGT GACCAGCACA TTCAGCTGCA GCTCAGCGCG 241 GAAGATGTGG GCGAGGTCTA TATAAAGAGC ACAGCGTCGG GGCAGTACCT GGCAATGGAC 301 ACCAACGGGC TCCTGTATGG CTCGCAGCTA CCAGGCGAGG AGTGCTTGTT CCTTGAGAGG 361 CTCGAGGAGA ACCATTACAA CACATACATC TCCAAAAAGC ACGCAGACAA GAACTGGTTC 421 GTCGGGCTGA AGAAAAACGG GAACAGCAAG CTGGGGCCGC GGACTCACTA TGGGCAAAAG 481 GCGATCCTCT TCCTCCCATT GCCGGTGTCG GCTGACTGA Alpaca FGF1 gene coding sequence (1-155, excluding 1-57) (SEQ ID NO: 93) (Ensembl accession no. ENSVPAT00000008395, which is hereby incorporated by reference in its entirety): 1 CAGCTGCAGC TCAGTGCGGA AAGCGTGGGG GAGGTGTATA TAAAGAGTAC CGAGACTGGC 61 CAGTACTTGG CCATGGACAC CGACGGGCTT TTGCACGGCT CACAGACACC AAATGAGGAA 121 TGTTTGTTCC TGGAAAGGCT GGAGGAGAAC CATTACAACA CCTACACGTC CAAGAAGCAC 181 GCCGAAAAGA ATTGGTTTGT TGGTCTCAAG AAGAATGGAA GCTGCAAACG CGGTCCTCGG 241 ACTCACTACG GCCAGAAGGC GATCTTGTTT CTCCCCTTGC CAGTCTCCTC TGATTAA Anole lizard FGF1 gene coding sequence (1-155) (SEQ ID NO: 94) (Ensembl accession no. ENSACAT00000013467, which is hereby incorporated by reference in its entirety): 1 ATGGCTGAAG GTGAAATAAC AACATTCACA GCCTTGACCG AGAGGTTTGC TCTCCCAATG 61 GAGAATTACA AGAAGCCCAA ACTCCTGTAT TGCAGCAATG GAGGCCACTT CCTGAGGATC 121 CTTCCAGATG GAAAAGTGGA TGGCACCATG GACCGGAATG ACAGCTATAT TCAGTTGCTG 181 TTAACAGCAG AAGATGTGGG TGTGGTATAT ATAAAAGGCA CTGAGACCGG GCAGTACTTG 241 GCCATGGATG CCAATGGACA TTTATATGGC TCGCAGTTGC CAACAGAAGA GTGTTTATTT 301 GTGGAAACGC TGGAAGAAAA CCATTACAAT ACATATACCT CAAAGATGCA TGGCGATAAG 361 AAGTGGTATG TTGGCTTGAA AAAGAATGGG AAAGGCAAAC TGGGGCCACG GACTCATCGC 421 GGCCAAAAGG CAATACTTTT CCTTCCACTG CCAGTATCAC CTGATTAG Bushbaby FGF1 gene coding sequence (1-155) (SEQ ID NO: 95) (Ensembl accession no. ENSOGAT00000005081, which is hereby incorporated by reference in its entirety): 1 ATGGCTGAAG GGGAAATCAC AACCTTCACA GCCCTCACAG AGAAGTTTAA TCTGCCTCTA 61 GGAAATTACA AGAAGCCCAA GCTCCTCTAC TGTAGCAACG GGGGTCACTT TCTGAGGATC 121 CTGCCGGATG GCACCGTGGA TGGGACACAA GACAGGAGCG ACCAGCACAT TCAGCTGCAG 181 CTCAGTGCGG AAAGCGTGGG GGAGGTGTAT ATAAAGAGTA CCCAGACTGG CCAGTACTTG 241 GCCATGGACT CCGACGGGCT TTTATACGGC TCACAAACAC CAAATGAGGA ATGCCTGTTC 301 CTGGAACGGC TGGAGGAAAA CCATTACAAC ACCTATGTGT CCAAGAAGCA CGCCGAGAAG 361 AATTGGTTTG TCGGTCTCAA GAAGAACGGA AGTTGCAAAC GTGGTCCTCG GACTCACTAC 421 GGCCAGAAAG CAATCTTGTT TCTCCCCCTG CCAGTCTCCT CTGATTAA Cat FGF1 gene coding sequence (1-155) (SEQ ID NO: 96) (Ensembl accession no. ENSFCAT00000009123, which is hereby incorporated by reference in its entirety): 1 ATGGCTGAAG GGGAAATCAC AACCTTCACG GCCCTGACGG AGAAGTTCAA TCTGCCTCCA 61 GGGAATTACA AGAAACCCAA ACTCCTCTAC TGTAGCAACG GGGGCCACTT CCTGAGGATC 121 CTTCCAGATG GCACAGTGGA TGGGACGAGG GACAGGAGCG ACCAGCACAT TCAGCTGCAG 181 CTCAGTGCGG AAAGCGTGGG GGAGGTGTAT ATAAAGAGTA CCGAGACTGG CCAGTACTTG 241 GCCATGGACA CCGACGGGCT TTTGTACGGC TCACAGACAC CAAATGAGGA ATGCTTGTTC 301 CTGGAAAGGC TGGAAGAAAA CCATTACAAC ACCTACACAT CCAAGAAGCA CGCAGAAAAG 361 AATTGGTTTG TGGGTCTCAA GAAGAATGGA AGCTGCAAAC GCGGTCCCCG GACTCACTAT 421 GGCCAGAAGG CAATTTTGTT TCTCCCCCTG CCAGTCTCCT CTGATTAA Chinese softshell turtle FGF1 gene coding sequence (1-155) (SEQ ID NO: 97) (Ensemb accession no. EN5P5IT00000016432, which is hereby incorporated by reference in its entirety): 131 ATGGCTGAAG GGGAAATAAC AACGTTCACC GCCCTGACCG AAAAATTCAA 181 CCTTCCCCTG GGGAATTACA AGAATCCCAA ACTCTTATAT TGCAGCAATG GAGGCTACTT 241 CTTGAGGATA CATCCAGATG GCAAAGTAGA TGGGACAAGG GACCGAAGTG ACCAACACAT 301 TCAGCTGCAG CTAAGTGCGG AAAGCGTGGG TGAGGTATAT ATAAAGAGCA CTGAGTCTGG 361 ACAGTTTTTG GCTATGGACG CCAATGGACT TTTATATGGA TCACTGTCAC CGAGTGAGGA 291 ATGCTTATTC TTGGAAAGAA TGGAAGAAAA TCATTATAAC ACCTACATCT CCAAGAAGCA 351 TGCAGACAAG AACTGGTTCG TTGGCTTAAA GAAGAATGGA AGCTGCAAAC TGGGACCGCG 411 GACGCACTAC GGCCAAAAGG CCGTCCTTTT CCTTCCACTG CCAGTGTCAG CTGATTAA Coelacanth FGF1 gene coding sequence (1-155) (SEQ ID NO: 98) (Ensembl accession no. ENSLACT00000015212, which is hereby incorporated by reference in its entirety): 1 ATGGCTGAAG ACAAAATAAC AACACTGAAG GCCTTGGCTG AAAAATTTAA CCTTCCTATG 61 GGAAATTACA AGAAAGCAAA ACTCCTCTAC TGCAGCAACG GAGGGTATTT CCTGCGAATA 121 CCCCCAGACG GGAAAGTGGA AGGAATTAGA GAACGAAGCG ACAAGTACAT TCAGCTGCAA 181 ATGAATGCAG AAAGTTTAGG CATGGTGTCT ATAAAGGGTG TGGAGGCAGG GCAATACCTA 241 GCTATGAATA CAAATGGACT CCTGTATGGA TCTCAGTCTC TAACTGAAGA ATGCCTTTTC 301 ATGGAAAAGA TGGAAGAAAA CCACTACAAC ACATACAGGT CTAAGACACA TGCAGATAAA 361 AACTGGTATG TTGGCATTAG AAAGAACGGT AGCATCAAAC CAGGACCAAG GACTCACATT 421 GGCCAAAAGG CTGTTCTTTT TCTCCCTCTG CCTGCCTCGA GTGATTAG Dolphin FGF1 gene coding sequence (1-155) (SEQ ID NO: 99) (Ensembl accession no. ENSTTRT00000004742, which is hereby incorporated by reference in its entirety): 1 ATGGCTGAAG GGGAAATCAC AACCTTCACA GCCCTGACCG AGAAGTTTAA TCTGCCTCCA 61 GGGAATTACA AGAAGCCCAA ACTCCTCTAC TGTAGCAACG GGGGCCACTT CCTGAGGATC 121 CTTCCAGATG GCACAGTGGA TGGGACAAGG GACAGGAGTG ACCAGCACAT TCAGCTGCAG 181 CTCAGTGCGG AAAGCGTGGG GGAGGTGTAT ATAAAGAGTA CGGAGACTGG CCAGTACTTG 241 GCCATGGACA CCGACGGGCT TTTGTACGGC TCACAGACAC CCAATGAGGA ATGTTTGTTC 301 CTGGAAAGGT TGGAGGAAAA CCATTACAAC ACCTACGCAT CCAAGAAGCA TGCAGAAAAG 361 AATTGGTTCG TTGGTCTCAA GAAGAACGGA AGCTGCAAAC GCGGTCCTCG GACTCACTAC 421 GGCCAGAAAG CAATCTTGTT TCTCCCCCTG CCAGTCTCCT CCGATTAA Ferret FGF1 gene coding sequence (1-155) (SEQ ID NO: 100) (Ensembl accession no. ENSMPUT00000008013 which is hereby incorporated by reference in its entirety): 1 ATGGCT GAAGGGGAAA TCACAACCTT 61 CACAGCCCTG ATGGAGAAGT TTAATCTGCC TGCGGGGAAT TACAAGAAGC CCAAACTCCT 121 CTACTGTAGC AATGGGGGCC ACTTCCTGAG GATCCTTCCA GATGGCACAG TGGACGGCAC 181 AAGGGACAGG AGCGACCAGC ACATTCAGCT GCAGCTCAGT GCGGAAAGCG TGGGGGAGGT 241 GTACATAAAG AGTACCGAGA CTGGCCAGTA CTTGGCCATG GACACCGATG GGCTTTTGTA 301 CGGCTCACAA ACACCAAATG AGGAATGTCT GTTCCTGGAA AGGCTGGAGG AAAACCATTA 361 CAACACCTAC ACATCCAAGA AGCACGCTGA GAAGAATTGG TTTGTAGGTC TCAAGAAGAA 421 CGGAAGCTGC AAACGCGGTC CTCGGACTCA CTATGGCCAG AAAGCAATTC TGTTTCTCCC 481 CCTGCCAGTC TCCTCTGATT AA Gibbon FGF1 gene coding sequence (1-155) (SEQ ID NO: 101) (Ensembl accession no. ENSNLET00000012455, which is hereby incorporated by reference in its entirety): 241 ATGG CCGAAGGGGA 301 AATCACCACC TTCACAGCCC TGACCGAGAA GTTTAATCTG CCTCCAGGGA ATTACAAGAA 361 GCCCAAACTC CTCTACTGTA GCAACGGGGG CCACTTCTTG AGGATCCTTC CGGATGGCAC 421 AGTGGATGGG ACAAGGGACA GGAGCGACCA GCACATTCAG CTGCAGCTCA GTGCGGAAAG 481 CGTGGGGGAG GTGTATATAA AGAGTACCGA GACTGGCCAG TACTTGGCCA TGGACACCGA

541 CGGGCTTTTA TACGGCTCAC AGACACCAAA TGAGGAATGT TTGTTCCTGG AAAGGCTGGA 601 GGAGAACCAT TACAACACCT ATATATCCAA GAAGCATGCA GAGAAGAATT GGTTTGTTGG 661 CCTCAAGAAG AATGGAAGCT GCAAACGCGG TCCTCGGACT CACTATGGCC AGAAAGCAAT 721 CTTGTTTCTC CCCCTGCCAG TCTCTTCTGA TTAA Gorilla FGF1 gene coding sequence (1-155) (SEQ ID NO: 102) (Ensembl accession no. ENSGGOT00000025344, which is hereby incorporated by reference in its entirety): 121 ATGG CTGAAGGGGA 181 AATCACCACC TTCACAGCCC TGACCGAGAA GTTTAATCTG CCTCCAGGGA ATTACAAGAA 241 GCCCAAACTC CTCTACTGTA GCAATGGGGG CCACTTCTTG AGGATCCTTC CGGATGGCAC 301 AGTGGATGGG ACAAGGGACA GGAGCGACCA GCACATTCAG CTGCAGCTCA GTGCGGAAAG 361 CGTGGGGGAG GTGTATATAA AGAGTACCGA GACTGGCCAG TACTTGGCCA TGGACACCGA 421 CGGGCTTTTA TACGGCTCAC AGACACCAAA TGAGGAATGT TTGTTCCTGG AAAGGCTGGA 481 GGAGAACCAT TACAACACCT ATATATCCAA GAAGCATGCA GAGAAGAATT GGTTTGTTGG 541 CCTCAAGAAG AATGGAAGCT GCAAACGCGG TCCTCGGACT CACTATGGCC AGAAAGCAAT 601 CTTGTTTCTC CCCCTGCCAG TCTCTTCCGA TTAA Hedgehog FGF1 gene coding sequence (1-155) (SEQ ID NO: 103) (Ensembl accession no. ENSEEUT00000005832, which is hereby incorporated by reference in its entirety): 1 ATGGCTGAAG GAGAAATCAC CACCTTCACG GCCCTGACTG AGAAGTTTAA TCTGCCACTA 61 GGGAATTACA AGAAGCCCAA GCTCCTCTAC TGTAGCAACG GGGGCCACTT CCTGAGGATC 121 CTTCCAGATG GCACCGTGGA TGGGACAAGG GACAGGAGCG ACCAGCATAT TCAGCTGCAG 181 CTCAGTGCGG AAAGCGTGGG GGAGGTGTAT ATAAAGAGTA CGGAGACTGG CCAGTACTTG 241 GCCATGGACA CCGACGGGCT TTTATACGGC TCACAAACAC CAAATGAGGA ATGTCTGTTC 301 CTTGAAAGGC TGGAAGAGAA CCATTACAAT ACCTACACAT CCAAGAAGCA TGCCGAGAAG 361 AACTGGTTTG TTGGCCTCAA GAAGAATGGA AGCTGCAAGC GTGGTCCTCG GACTCATTAT 421 GGCCAGAAAG CTATTTTGTT TCTCCCCCTG CCAGTTTCCT CTGATTAA Hyrax FGF1 gene coding sequence (1-155, excluding 1-90) (SEQ ID NO: 104) (Ensembl accession no. ENSPCAT00000011746, which is hereby incorporated by reference in its entirety): 1 ATGGCTGAAG GCGAAATCAC AACCTTCACA GCCCTGACTG AGAAGTTTAA CCTGCCACTA 61 GAGAATTACA AGAAGCCCAA ACTCCTCTAC TGTAGCAACG GAGGCCACTT CCTGAGGATC 121 CTTCCGGACG GCACAGTGGA TGGCACCAGG GACAGGAGTG ACCAGCACAT TCAGCTGCAG 181 CTCAGTGCGG AAAGCGTGGG GGAGGTGTAT ATAAAGGGCA CCGAGACTGG CCAGTACTTG 241 GCCATGGACA CCGACGGGCT TTTATATGGC TCA Kangaroo rat FGF1 gene coding sequence (1-155, excluding 1-16 and 58-155) (SEQ ID NO: 105) (Ensembl accession no. ENSDORT00000007345, which is hereby incorporated by reference in its entirety): 1 ATGGCTGAAG GGGAAATCAC AACCTTCACA GCCCTGACGG AAAGGTTTAA ---------- 51 ---------- ---------- ---------- ---------- ---------T TCAGCTGCAA 62 CTGAGTGCGG AAAGCGTGGG GGAGGTCTAT ATAAAGAGCA CCGAGACTGG CCAATACTTG 122 GCCATGGATG CCGACGGGCT TTTATACGGC TCACAGACAC CTGATGAAGA ATGCTTGTTC 182 CTGGAGAGGC TGGAAGAAAA TCATTATAAC ACCTACATAG CCAAGAAACA TGCTGAAAAG 242 AATTGGTTTG TCGGCCTCAA AAAGAATGGA AGCTGCAAGC GTGGTCCTCG GACTCACTAT 302 GGCCAGAAAG CAATCCTGTT CCTCCCCTTG CCTGTCTCCT CTGATTAG Lamprey FGF1 gene coding sequence (1-155, excluding 94-155) (SEQ ID NO: 106) (Ensembl accession no. ENSPMAT00000010729, which is hereby incorporated by reference in its entirety): 1 ATGGAGGTGG GCCACATCGG CACGCTGCCC GTGGTCCCCG CGGGGCCCGT GTTCCCCGGC 61 AGTTTCAAGG AGCCACGGCG CCTCTACTGC CGCAGCGCGG GCCACCACCT CCAGATCCTG 121 GGGGACGGCA CCGTGAGTGG CACCCAGGAC GAGAACGAGC CCCACGCCGT TCTGCAGCTG 181 CAGGCGGTGC GCCGCGGGGT GGTGACGATC CGTGGGCTCT GCGCCGAGAG GTTCCTCGCC 241 ATGAGCACGG AGGGACACCT GTACGGGGCG GTGAGG Lesser hedgehog tenrec FGF1 gene coding sequence (1-155, excluding 1-57) (SEQ ID NO: 107) (Ensembl accession no. ENSETET00000017851, which is hereby incorporated by reference in its entirety): 1 CAGCTGAAGC TCGTTGCCGA AAGCGTGGGG GTGGTGTATA TAAAGAGCAT CAAGACCGGC 61 CAGTACTTGG CCATGAACCC CGACGGGCTT TTATACGGCT CCGAGACCCC AGAGGAAGAA 121 TGCTTGTTCC TGGAAACGCT GGAGGAAAAC CACTACACCA CCTTCAAATC TAAGAAGCAC 181 GTAGAGAAGA ATTGGTTCGT TGGTCTCCGG AAGAATGGAA GGGTCAAGAT CGGGCCTCGG 241 ACTCACCAAG GCCAGAAAGC AATCTTGTTC CTGCCCCTCC CGGTGTCCTC TGATTAA Rhesus monkey FGF1 gene coding sequence (1-155) (SEQ ID NO: 108) (Ensembl accession no. ENSMMUT00000033070, which is hereby incorporated by reference in its entirety): 36 ATGGC TGAAGGGGAA ATCACCACGT 61 TCACAGCCCT GACCGAGAAG TTTAATCTGC CTCCAGGGAA TTACAAGAAG CCCAAACTGC 121 TCTACTGTAG CAATGGGGGC CACTTCTTGA GGATCCTTCC GGATGGCACA GTGGATGGGA 181 CAAGGGACAG GAGCGACCAG CACATTCAGC TGCAGCTCAG TGCGGAAAGC GTGGGGGAGG 241 TGTATATAAA GAGTACCGAG ACTGGCCAGT ACTTGGCCAT GGACACCGAC GGGCTTTTAT 301 ACGGCTCACA GACACCAAAT GAGGAATGTT TGTTCCTGGA AAGGCTGGAG GAGAACCATT 361 ACAACACCTA TACATCCAAG AAGCACGCAG AGAAGAATTG GTTTGTTGGC CTCAAGAAGA 421 ATGGAAGCTG CAAACGTGGT CCTCGGACTC ACTATGGCCA GAAAGCAATC TTGTTTCTTC 481 CCCTGCCAGT CTCTTCTGAT TAA Megabat FGF1 gene coding sequence (1-155) (SEQ ID NO: 109) (Ensembl accession no. ENSPVAT00000004596, which is hereby incorporated by reference in its entirety): 1 ATGGCCGAGG GGGAAGTCAC GACGTTCACG GCCCTGACCG AGAGGTTTAA CCTGCCTCCA 61 GGGAATTACA AGAAGCCCAA ACTTCTCTAC TGCAGCAACG GGGGCCACTT CCTGAGGATC 121 CTCCCAGATG GCACAGTGGA TGGGACAAGG GACAAGAGCG ACCAGCACAT TCAGCTGCAG 181 CTCAGTGCGG AAAGTGTGGG GGAGGTGTAT ATAAAGAGCA CCGAGAGTGG CCAGTACTTG 241 GCCATGGACT CCGACGGGCT TTTGTACGGC TCACAGACAC CAGATGAGGA CTGTTTGTTC 301 CTGGAAAGGC TGGAGGAAAA CCATTACAAC ACCTACACAT CCAAGAAGCA CGCAGAGAAG 361 AATTGGTTTG TTGGGCTCAA GAAGAATGGA AGCTGCAAGC GCGGTCCCCG GACTCACTAC 421 GGCCAGAAAG CGATCCTGTT TCTCCCCCTG CCAGTCTCCT CTGATTAG Microbat FGF1 gene coding sequence (1-155) (SEQ ID NO: 110) (Ensembl accession no. ENSMLUT00000007098, which is hereby incorporated by reference in its entirety): 66 ATGGC TGAGGGGGAA GTCACCACAT TCACGGCCCT GACCGAGAGG TTCAATCTGC 121 CTCTGGAGAA CTACAAGAAG CCCAAGCTTC TCTACTGCAG CAACGGGGGC CACTTCCTGC 181 GGATCCTCCC AGACGGCACC GTGGACGGGA CGAGGGACAG GAGCGACCAG CACATTCAGC 241 TGCAGCTCAG TGCGGAAAGC GTGGGGGAGG TGTATATAAA GAGCACCGAG AGTGGCCAGT 301 ACTTGGCCAT GGACTCCGAC GGGCTTTTGT ACGGCTCACA AACACCCAAT GAGGAATGTT 361 TGTTCCTGGA AAGGCTGGAG GAGAACCACT ACAACACCTA CACGTCCAAG AAGCACGCAG 421 AAAAGAATTG GTTCGTTGGG CTCAAGAAGA ACGGAAGCTG CAAGCGTGGT CCTCGGACGC 481 ATTATGGCCA GAAAGCAATC TTGTTTCTCC CCCTGCCAGT CTCCTCCGAT TAA Mouse lemur FGF1 gene coding sequence (1-155) (SEQ ID NO: 111) (Ensembl accession no. ENSMICT00000009454, which is hereby incorporated by reference in its entirety): 1 ATGGCCGAAG GGGAGATCAC AACCTTCACG GCCCTCACCG AGAAGTTTAA CCTGCCTCCG 61 GGGAACTACA AGAAGCCCAA GCTCCTCTAC TGCAGCAACG GCGGCCACTT CCTGCGCATC 121 CTTCCCGACG GCACCGTGGA TGGCACGAGA GACAGGAGCG ACCAGCACAT TCAGCTGCAG 181 CTCAGTGCGG AAAGCGCGGG GGAGGTGTAT ATAAAGAGCA CCCAGACTGG CCGGTACTTG 241 GCCATGGACG CCGACGGGCT TTTATACGGC TCACAAACAC CAAATGAGGA ATGTTTGTTC 301 CTGGAAAGGC TGGAGGAAAA CCATTACAAC ACCTACGTAT CCAAGAAGCA CGCAGAGAAG 361 AATTGGTTTG TTGGCCTCAA GAAGAATGGA AGTTGCAAAC GCGGCCCCCG GACTCACTAT 421 GGCCAGAAAG CAATCTTGTT TCTGCCCCTG CCAGTCTCCT CTGATTAA Pika FGF1 gene coding sequence (1-155, excluding 57-67) (SEQ ID NO: 112) (Ensembl accession no. ENSOPRT00000012854, which is hereby incorporated by reference in its entirety): 1 ATGGCCGAGG GAGAAGTCAC CACCTTCTCA GCCCTGACGG AGAAGTTCAA TCTGCCTGGA 61 GGAAACTACA AGTTGCCCAA GCTCCTTTAC TGTAGCAACG GAGGCCACTT CCTGAGGATC 121 CTTCCAGATG GCACAGTGGA TGGGACCAGG GACAGGAGCG ACCTGCACA- ---------- 170 ---------- ---------- -GAGGTGTTT ATAAAGAGTA CGGAGACTGG CCAGTACTTG 209 GCTATGGACA CCGATGGCCT TTTATATGGC TCGCAGACAC CCAGTGAGGA GTGTTTGTTC 269 CTGGAGCGGC TGGAGGAGAA CCACTACAAC ACCTACACAT CCAAGAAGCA TGCCGAGAAG 329 AACTGGTTTG TGGGCATCAA GAAGAATGGA AGCTGCAAGC GTGGTCCTCG GACTCACTAC 389 GGCCAGAAAG CCATCTTGTT TCTCCCTCTG CCAGTCTCTT CTGACTAA Rat FGF1 gene coding sequence (1-155) (SEQ ID NO: 113) (Ensembl accession no. ENSRNOT00000018577, which is hereby incorporated by reference in its entirety): 268 ATG GCCGAAGGGG AGATCACAAC CTTTGCAGCC 301 CTGACCGAGA GGTTCAATCT GCCTCTAGGG AACTACAAAA AACCCAAACT GCTCTACTGC 361 AGCAACGGGG GCCACTTCTT GAGGATTCTT CCCGATGGCA CCGTGGATGG GACCAGGGAC 421 AGGAGCGACC AGCACATTCA GCTGCAGCTC AGTGCGGAAA GCGCGGGCGA AGTGTATATA 481 AAGGGTACAG AGACTGGCCA GTACTTGGCC ATGGACACCG AAGGGCTTTT ATACGGCTCG 541 CAGACACCAA ATGAAGAATG CCTATTCCTG GAAAGGCTAG AAGAAAACCA TTATAACACT 601 TACACATCCA AGAAGCACGC GGAGAAGAAC TGGTTTGTGG GCCTCAAGAA GAACGGGAGT 661 TGTAAGCGCG GTCCTCGGAC TCACTACGGC CAGAAAGCCA TCTTGTTTCT CCCCCTCCCG 721 GTATCTTCTG ACTAA Sloth FGF1 gene coding sequence (1-155) (SEQ ID NO: 114) (Ensembl accession no. ENSCHOT00000012416, which is hereby incorporated by reference in its entirety): 1 ATGGCTGAAG GGGAAATCAC AACCTTCACA GCTCTGATGG AGAAGTTTAA CCTGCCACCA 61 GGGAATTACA TGAAGCCCAA ACTCCTCTAC TGTAGCAACG GGGGCCACTT CTTGAGGATC 121 CTTCCAGACG GCACAGTGGA TGGGACAAGG GACAGGAGCG ACCTGCACAT TCAGCTGCAG 181 CTCAGTGCGG AAAGCGTGGG GGAGGTGTAT ATAAAGAGTG CGGAGACCGG CCAGTACTTA 241 GCCATGGACA CCGGCGGGCT TTTATACGGC TCACAGACAC CAAGTGAGGA ATGCCTGTTC 301 CTAGAAAGGC TGGAGGAAAA CCATTACAAC ACCTACGTAT CCAAGAAGCA TGCGGAGAAG 361 AACTGGTTCG TTGGCCTAAA GAAGAATGGA AGCAGCAAAC GCGGCCCCCG GACTCACTAT 421 GGCCAGAAAG CCATCTTGTT TCTTCCCCTG CCAGTCTCCT CTGATTAA Squirrel FGF1 gene coding sequence (1-155) (SEQ ID NO: 115) (Ensembl accession no. ENSST0T00000029249, which is hereby incorporated by reference in its entirety): 1 ATGG 5 CTGAAGGGGA AATCACAACC TTCACAGCCC TGACCGAGAA GTTCAATCTG CCTCCAGGGA 65 ACTACAAGAA GCCCAAACTG CTCTACTGTA GCAACGGAGG CCACTTCTTG AGGATCCTTC 125 CTGATGGCAC AGTGGATGGG ACAAGAGACA GGAGCGACCA ACACATTCAG CTGCAGCTCA 185 GTGCGGAAAG CGTGGGGGAG GTGTATATAA AGAGTACCGA GACCGGCCAG TACTTGGCCA 245 TGGACACCGA CGGGCTTTTA TATGGCTCAC AGACCCCAAA TGAGGAATGC TTATTCCTGG 305 AAAGGCTGGA GGAAAACCAT TACAACACGT ACACATCCAA GAAGCATGCA GAGAAGAATT 365 GGTTTGTTGG CCTCAAGAAG AACGGAAGCT GCAAGCGCGG TCCCCGGACT CACTATGGCC 425 AGAAAGCGAT CTTGTTTCTC CCACTGCCTG TCTCCTCTGA TTAG Tarsier FGF1 gene coding sequence (1-155) (SEQ ID NO: 116) (Ensembl accession no. ENSTSYT00000007425, which is hereby incorporated by reference in its entirety): 1 ATGGCCGAAG GGGAAATCAC AACCTTCACA GCCCTGACCG AGAAGTTCAA CCTGCCCCCG 61 GGGAATTACA AGAAGCCCAA ACTCCTCTAC TGCAGCAACG GGGGCCACTT CTTGAGGATC 121 CTTCCGGATG GCACTGTGGA TGGAACGAGG GACAGGAGCG ACCAGCACAT TCAGCTGCAG 181 CTCAGCGCGG AAAGCGTGGG GGAGGTGTAT ATAAAGAGTA CCGAGACCGG CCAGTACTTG 241 GCCATGGACA CCGACGGGCT TTTGTACGGC TCACAGACAC CAAATGAGGA GTGTCTGTTC 301 CTGGAAAGGC TGGAAGAGAA TCATTACAAT ACCTACGTGT CCAAGAAGCA TGCGGAGAAG 361 AATTGGTTTG TCGGCCTCAA GAAGAATGGA AGCTGCAAAC GCGGTCCTCG GACTCACTAT 421 GGCCAGAAAG CAATCTTGTT TCTCCCCCTG CCAGTTTCCT CTGATTAA Tree shrew FGF1 gene coding sequence (1-155) (SEQ ID NO: 117) (Ensembl accession no. ENSTBET00000011861, which is hereby incorporated by reference in its entirety): 1 ATGGCTGAAG GGGAAATCAC GACCTTCGCA GCCCTGACCG AGAAGTTTGA TCTGCCTCCA 61 GGGAATTACA AGAAGCCCAA ACTTCTCTAC TGTAGCAACG GGGGCCATTT CTTGAGGATT

121 CTTCCAGATG GCACCGTGGA TGGGACAAGA GACAGGAGCG ACCAGCACAT TCAGCTGCAG 181 CTCACTGCGG AAAACGTGGG GGAGGTGTAC ATAAAGAGTA CGGAGACTGG CCAGTACTTG 241 GCCATGGACG CCGACGGGCT TTTATATGGC TCACAGACAC CAAACGAGGA ATGTTTGTTC 301 CTGGAAAGGC TGGAGGAGAA CCATTACAAC ACCTACATAT CCAAGAAGCA CGCAGAGAAG 361 AATTGGTTTG TTGCCCTCAA GAAGAACGGA AGCTGCAAAC TCGGTCCTCG GACTCACTAT 421 GGCCAGAAAG CAATCTTGTT TCTCCCCCTG CCAGTCTCCT CTGATTAA Turkey FGF1 gene coding sequence (1-155, excluding 57-155) (SEQ ID NO: 118) (Ensembl accession no. ENSMGAT00000017372, which is hereby incorporated by reference in its entirety): 1 ATGGCCGAGG GGGAGATAAC CACCTTCACA GCCCTGACCG AGCGCTTCGG CCTGCCGCTG 61 GGCAACTACA AGAAGCCCAA ACTCCTGTAC TGCAGCAACG GGGGCCACTT CCTACGGATC 121 CTGCCGGACG GCAAGGTGGA CGGGACGCGG GACCGGAGCG ACCAGCAC Wallaby FGF1 gene coding sequence (1-155) (SEQ ID NO: 119) (Ensembl accession no. ENSMEUT00000016544, which is hereby incorporated by reference in its entirety): 1 ATGGCCGAAG GGGAGATCAC AACCTTCACA GCCCTGACCG AAAGATTTAA CCTGCCACTG 61 GGGAATTACA AGAAGCCCAA GCTTCTCTAC TGTAGCAATG GGGGCCACTT TTTGAGGATC 121 CTTCCTGATG GCAAAGTGGA TGGGACAAGG GACAGAAATG ATCAACACAT TCAACTGCAA 181 CTAAGCGCGG AAAGCGTGGG TGAGGTGTAT ATAAAGAGCA CTGAGTCTGG GCAGTATTTG 241 GCCATGGACA CCAATGGACT TTTATATGGC TCACAGACCC CCAGCGAAGA ATGCTTATTC 301 CTGGAGAGGT TGGAGGAGAA TCATTACAAC ACCTACATAT CAAAGAAGCA TGCGGAGAAA 361 AATTGGTTTG TTGGCCTCAA GAAGAACGGA AGTTGCAAAA GAGGTCCCAG GACTCACTAT 421 GGCCAGAAAG CCATCCTATT CCTTCCCCTC CCTGTGTCCT CTGAGTAA Zebrafish FGF1 gene coding sequence (1-147) (SEQ ID NO: 120) (Ensembl accession no. ENSDART00000005842, which is hereby incorporated by reference in its entirety): 178 ATG 181 ACCGAGGCCG ATATTGCGGT AAAGTCCAGC CCGCGCGACT ATAAAAAACT GACGCGGCTG 241 TACTGTATGA ATGGAGGATT TCACCTTCAG ATCCTGGCGG ACGGGACAGT GGCTGGAGCA 124 GCAGACGAAA ACACATACAG CATACTGCGC ATAAAAGCAA CAAGTCCAGG AGTGGTGGTG 184 ATCGAAGGAT CAGAAACAGG TCTTTACCTC TCGATGAATG AACATGGCAA GCTGTACGCT 244 TCATCATTAG TGACGGATGA AAGTTATTTC CTGGAGAAGA TGGAGGAAAA CCACTACAAC 304 ACATATCAGT CTCAAAAGCA CGGTGAAAAC TGGTACGTCG GAATAAAAAA GAACGGGAAA 364 ATGAAACGGG GCCCAAGAAC TCACATCGGA CAAAAGGCCA TTTTCTTTCT TCCACGACAG 424 GTGGAGCAGG AAGAGGACTG A

As noted above, also encompassed within the present invention are portions of paracrine FGFs other than FGF1 (e.g., FGF2, FGF4, FGF5, FGF6, FGF9, FGF16, and FGF20). The portions derived from paracrine FGF2 include portions corresponding to the above-identified amino acid sequences of FGF1. Corresponding portions may be determined by, for example, sequence analysis and structural analysis.

In one embodiment, the paracrine FGF is FGF2. In one embodiment, the portion of the FGF2 is derived from human FGF2 having the amino acid sequence of SEQ ID NO: 121 (GenBank Accession No. EAX05222, which is hereby incorporated by reference in its entirety), as follows:

TABLE-US-00005 1 MAAGSITTLP ALPEDGGSGA FPPGHFKDPK RLYCKNGGFF LRIHPDGRVD GVREKSDPHI 61 KLQLQAEERG VVSIKGVCAN RYLAMKEDGR LLASKCVTDE CFFFERLESN NYNTYRSRKY 121 TSWYVALKRT GQYKLGSKTG PGQKAILFLP MSAKS

In one embodiment, the portion of the paracrine FGF includes an amino acid sequence beginning at any one of residues 1 to 25 and ending at any one of residues 151 to 155 of SEQ ID NO: 121. In one embodiment, the portion of the paracrine FGF includes amino acid residues 1-151, 1-152, 1-153, 1-154, 1-155, 2-151, 2-152, 2-153, 2-154, 2-155, 3-151, 3-152, 3-153, 3-154, 3-155, 4-151, 4-152, 4-153, 4-154, 4-155, 5-151, 5-152, 5-153, 5-154, 5-155, 6-151, 6-152, 6-153, 6-154, 6-155, 7-151, 7-152, 7-153, 7-154, 7-155, 8-151, 8-152, 8-153, 8-154, 8-155, 9-151, 9-152, 9-153, 9-154, 9-155, 10-151, 10-152, 10-153, 10-154, 10-155, 11-151, 11-152, 11-153, 11-154, 11-155, 12-151, 12-152, 12-153, 12-154, 12-155, 13-151, 13-152, 13-153, 13-154, 13-155, 14-151, 14-152, 14-153, 14-154, 14-155, 15-151, 15-152, 15-153, 15-154, 15-155, 16-151, 16-152, 16-153, 16-154, 16-155, 17-151, 17-152, 17-153, 17-154, 17-155, 18-151, 18-152, 18-153, 18-154, 18-155, 19-151, 19-152, 19-153, 19-154, 19-155, 20-151, 20-152, 20-153, 20-154, 21-155, 21-151, 21-152, 21-153, 21-154, 21-155, 22-151, 22-152, 22-153, 22-154, 22-155, 23-151, 23-152, 23-153, 23-154, 23-155, 24-151, 24-152, 24-153, 24-154, 24-155, 25-151, 25-152, 25-153, 25-154, or 25-155 of FGF2 (SEQ ID NO: 121). In one embodiment, the portion of the paracrine FGF includes amino acid residues 1-151 or 1-152 of SEQ ID NO: 121.

In one embodiment, the portion of the paracrine FGF of the chimeric protein includes an amino acid sequence that has at least 80%, at least 85%, at least 90%, at least 95%, at least 97% or at least 99% amino acid sequence identity to the corresponding amino acid sequence of native paracrine FGF (e.g., SEQ ID NO: 121). In one embodiment, the portion of the paracrine FGF includes an amino acid sequence that has at least 80%, at least 85%, at least 90%, at least 95%, at least 97% or at least 99% amino acid sequence identity to an amino acid sequence beginning at any one of residues 1 to 25 and ending at any one of residues 151 to 155 of SEQ ID NO: 121. In one embodiment, the portion of the paracrine FGF includes an amino acid sequence that has at least 80%, at least 85%, at least 90%, at least 95%, at least 97% or at least 99% amino acid sequence homology to the corresponding amino acid sequence of native paracrine FGF (e.g., SEQ ID NO: 121). In one embodiment, the portion of the paracrine FGF includes an amino acid sequence that has at least 80%, at least 85%, at least 90%, at least 95%, at least 97% or at least 99% amino acid sequence homology to an amino acid sequence beginning at any one of residues 1 to 25 and ending at any one of residues 151 to 155 of SEQ ID NO: 121.

Also encompassed within the present invention are portions of paracrine FGFs other than FGF2 (e.g., FGF1, FGF4, FGF5, FGF6, FGF9, FGF16, and FGF20). The portions derived from paracrine FGFs other than FGF2 include portions corresponding to the above-identified amino acid sequences of FGF2. Corresponding portions may be determined by, for example, sequence analysis and structural analysis.

In one embodiment of the present invention, the portion of the paracrine FGF is derived from an ortholog of a human paracrine FGF. In one embodiment of the present invention, the portion of the paracrine FGF of the chimeric protein is derived from an ortholog of human FGF2. In one embodiment, the portion of the FGF2 is derived from Gorilla gorilla, Pongo abelii, Macaca mulatta, Pan troglodytes, Pan paniscus, Saimiri boliviensis boliviensis, Nomascus leucogenys, Equus caballus, Bos taurus, Papio Anubis, Vicugna pacos, Ovis aries, Capreolus capreolus, Loxodonta Africana, Sus scrofa, Ailuropoda melanoleuca, Choloepus hoffmanni, Bubalus bubalis, Canis lupus familiaris, Rattus norvegicus, Heterocephalus glaber, Otolemur garnettii, Mus musculus, Ictidomys tridecemlineatus, Felis catus, Cavia porcellus, Sarcophilus harrisii, Monodelphis domestica, Oryctolagus cuniculus, Meleagris gallopavo, Gallus gallus, Taeniopygia guttata, Cynops pyrrhogaster, Xenopus laevis, Didelphis albiventris, Myotis lucifugus, Anolis carolinensis, Dasypus novemcinctus, Tupaia belangeri, Xenopus silurana tropicalis, Latimeria chalumnae, Tetraodon nigroviridis, Gasterosteus aculeatus, Takifugu rubripes, Oncorhynchus mykiss, Salmo salar, Danio rerio, Oreochromis niloticus, or Oryzias latipes. The portions of an ortholog of human paracrine FGF include portions corresponding to the above-identified amino acid sequences of FGF2. Corresponding portions may be determined by, for example, sequence analysis and structural analysis.

In one embodiment, the portion of the FGF2 of the chimeric protein of the present invention is derived from an ortholog of human FGF2 having the amino acid sequence shown in Table 3.

TABLE-US-00006 TABLE 3 Amino acid sequence of Gorilla gorilla (gorilla) FGF2 (SEQ ID NO: 122) (Ensembl accession no. ENSGGOP00000004720, which is hereby incorporated by reference in its entirety): 104 MAAGSI TTLPALPEDG 120 GSGAFPPGHF KDPKRLYCKN GGFFLRIHPD GRVDGVREKS DPHIKLQLQA EERGVVSIKG 180 VCANRYLAMK EDGRLLASKC VTDECFFFER LESNNYNTYR SRKYTSWYVA LKRTGQYKLG 240 SKTGPGQKAI LFLPMSAKS Amino acid sequence of Pongo abelii (sumatran orangutan) FGF2 (SEQ ID NO: 123) (GenBank accession no. XP_002815172, which is hereby incorporated by reference in its entirety): 168 MAA GSITTLPALP 181 EDGGSGAFPP GHFKDPKRLY CKNGGFFLRI HPDGRVDGVR EKSDPHIKLQ LQAEERGVVS 241 IKGVCANRYL AMKEDGRLLA SKCVTDECFF FERLESNNYN TYRSRKYTSW YVALKRTGQY 301 KLGSKTGPGQ KAILFLPMSA KS Amino acid sequence of Macaca mulatta (rhesus monkey) FGF2 (SEQ ID NO: 124) (GenBank accession no. XP_001099284, which is hereby incorporated by reference in its entirety): 83 MAAGSITT LPALPEDGGS GAFPPGHFKD PKRLYCKNGG 121 FFLRIHPDGR VDGVREKSDP HIKLQLQAEE RGVVSIKGVC ANRYLAMKED GRLLASKCVT 181 DECFFFERLE SNNYNTYRSR KYTSWYVALK RTGQYKLGSK TGPGQKAILF LPMSAKS Amino acid sequence of Pan troglodytes (chimpanzee) FGF2 (SEQ ID NO: 125) (GenBank accession no. NP_001103711, which is hereby incorporated by reference in its entirety): 134 MAAGSIT TLPALPEDGG SGAFPPGHFK DPKRLYCKNG GFFLRIHPDG 181 RVDGVREKSD PHIKLQLQAE ERGVVSIKGV CANRYLAMKE DGRLLASKCV TDECFFFERL 241 ESNNYNTYRS RKYTSWYVAL KRTGQYKLGS KTGPGQKAIL FLPMSAKS Amino acid sequence of Pan paniscus (Pygmy chimpanzee) FGF2 (SEQ ID NO: 126) (GenBank accession no. XP_003816481, which is hereby incorporated by reference in its entirety): 112 MAAGSITTL 121 PALPEDGGSG AFPPGHFKDP KRLYCKNGGF FLRIHPDGRV DGVREKSDPH IKLQLQAEER 181 GVVSIKGVCA NRYLAMKEDG RLLASKCVTD ECFFFERLES NNYNTYRSRK YTSWYVALKR 241 TGQYKLGSKT GPGQKAILFL PMSAKS Amino acid sequence of Saimiri boliviensis boliviensis (Bolivian squirrel monkey) FGF2 (SEQ ID NO: 127) (GenBank accession no. XP_003936290, which is hereby incorporated by reference in its entirety): 1 MAAGSITTLP ALPEDGGSGA FPPGHFKDPK RLYCKNGGFF LRIHPDGRVD GVREKSDPHI 61 KLQLQAEERG VVSIKGVCAN RYLAMKEDGR LLASKCVTDE CFFFERLESN NYNTYRSRKY 121 TSWYVALKRT GQYKLGSKTG PGQKAILFLP MSAKS Amino acid sequence of Nomascus leucogenys (Northern white-cheeked gibbon) FGF2 (SEQ ID NO: 128) (GenBank accession no. XP_003271404, which is hereby incorporated by reference in its entirety): 1 MAAGSITTLP ALPEDGGSGA FPPGHFKDPK RLYCKNGGFF LRIHPDGRVD GVREKSDPHI 61 KLQLQAEERG VVSIKGVCAN RYLAMKEDGR LLASKCVTDE CFFFERLESN NYNTYRSRKY 121 TSWYVALKRT GQYKLGSKTG PGQKAILFLP MSAKS Amino acid sequence of Equus caballus (horse) FGF2 (SEQ ID NO: 129) (GenBank accession no. NP_001182150, which is hereby incorporated by reference in its entirety): 1 MAAGSITTLP ALPEDGGSGA FPPGHFKDPK RLYCKNGGFF LRIHPDGRVD GVREKSDPHI 61 KLQLQAEERG VVSIKGVCAN RYLAMKEDGR LLASKCVTDE CFFFERLESN NYNTYRSRKY 121 SSWYVALKRT GQYKLGPKTG PGQKAILFLP MSAKS Amino acid sequence of Bos taurus (cattle) FGF2 (SEQ ID NO: 130) (GenBank accession no. NP_776481, which is hereby incorporated by reference in its entirety): 1 MAAGSITTLP ALPEDGGSGA FPPGHFKDPK RLYCKNGGFF LRIHPDGRVD GVREKSDPHI 61 KLQLQAEERG VVSIKGVCAN RYLAMKEDGR LLASKCVTDE CFFFERLESN NYNTYRSRKY 121 SSWYVALKRT GQYKLGPKTG PGQKAILFLP MASKS Amino acid sequence of Papio anubis (Olive baboon) FGF2 (SEQ ID NO: 131) (GenBank accession no. XP_003899210, which is hereby incorporated by reference in its entirety): 1 MAAGSITTLP ALPEDGGSGA FPPGHFKDPK RLYCKNGGFF LRIHPDGRVD GVREKSDPHI 61 KLQLQAEERG VVSIKGVCAN RYLAMKEDGR LLASKCVTDE CFFFERLESN NYNTYRSRKY 121 TSWYVALKRT GQYKLGSKTG PGQKAILFLP MSAKS Amino acid sequence of Vicugna pacos (alpaca) FGF2 (SEQ ID NO: 132) (Ensembl accession no. ENSVPAP00000009804, which is hereby incorporated by reference in its entirety): 111 MAAGSITTLP 121 ALPEDGGSGA FPPGHFKDPK RLYCKNGGFF LRIHPDGRVD GVREKSDPHI KLQLQAEERG 181 VVSIKGVCAN RYLAMKEDGR LLASKCVTDE CFFFERLESN NYNTYRSRKY SSWYVALKRT 241 GQYKLGPKTG PGQKAILFLP MSAKS Amino acid sequence of Ovis aries (sheep) FGF2 (SEQ ID NO: 133) (GenBank accession no. NP_001009769, which is hereby incorporated by reference in its entirety): 1 MAAGSITTLP ALPEDGGSSA FPPGHFKDPK RLYCKNGGFF LRIHPDGRVD GVREKSDPHI 61 KLQLQAEERG VVSIKGVCAN RYLAMKEDGR LLASKCVTDE CFFFERLESN NYNTYRSRKY 121 SSWYVALKRT GQYKLGPKTG PGQKAILFLP MSAKS Amino acid sequence of Capreolus capreolus (Western roe deer) FGF2 (partial amino acid sequence corresponding to human FGF2 residues 42 to 149)(SEQ ID NO: 134) (GenBank accession no. AAF73226, which is hereby incorporated by reference in its entirety): 1 RIHPDGRVDG VREKSDPHIK LQLQAEERGV VSIKGVCANR YLAMKEDGRL LASKCVTDEC 61 FFFERLESNN YNTYRSRKYS SWYVALKRTG QYKLGPKTGP GQKAILFL Amino acid sequence of Loxodonta africana (elephant) FGF2 (partial amino acid sequence corresponding to human FGF2 residues 60 to 155) (SEQ ID NO: 135) (Ensembl accession no. ENSLAFP00000008249, which is hereby incorporated by reference in its entirety): 1 VKLQLQAEER GVVSIKGVCA NRYLAMKEDG RLLASRCVTD ECFFFERLES NNYNTYRSRK 61 YTSWYVALKR TGQYKLGSKT GPGQKAILFL PMSAKS Amino acid sequence of Sus scrofa (pig) FGF2 (partial amino acid sequence corresponding to human FGF residues 36 to 155) (SEQ ID NO: 136) (GenBank accession no. CAE11791 and Ensembl accession no. ENSSSCP00000009695, which is hereby incorporated by reference in its entirety): 1 NGGFFLRIHP DGRVDGVREK SDPHIKLQLQ AEERGVVSIK GVCANRYLAM KEDGRLLASK 61 CVTDECFFFE RLESNNYNTY RSRKYSSWYV ALKRTGQYKL GPKTGPGQKA ILFLPMSAKS Amino acid sequence of Ailuropoda melanoleuca (panda) FGF2 (partial amino acid sequence corresponding to human FGF2 residues 60 to 155)(SEQ ID NO: 137) (Ensembl accession no. ENSAMEP00000018489, which is hereby incorporated by reference in its entirety): 1 VKLQLQAEER GVVSIKGVCA NRYLAMKEDG RLLASKCVTD ECFFFERLES NNYNTYRSRK 61 YSSWYVALKR TGQYKLGPKT GPGQKAILFL PMSAKS Amino acid sequence of Choloepus hoffmanni (sloth) FGF2 (SEQ ID NO: 138) (Ensembl accession no. ENSCHOP00000010051, which is hereby incorporated by reference in its entirety): 14 MAAGSIT 21 TLPALPEDGG SGALPPGHFK DPKRLYCKNG GFFLRIHPDG RVDGVREKSD PHIKLQLQAE 81 ERGVVSIKGV CANRYLAMKE DGRLQASKCV TDECFFFERL ESNNYNTYRS RKYSSWYVAL 141 KRTGQYKLGP KTGPGQKAIL FLPMSAKS Amino acid sequence of Bubalus bubalis (water buffalo) FGF2 (SEQ ID NO: 139) (GenBank accession no. AFH66795, which is hereby incorporated by reference in its entirety): 1 MAAGSITTLP PLPEDGGSGA FPPGHFKDPK RLYCKNGGFF LRIHPDGRVD GVREKSDPHI 61 KLQLQAEERG VVSIKGVCAN RYLAMKEDGR LLASKCVTDE CFFFERLESS NYNTYRSRKY 121 SSWYVALKRT GQYKLGPKTG PGQKAILFLP MSAKS Amino acid sequence of Canis lupus familiaris (dog) FGF2 (SEQ ID NO: 140) (GenBank accession no. XP_003432529, which is hereby incorporated by reference in its entirety): 40 M AAGSITTLPA LPEDGGSGAF 61 PPGHFKDPKR LYCKKGGFFL RIHPDGRVDG VREKSDPHVK LQLQAEERGV VSIKGVCANR 121 YLAMKEDGRL LASKCVTDEC FFFERLESNN YNTYRSRKYS SWYVALKRTG QYKLGPKTGP 181 GQKAILFLPM SAKS Amino acid sequence of Rattus norvegicus (Norway rat) FGF2 (SEQ ID NO: 141) (GenBank accession no. NP_062178, which is hereby incorporated by reference in its entirety): 1 MAAGSITSLP ALPEDGGGAF PPGHFKDPKR LYCKNGGFFL RIHPDGRVDG VREKSDPHVK 61 LQLQAEERGV VSIKGVCANR YLAMKEDGRL LASKCVTEEC FFFERLESNN YNTYRSRKYS 121 SWYVALKRTG QYKLGSKTGP GQKAILFLPM SAKS Amino acid sequence of Heterocephalus glaber (naked mole-rat) FGF2 (partial amino acid sequence corresponding to human FGF2 residues 22 to 155) (SEQ ID NO: 142) (GenBank accession no. EHB17407, which is hereby incorporated by reference in its entirety): 1 ppghfkdpkr lycknggffl rihpdgrvdg vreksdphvk lqlqaeergv vsikgvcanr 61 ylamkedgrl laskcvtdec ffferlesnn yntyrsrkys swyvalkrtg qyklgsktgp 121 gqkailflpm saks Amino acid sequence of Otolemur garnettii (bushbaby) FGF2 (SEQ ID NO: 143) (Ensembl accession no. ENSOGAP00000021960, which is hereby incorporated by reference in its entirety): 52 MAAGSITTL 61 PSLPEDGGSD AFPPGHFKDP KRLYCKNGGF FLRIHPDGRV DGVREKSDPY IKLQLQAEER 121 GVVSIKGVCA NRYLAMKEDG RLLASKLITD ECFFFERLES NNYNTYRSRK YSSWYVALKR 181 TGQYKLGSKT GPGQKAILFL PMSAKS Amino acid sequence of Mus musculus (house mouse) FGF2 (SEQ ID NO: 144) (GenBank accession no. NP_032032, which is hereby incorporated by reference in its entirety): 1 MAASGITSLP ALPEDGGAAF PPGHFKDPKR LYCKNGGFFL RIHPDGRVDG VREKSDPHVK 61 LQLQAEERGV VSIKGVCANR YLAMKEDGRL LASKCVTEEC FFFERLESNN YNTYRSRKYS 121 SWYVALKRTG QYKLGSKTGP GQKAILFLPM SAKS Amino acid sequence of Ictidomys tridecemlineatus (squirrel) FGF2 (partial amino acid sequence corresponding to human FGF2 residues 12 to 155) (SEQ ID NO: 145) (Ensembl accession no. EN55T0P00000015653, which is hereby incorporated by reference in its entirety): 1 LPEDGGGGAF PPGHFKDPKR LYCKNGGFFL RIHPDGRVDG VREKSDPHIK LQLQAEDRGV 61 VSIKGVCANR YLAMKEDGRL LASKCVTDEC FFFERLESNN YNTYRSRKYS SWYVALKRTG 121 QYKLGSKTGP GQKAILFLPM SAKS Amino acid sequence of Felis catus (domestic cat) FGF2 (partial amino acid sequence corresponding to human FGF2 residues 25 to 130) (SEQ ID NO: 146) (GenBank accession no. ABY47638, which is hereby incorporated by reference in its entirety): 1 HFKDPKRLYC KNGGFFLRIH PDGRVDGVRE KSDPHIKLQL QAEERGVVSI KGVCANRYLA 61 MKEDGRLLAS KCVTDECFFF ERLESNNYNT YRSRKYSSWY VALKRT Amino acid sequence of Cavia porcellus (guinea pig) FGF2 (partial amino acid sequence corresponding to human FGF2 residues 60 to 155) (SEQ ID NO: 147) (Ensembl accession no. ENSCPOP00000004847, which is hereby incorporated by reference in its entirety): 1 VKLQLQAEDR GVVSIKGVCA NRYLAMKEDG RLLASKCVTD ECFFFERLES NNYNTYRSRK 61 YSSWYVALKR TGQYKLGSKT GPGQKAILFL PMSAKS Amino acid sequence of Sarcophilus harrisii (Tasmanian devil) FGF2 (SEQ ID NO: 148) (Ensembl accession no. EN55HAP00000012215, which is hereby incorporated by reference in its entirety): 48 MAA GSITTLPALA 61 GDGASGGAFP PGHFQDPKRL YCKNGGFFLR IHPDGHVDGI REKSDPHIKL QLQAEERGVV 121 SIKGVCANRY LAMKEDGRLL ALKCVTEECF FFERLESNNY NTYRSRKYSN WYVALKRTGQ 181 YKLGSKTGPG QKAILFLPMS AKS Amino acid sequence of Monodelphis domestica (gray short-tailed opossum) FGF2 (SEQ ID NO: 149) (GenBank accession no. NP_001029148, which is hereby incorporated by reference in its entirety): 1 MAAGSITTLP ALSGDGGGGG AFPPGHFKDP KRLYCKNGGF FLRIHPDGRV DGIREKSDPN 61 IKLQLQAEER GVVSIKGVCA NRYLAMKEDG RLLALKYVTE ECFFFERLES NNYNTYRSRK 121 YSNWYVALKR TGQYKLGSKT GPGQKAILFL PMSAKS Amino acid sequence of Oryctolagus cuniculus (rabbit) FGF2 (SEQ ID NO: 150) (GenBank accession no. XP_002717284, which is hereby incorporated by reference in its entirety): 1 MAAESITTLP ALPEDGGSGA FPPGHFKDPK RLYCKNGGFF LRIHPDGRVD GVREKSDPHI 61 KLQLQAEERG VVSIKGVCAN RYLAMKEDGR LLASKCVTDE CFFFERLESN NYNTYRSRKY 121 SSWYVALKRT GQYKLGSKTG PGQKAILFLP MSAKS Amino acid sequence of Meleagris gallopavo (turkey) FGF2 (partial amino acid sequence corresponding to human FGF2 residues 31 to 155) (SEQ ID NO: 151) (Ensembl accession no. ENSMGAP00000010977, which is hereby incorporated by reference in its entirety): 1 RLYCKNGGFF LRINPDGRVD GVREKSDPHI KLQLQAEERG VVSIKGVSAN RFLAMKEDGR 61 LLALKCATEE CFFFERLESN NYNTYRSRKY SDWYVALKRT GQYKPGPKTG PGQKAILFLP 121 MSAKS Amino acid sequence of Gallus gallus (chicken) FGF2 (SEQ ID NO: 152) (GenBank accession no. NP_990764 1 maagaagsit tlpalpddgg ggafppghfk dpkrlyckng gfflrinpdg rvdgvreksd 61 PHIKLQLQAE ERGVVSIKGV SANRFLAMKE DGRLLALKCA TEECFFFERL ESNNYNTYRS 121 RKYSDWYVAL KRTGQYKPGP KTGPGQKAIL FLPMSAKS Amino acid sequence of Taeniopygia guttata (zebra finch) FGF2 (SEQ ID NO: 153) (GenBank accession no. XP_002188397, which is hereby incorporated by reference in its entirety): 1 MAAAGGIATL PDDGGSGAFP PGHFKDPKRL YCKNGGFFLR INPDGKVDGV REKSDPHIKL 61 QLQAEERGVV SIKGVSANRF LAMKEDGRLL ALKYATEECF FFERLESNNY NTYRSRKYSD 121 WYVALKRTGQ YKPGPKTGPG QKAILFLPMS AKS Amino acid sequence of Cynops pyrrhogaster (Japanese firebelly newt) FGF2 (SEQ ID NO: 154) (GenBank accession no. BAB63249, which is hereby incorporated by reference in its entirety): 1 MAAGSITSLP ALPEDGNGGT FTPGGFKEPK RLYCKNGGFF LRINSDGKVD GAREKSDSYI 61 KLQLQAEERG VVSIKGVCAN RYLAMKDDGR LMALKWITDE CFFFERLESN NYNTYRSRKY 121 SDWYVALKRT GQYKNGSKTG AGQKAILFLP MSAKS Amino acid sequence of Xenopus laevis (African clawed frog) FGF2 (SEQ ID NO: 155) (GenBank accession no. NP_001093341, which is hereby incorporated by reference in its entirety): 1 MAAGSITTLP TESEDGGNTP FSPGSFKDPK RLYCKNGGFF LRINSDGRVD GSRDKSDSHI 61 KLQLQAVERG VVSIKGITAN RYLAMKEDGR LTSLRCITDE CFFFERLEAN NYNTYRSRKY

121 SSWYVALKRT GQYKNGSSTG PGQKAILFLP MSAKS Amino acid sequence of Didelphis albiventris (white-eared opossum) FGF2 (SEQ ID NO: 156) (GenBank accession no. ABL77404, which is hereby incorporated by reference in its entirety): 1 MAAGSITTLP ALSGDGGGGG AFPPGHFKDP KRLYCKNGGF FLRIHPDGRV DGIREKSDPN 61 IKLQLQAEER GVVSIKGVCA NRYLAMKEDG RLLALKYVTE ECFFFERLES NNYNTYRSRK 121 YSNWYVALKR TGQYKLGSKT GPGQKAILFS PCLLRC Amino acid sequence of Myotis lucifugus (microbat) FGF2 (partial amino acid sequence corresponding to human FGF2 residues 60 to 155) (SEQ ID NO: 157) (Ensembl accession no. ENSMLUP00000017859, which is hereby incorporated by reference in its entirety): 1 VKLQLQAEER GVVSIKGVCA NRYLAMKEDG RLQASKCVTD ECFFFERLES NNYNTYRSRK 61 YSSWYVALKR NGQYKLGPKT GPGQKAILFL PMSAKS Amino acid sequence of Anolis carolinensis (anole lizard) FGF2 (partial amino acid sequence corresponding to human FGF2 residues 16 to 155) (SEQ ID NO: 158) (Ensembl accession no. ENSACAP00000011657, which is hereby incorporated by reference in its entirety): 1 AAAASFPPGP FKDPKRLYCK NGGFFLRINP DGGVDGVREK SDPNIKLLLQ AEERGVVSIK 61 GVCANRFLAM NEDGRLLALK YVTDECFFFE RLESNNYNTY RSRKYRDWYI ALKRTGQYKL 121 GPKTGRGQKA ILFLPMSAKS Amino acid sequence of Dasypus novemcinctus (armadillo) FGF2 (partial amino acid sequence corresponding to human FGF2 residues 1 to 94) (SEQ ID NO: 159) (Ensembl accession no. ENSDNOP00000011351, which is hereby incorporated by reference in its entirety): 124 MAAGSIT TLPALPEDGG SGAFPPGHFK DPKRLYCKNG GFFLRIHPDG RVDGVREKSD 181 PNIKLQLQAE ERGVVSIKGV CANRYLAMRE DGRLQAS Amino acid sequence of Tupaia belangeri (tree shrew) FGF2 (SEQ ID NO: 160) (Ensembl accession no. ENSTBEP00000000985, which is hereby incorporated by reference in its entirety): 1 AGVRAEREEA PGSGDSRGTD PAARSLIRRP DAAAREALLG ARSRVQGSST SWPASSRTGI 61 KLPDDSGQGM GGYPLDRPSR STGRGLGGAP DPAVKLQLQA EERGVVSIKG VCANRYLAMK 121 EDGRLLASKC VTDECFFFER LESNNYNTYR SRKYSSWYVA LKRTGQYKLG SKTGPGQKAI 181 LFLPMSAKS Amino acid sequence of Xenopus silurana tropicalis (western clawed frog) FGF2 (SEQ ID NO: 161) (GenBank accession no. NP_001017333, which is hereby incorporated by reference in its entirety): 1 MAAGSITTLP TESEDGNTPF PPGNFKDPKR LYCKNGGYFL RINSDGRVDG SRDKSDLHIK 61 LQLQAVERGV VSIKGITANR YLAMKEDGRL TSLKCITDEC FFYERLEANN YNTYRSRKNN 121 SWYVALKRTG QYKNGSTTGP GQKAILFLPM SAKS Amino acid sequence of Latimeria chalumnae (coelacanth) FGF2 (SEQ ID NO: 162) (Ensembl accession no. ENSLACP00000019200, which is hereby incorporated by reference in its entirety): 1 MAAGGITTLP AVPEDGGSST FPPGNFKEPK RLYCKNGGYF LRINPDGRVD GTREKNDPYI 61 KLQLQAESIG VVSIKGVCSN RYLAMNEDCR LFGLKYPTDE CFFHERLESN NYNTYRSKKY 121 SDWYVALKRT GQYKPGPKTG LGQKAILFLP MSAKS Amino acid sequence of Tetraodon nigroviridis (spotted green pufferfish) FGF2 (SEQ ID NO: 163) (GenBank accession no. CAG04681, which is hereby incorporated by reference in its entirety): 34 MATGGIT TLPSTPEDGG SSGFPPGSFK 61 DPKRLYCKNG GFFLRIKSDG VVDGIREKSD PHIKLQLQAT SVGEVVIKGV CANRYLAMNR 121 DGRLFGTKRA TDECHFLERL ESNNYNTYRS RKYPTMFVGL TRTGQYKSGS KTGPGQKAIL 181 FLPMSAKC Amino acid sequence of Gasterosteus aculeatus (stickleback) FGF2 (SEQ ID NO: 164) (Ensembl accession no. ENSGACP00000022078, which is hereby incorporated by reference in its entirety): 1 MATAGFATLP STPEDGGSGG FTPGGFKDPK RLYCKNGGFF LRIRSDGGVD GIREKSDAHI 61 KLQIQATSVG EVVIKGVCAN RYLAMNRDGR LFGVRRATDE CYFLERLESN NYNTYRSRKY 121 PGMYVALKRT GQYKSGSKTG PGQKAILFLP MSAKC Amino acid sequence of Takifugu rubripes (fugu rubripes) FGF2 (SEQ ID NO: 165) (GenBank accession no. CAD19830, which is hereby incorporated by reference in its entirety): 1 MATGGITTLP STPEDGGSGG FPPGSFKDPK RLYCKNGGFF LRIRSDGAVD GTREKTDPHI 61 KLQLQATSVG EVVIKGVCAN RYLAMNRDGR LFGMKRATDE CHFLERLESN NYNTYRSRKY 121 PNMFVGLTRT GNYKSGTKTG PCQKAILFLP MSAKY Amino acid sequence of Oncorhynchus mykiss (rainbow trout) FGF2 (SEQ ID NO: 166) (GenBank accession no. NP_001118008, which is hereby incorporated by reference in its entirety): 1 MATGEITTLP ATPEDGGSGG FLPGNFKEPK RLYCKNGGYF LRINSNGSVD GIRDKNDPHN 61 KLQLQATSVG EVVIKGVSAN RYLAMNADGR LFGPRRTTDE CYFMERLESN NYNTYRSRKY 121 PEMYVALKRT GQYKSGSKTG PGQKAILFLP MSARR Amino acid sequence of Salmo salar (salmon) FGF2 (SEQ ID NO: 167) (GenBank accession no. ACJ02099, which is hereby incorporated by reference in its entirety): 1 MATGEITTLP ATPEDGGSGG FPPGNFKDPK RLYCKNGGYF LRINSNGSVD GIREKNDPHK 61 QPQFVRAWTL QGVKRSTGML AHVDSNASHN CVKVAGCSLG EFGSMSNRPH NRRPRVATPA 121 QDLHIRLLHL RDRLKPATRT ADKTEEYFCL Amino acid sequence of Danio rerio (zebrafish) FGF2 (SEQ ID NO: 168) (GenBank accession no. AAP32155, which is hereby incorporated by reference in its entirety): 1 MATGGITTLP AAPDAENSSF PAGSFRDPKR LYCKNGGFFL RINADGRVDG ARDKSDPHIR 61 LQLQATAVGE VLIKGICTNR FLAMNADGRL FGTKRTTDEC YFLERLESNN YNTYRSRKYP 121 DWYVALKRTG QYKSGSKTSP GQKAILFLPM SAKC Amino acid sequence of Oreochromis niloticus (Nile tilapia) FGF2 (SEQ ID NO: 169) (GenBank accession no. XP_003443412, which is hereby incorporated by reference in its entirety): 1 MATGGITTLP ATPEDGGSSG FPPGNFKDPK RLYCKNGGFF LRIKSDGGVD GIREKNDPHI 61 KLQLQATSVG EVVIKGICAN RYLAMNRDGR LFGARRATDE CYFLERLESN NYNTYRSRKY 121 PNMYVALKRT GQYKSGSKTG PGQKAILFLP MSAKC Amino acid sequence of Oryzias latipes (medaka) FGF2 (SEQ ID NO: 170) (Ensembl accession no. EN50RLP00000025834, which is hereby incorporated by reference in its entirety): 1 MATGEITTLP SPAENSRSDG FPPGNYKDPK RLYCKNGGLF LRIKPDGGVD GIREKKDPHV 61 KLRLQATSAG EVVIKGVCSN RYLAMHGDGR LFGVRQATEE CYFLERLESN NYNTYRSKKY 121 PNMYVALKRT GQYKPGNKTG PGQKAILFLP MSAKY

As noted above, the portion of the paracrine FGF may be modified to decrease binding affinity for heparin and/or heparan sulfate compared to the portion without the modification. In one embodiment, the modification of the paracrine FGF includes one or more substitutions, additions, or deletions.

In one embodiment, the modification is one or more substitutions located at one or more amino acid residues of SEQ ID NO: 121 selected from N36, K128, R129, K134, K138, Q143, K144, C78, C96, and combinations thereof. In one embodiment, the one or more substitutions are selected from N36T, K128D, R129Q, K134V, K138H, Q143M, K144T/L/I, C78S, C96S, and combinations thereof. In one embodiment, the modification is one or more substitutions which are located at one or more amino acid residues corresponding to residues of SEQ ID NO: 121 selected from N36, K128, R129, K134, K138, Q143, K144, C78, C96, and combinations thereof. In one embodiment, the modification is one or more substitutions which are located at one or more amino acid residues corresponding to residues of SEQ ID NO: 121 selected from N36, K128, R129, K134, K138, Q143, K144, C78, C96, and combinations thereof. Amino acid residues corresponding to those of SEQ ID NO: 121 may be determined by, for example, sequence analysis and structural analysis.

It will be understood that the portion of the paracrine FGF according to the present invention may be derived from a nucleotide sequence that encodes a paracrine FGF protein. For example, in one embodiment, nucleotide sequence is the nucleotide sequence that encodes human FGF2 (GenBank Accession No. NM_002006, which is hereby incorporated by reference in its entirety)(SEQ ID NO: 171), as follows:

TABLE-US-00007 468 ATG GCAGCCGGGA 481 GCATCACCAC GCTGCCCGCC TTGCCCGAGG ATGGCGGCAG CGGCGCCTTC CCGCCCGGCC 541 ACTTCAAGGA CCCCAAGCGG CTGTACTGCA AAAACGGGGG CTTCTTCCTG CGCATCCACC 601 CCGACGGCCG AGTTGACGGG GTCCGGGAGA AGAGCGACCC TCACATCAAG CTACAACTTC 661 AAGCAGAAGA GAGAGGAGTT GTGTCTATCA AAGGAGTGTG TGCTAACCGT TACCTGGCTA 721 TGAAGGAAGA TGGAAGATTA CTGGCTTCTA AATGTGTTAC GGATGAGTGT TTCTTTTTTG 781 AACGATTGGA ATCTAATAAC TACAATACTT ACCGGTCAAG GAAATACACC AGTTGGTATG 841 TGGCACTGAA ACGAACTGGG CAGTATAAAC TTGGATCCAA AACAGGACCT GGGCAGAAAG 901 CTATACTTTT TCTTCCAATG TCTGCTAAGA GCTGA

In another embodiment of the present invention, the portion of the paracrine FGF of the chimeric protein may be derived from a nucleotide sequence that encodes an ortholog of human FGF2. Nucleotide sequences that encode FGF2 orthologs are shown in Table 4.

TABLE-US-00008 TABLE 4 Gorilla FGF2 gene coding sequence (amino acids ("aa") 104-258) (SEQ ID NO: 172) (Ensembl accession no. ENSGGOT00000004842, which is hereby incorporated by reference in its entirety): 310 ATGGCAGCC GGGAGCATCA CCACGCTGCC CGCCTTGCCC GAGGATGGCG 359 GCAGCGGCGC CTTCCCGCCC GGCCACTTCA AGGACCCCAA GCGGCTGTAC TGCAAAAACG 419 GGGGCTTCTT CCTGCGCATC CACCCCGACG GCCGAGTTGA CGGGGTCCGG GAGAAGAGCG 479 ACCCTCACAT CAAGCTACAA CTTCAAGCAG AAGAGAGAGG AGTTGTGTCT ATCAAAGGAG 539 TGTGTGCTAA CCGTTACCTT GCTATGAAGG AAGATGGAAG ATTACTGGCT TCTAAATGTG 599 TTACGGATGA GTGTTTCTTT TTTGAACGAT TGGAATCTAA TAACTACAAT ACTTACCGGT 659 CAAGGAAATA CACCAGTTGG TATGTGGCAC TGAAACGAAC TGGGCAGTAT AAACTTGGAT 719 CCAAAACAGG ACCTGGGCAG AAAGCTATAC TTTTTCTTCC AATGTCTGCT AAGAGCTGA Sumatran orangutan FGF2 gene coding sequence (aa 168-322) (SEQ ID NO: 173) (GenBank accession no. XM_002815126, which is hereby incorporated by reference in its entirety): 504 ATGGCAG CCGGGAGCAT CACCACGCTG CCCGCCTTGC 541 CCGAGGATGG CGGCAGCGGC GCCTTCCCGC CGGGCCACTT CAAGGACCCC AAGCGGCTGT 601 ACTGCAAAAA CGGGGGCTTC TTCCTGCGCA TCCACCCCGA CGGCCGAGTT GACGGGGTCC 661 GAGAGAAGAG CGACCCTCAC ATCAAACTAC AACTTCAAGC AGAAGAAAGA GGAGTTGTGT 721 CTATCAAAGG AGTGTGTGCT AACCGCTACC TTGCTATGAA GGAAGATGGA AGATTACTGG 781 CTTCTAAATG TGTTACGGAT GAGTGTTTCT TTTTTGAACG ATTGGAATCT AATAACTACA 841 ATACTTACCG GTCAAGGAAA TACACCAGTT GGTATGTGGC ACTGAAACGA ACTGGGCAGT 901 ATAAACTTGG ATCCAAAACA GGACCTGGGC AGAAAGCTAT ACTTTTTCTT CCAATGTCTG 961 CTAAGAGCTG A Rhesus monkey FGF2 gene coding sequence (aa 83-237) (SEQ ID NO: 174) (GenBank accession no. XM_001099284, which is hereby incorporated by reference in its entirety): 247 ATGG CAGCCGGGAG CATCACCACG CTGCCCGCCT TGCCCGAGGA TGGCGGCAGC 301 GGCGCCTTCC CGCCTGGCCA CTTCAAGGAC CCCAAGCGGC TGTACTGCAA AAACGGGGGC 361 TTCTTCCTGC GCATTCACCC CGACGGCCGA GTTGACGGGG TCCGGGAGAA GAGCGACCCT 421 CACATCAAAT TACAACTTCA AGCAGAAGAG AGAGGAGTTG TGTCTATCAA AGGAGTGTGT 481 GCTAACCGTT ACCTTGCTAT GAAGGAAGAT GGAAGATTAC TGGCTTCTAA ATGTGTTACA 541 GATGAGTGTT TCTTTTTTGA ACGATTGGAA TCTAATAACT ACAATACTTA CCGGTCAAGG 601 AAATACACCA GTTGGTATGT GGCACTGAAA CGAACTGGGC AATATAAACT TGGATCCAAA 661 ACAGGACCTG GGCAGAAAGC TATACTTTTT CTTCCAATGT CTGCTAAGAG CTGA Chimpanzee FGF2 gene coding sequence (aa 134-288) (SEQ ID NO: 175) (GenBank accession no. NM_001110241, which is hereby incorporated by reference in its entirety): 400 A TGGCAGCCGG GAGCATCACC 421 ACGCTGCCCG CCTTGCCCGA GGATGGCGGC AGCGGCGCCT TCCCGCCCGG CCACTTCAAG 481 GACCCCAAGC GGCTGTACTG CAAAAACGGG GGCTTCTTCC TGCGCATCCA CCCCGACGGC 541 CGAGTTGACG GGGTCCGGGA GAAGAGCGAC CCTCACATCA AGCTACAACT TCAAGCAGAA 601 GAGAGAGGAG TTGTGTCTAT CAAAGGAGTG TGTGCTAACC GTTACCTTGC TATGAAGGAA 661 GATGGAAGAT TACTGGCTTC TAAATGTGTT ACGGATGAGT GTTTCTTTTT TGAACGATTG 721 GAATCTAATA ACTACAATAC TTACCGGTCA AGGAAATACA CCAGTTGGTA TGTGGCACTG 781 AAACGAACTG GGCAGTATAA ACTTGGATCC AAAACAGGAC CTGGGCAGAA AGCTATACTT 841 TTTCTTCCAA TGTCTGCTAA GAGCTGA Pygmy chimpanzee FGF2 gene coding sequence (112-266) (SEQ ID NO: 176) (GenBank accession no. XM_003816433, which is hereby incorporated by reference in its entirety): 334 ATGGCAG CCGGGAGCAT CACCACGCTG 361 CCCGCCTTGC CCGAGGATGG CGGCAGCGGC GCCTTCCCGC CCGGCCACTT CAAGGACCCC 421 AAGCGGCTGT ACTGCAAAAA CGGGGGCTTC TTCCTGCGCA TCCACCCCGA CGGCCGAGTT 481 GACGGGGTCC GGGAGAAGAG CGACCCTCAC ATCAAGCTAC AACTTCAAGC AGAAGAGAGA 541 GGAGTTGTGT CTATCAAAGG AGTGTGTGCT AACCGTTACC TTGCTATGAA GGAAGATGGA 601 AGATTACTGG CTTCTAAATG TGTTACGGAT GAGTGTTTCT TTTTTGAACG ATTGGAATCT 661 AATAACTACA ATACTTACCG GTCAAGGAAA TACACCAGTT GGTATGTGGC ACTGAAACGA 721 ACTGGGCAGT ATAAACTTGG ATCCAAAACA GGACCTGGGC AGAAAGCTAT ACTTTTTCTT 781 CCAATGTCTG CTAAGAGCTG A Bolivian squirrel monkey FGF2 gene coding sequence (1-155) (SEQ ID NO: 177) (GenBank accession no. XM_003936241, which is hereby incorporated by reference in its entirety): 23 ATGGCAGC CGGGAGCATC ACCACGCTGC CCGCCCTGCC 61 CGAAGACGGC GGCAGCGGCG CCTTCCCGCC CGGCCACTTC AAAGACCCCA AGCGGCTGTA 121 CTGCAAAAAC GGGGGCTTCT TCCTGCGAAT CCACCCCGAC GGCCGAGTGG ACGGGGTCCG 181 GGAGAAGAGC GACCCTCACA TCAAACTACA ACTTCAAGCA GAAGAGAGAG GAGTTGTATC 241 TATCAAAGGA GTGTGTGCTA ACCGTTACCT TGCTATGAAG GAAGATGGAA GATTACTGGC 301 TTCTAAATGT GTTACGGACG AGTGTTTCTT TTTTGAACGA TTGGAATCTA ATAACTACAA 361 TACTTACCGA TCAAGGAAAT ACACCAGTTG GTATGTGGCA CTGAAACGAA CTGGGCAGTA 421 TAAACTTGGA TCCAAAACAG GACCTGGGCA GAAAGCTATA CTTTTTCTTC CAATGTCTGC 481 TAAGAGCT GA Northern white-cheeked gibbon FGF2 gene coding sequence (aa 1-155) (SEQ ID NO: 178) (GenBank accession no. XM_003271356, which is hereby incorporated by reference in its entirety): 435 ATG GCAGCCGGGA 481 GCATCACCAC GCTGCCCGCC TTGCCGGAGG ATGGCGGCAG CGGCGCCTTC CCGCCCGGCC 541 ACTTCAAGGA CCCCAAGCGG CTGTACTGCA AAAACGGGGG TTTCTTCCTG CGCATCCACC 601 CCGACGGTCG AGTTGACGGG GTCCGGGAGA AGAGCGACCC TCACATCAAA CTACAACTTC 661 AAGCAGAAGA GAGAGGAGTT GTGTCTATCA AAGGAGTGTG TGCTAACCGT TACCTTGCTA 721 TGAAGGAAGA TGGAAGATTA CTGGCTTCTA AATGTGTTAC GGATGAGTGT TTCTTTTTTG 781 AACGATTGGA ATCTAATAAC TACAATACTT ACCGGTCAAG GAAATACACC AGTTGGTATG 841 TGGCACTGAA ACGAACTGGG CAGTATAAAC TTGGATCCAA AACAGGACCT GGGCAGAAAG 901 CTATACTTTT TCTTCCAATG TCTGCTAAGA GCTGA Horse FGF2 gene coding sequence (aa 1-155) (SEQ ID NO: 179) (GenBank accession no. NM_001195221, which is hereby incorporated by reference in its entirety): 54 ATGGCAG 61 CCGGGAGCAT CACCACGCTG CCCGCCCTGC CCGAGGACGG CGGCAGCGGC GCCTTCCCGC 121 CCGGCCACTT CAAGGACCCC AAGCGGCTCT ACTGCAAAAA CGGGGGCTTC TTCCTGCGCA 181 TCCACCCCGA CGGCCGAGTG GACGGGGTCC GGGAGAAGAG CGACCCTCAC ATCAAACTAC 241 AACTTCAAGC AGAAGAGAGA GGGGTTGTGT CTATCAAAGG AGTGTGTGCG AACCGTTATC 301 TTGCTATGAA GGAAGATGGA AGGTTACTGG CTTCTAAATG TGTTACGGAC GAGTGTTTCT 361 TTTTTGAACG ATTGGAATCT AATAACTACA ATACTTACCG GTCAAGGAAA TACTCCAGTT 421 GGTATGTGGC CCTGAAACGA ACGGGGCAGT ATAAACTTGG ACCCAAAACA GGACCTGGAC 481 AGAAAGCTAT ACTTTTTCTT CCAATGTCTG CTAAGAGCTG A Cattle FGF2 gene coding sequence (aa 1-155) (SEQ ID NO: 180) (GenBank accession no. NM_174056, which is hereby incorporated by reference in its entirety): 104 ATGGCCG CCGGGAGCAT 121 CACCACGCTG CCAGCCCTGC CGGAGGACGG CGGCAGCGGC GCTTTCCCGC CGGGCCACTT 181 CAAGGACCCC AAGCGGCTGT ACTGCAAGAA CGGGGGCTTC TTCCTGCGCA TCCACCCCGA 241 CGGCCGAGTG GACGGGGTCC GCGAGAAGAG CGACCCACAC ATCAAACTAC AACTTCAAGC 301 AGAAGAGAGA GGGGTTGTGT CTATCAAAGG AGTGTGTGCA AACCGTTACC TTGCTATGAA 361 AGAAGATGGA AGATTACTAG CTTCTAAATG TGTTACAGAC GAGTGTTTCT TTTTTGAACG 421 ATTGGAGTCT AATAACTACA ATACTTACCG GTCAAGGAAA TACTCCAGTT GGTATGTGGC 481 ACTGAAACGA ACTGGGCAGT ATAAACTTGG ACCCAAAACA GGACCTGGGC AGAAAGCTAT 541 ACTTTTTCTT CCAATGTCTG CTAAGAGCTG A Olive baboon FGF2 gene coding sequence (1-155) (SEQ ID NO: 181) (GenBank accession no. XM_003899161, which is hereby incorporated by reference in its entirety): 467 ATGG CAGCCGGGAG 481 CATCACCACG CTGCCCGCCT TGCCCGAGGA TGGCGGCAGC GGCGCCTTCC CGCCCGGCCA 541 CTTCAAGGAC CCCAAGCGGC TGTACTGCAA AAACGGGGGC TTCTTCCTGC GCATTCACCC 601 CGACGGCCGA GTTGACGGGG TCCGGGAGAA GAGCGACCCT CACATCAAAT TACAACTTCA 661 AGCAGAAGAG AGAGGAGTTG TGTCTATCAA AGGAGTGTGT GCTAACCGTT ACCTTGCTAT 721 GAAGGAAGAT GGAAGATTAC TGGCTTCTAA ATGTGTTACG GATGAGTGTT TCTTTTTTGA 781 ACGATTGGAA TCTAATAACT ACAATACTTA CCGGTCAAGG AAATACACCA GTTGGTATGT 841 GGCACTGAAA CGAACTGGGC AGTATAAACT TGGATCCAAA ACAGGACCTG GGCAGAAAGC 901 TATACTTTTT CTTCCAATGT CTGCTAAGAG CTGA Alpaca FGF2 gene coding sequence (aa 111-265) (SEQ ID NO: 182) (Ensembl accession no. ENSVPAT00000010536, which is hereby incorporated by reference in its entirety): 341 ATGGCAGCTG GGAGCATCAC CACGCTGCCC 361 GCCCTGCCGG AGGACGGCGG CAGCGGCGCC TTCCCGCCCG GCCACTTCAA GGACCCCAAG 421 CGGTTGTACT GCAAAAACGG GGGCTTCTTC CTGCGCATCC ACCCCGACGG CCGAGTGGAC 481 GGGGTCCGGG AGAAGAGCGA CCCTCACATC AAACTACAAC TTCAAGCAGA AGAGAGAGGG 541 GTCGTGTCTA TCAAAGGAGT GTGTGCAAAC CGTTACCTTG CTATGAAGGA AGATGGAAGA 601 TTACTGGCTT CTAAATGTGT CACAGACGAG TGTTTCTTTT TTGAACGATT GGAATCTAAT 661 AACTACAATA CTTACCGGTC AAGGAAATAC TCCAGTTGGT ATGTGGCACT GAAACGAACT 721 GGGCAGTACA AACTTGGACC CAAAACAGGA CCTGGGCAGA AAGCTATACT TTTCCTTCCA 781 ATGTCTGCTA AGAGCTGA Sheep FGF2 gene coding sequence (aa 1-155) (SEQ ID NO: 183) (GenBank accession no. NM_001009769, which is hereby incorporated by reference in its entirety): 1 ATGGCCGCCG GGAGCATCAC CACGCTGCCA GCCCTGCCGG AGGACGGCGG CAGCAGCGCT 61 TTCCCGCCCG GCCACTTTAA GGACCCCAAG CGGCTGTACT GCAAGAACGG GGGCTTCTTC 121 CTGCGCATCC ACCCCGACGG CCGAGTGGAC GGGGTCCGCG AGAAGAGCGA CCCTCACATC 181 AAACTACAAC TTCAAGCAGA AGAGAGAGGG GTTGTGTCTA TCAAAGGAGT GTGTGCAAAC 241 CGTTACCTTG CTATGAAAGA AGATGGAAGA TTACTAGCTT CTAAATGTGT TACAGACGAG 301 TGTTTCTTTT TTGAACGATT GGAGTCTAAT AACTACAATA CTTACCGGTC AAGGAAATAC 361 TCCAGTTGGT ATGTGGCACT GAAACGAACT GGGCAGTATA AACTTGGACC CAAAACAGGA 421 CCTGGGCAGA AAGCTATACT TTTTCTTCCA ATGTCTGCTA AGAGCTGA Western roe deer FGF2 gene coding sequence (1-108; partial amino acid sequence corresponding to human FGF2 residues 42 to 149) (SEQ ID NO: 184) (GenBank accession no. AF152587, which is hereby incorporated by reference in its entirety): 1 GCGCATCCAC CCCGACGGCC GAGTGGACGG GGTCCGCGAG AAGAGTGACC CTCACATCAA 61 ACTACAACTT CAAGCAGAAG AGAGAGGGGT TGTGTCTATC AAAGGAGTGT GTGCGAACCG 121 TTATCTTGCT ATGAAAGAAG ACGGAAGATT ATTGGCTTCA AAATGTGTTA CAGACGAATG 181 TTTCTTTTTT GAACGATTGG AGTCTAATAA CTACAATACT TACCGGTCAA GGAAATACTC 241 CAGTTGGTAT GTGGCACTGA AACGAACTGG GCAGTATAAA CTTGGACCCA AAACAGGACC 301 TGGGCAGAAA GCTATACTTT TTCTT Elephant FGF2 gene coding sequence (1-96; partial amino acid sequence corresponding to human FGF2 residues 60 to 155) (SEQ ID NO: 185) (Ensembl accession no. ENSLAFT00000008249, which is hereby incorporated by reference in its entirety): 1 GTTAAACTAC AGCTTCAAGC AGAAGAGAGA GGTGTTGTGT CTATCAAAGG AGTGTGTGCC 61 AACCGTTATC TGGCTATGAA GGAAGATGGA AGATTGCTGG CTTCTAGATG TGTGACAGAT 121 GAATGTTTCT TCTTTGAACG ACTGGAATCT AATAACTACA ATACTTACCG GTCAAGGAAA 181 TACACCAGTT GGTATGTGGC ACTGAAACGA ACGGGGCAGT ATAAACTTGG ATCCAAAACA 241 GGACCTGGAC AGAAAGCTAT ACTTTTTCTT CCCATGTCTG CTAAGAGC Pig FGF2 gene coding sequence (1-120; partial amino acid sequence corresponding to human FGF2 residues 36 to 155) (SEQ ID NO: 186) (GenBank accession no. AJ577089 and Ensembl accession no. EN555CT00000009952, which is hereby incorporated by reference in its entirety): 1 GAACGGGGGC TTCTTCCTGC GCATCCACCC CGACGGCCGA GTGGATGGGG TCCGGGAGAA 61 GAGCGACCCT CACATCAAAC TACAACTTCA AGCAGAAGAG AGAGGGGTTG TGTCTATCAA 121 AGGAGTGTGT GCAAACCGTT ATCTTGCTAT GAAGGAAGAT GGAAGATTAC TGGCTTCTAA 181 ATGTGTTACA GACGAGTGTT TCTTTTTTGA ACGACTGGAA TCTAATAACT ACAATACTTA 241 CCGGTCGAGG AAATACTCCA GTTGGTATGT GGCACTGAAA CGAACTGGGC AGTATAAACT 301 TGGACCCAAA ACAGGACCTG GGCAGAAAGC TATACTTTTT CTTCCAATGT CTGCTAAGAG 361 C Panda FGF2 gene coding sequence (1-96; partial amino acid sequence corresponding to human FGF2 residues 60 to 155) (SEQ ID NO: 187) (Ensembl accession no. ENSAMET00000019232, which is hereby incorporated by reference in its entirety): 1 GTCAAACTGC AACTTCAAGC GGAAGAGAGA GGGGTTGTAT CCATCAAAGG AGTATGTGCA 61 AATCGCTATC TTGCCATGAA GGAAGATGGA AGATTACTGG CTTCTAAATG TGTTACCGAT 121 GAGTGTTTCT TTTTTGAGCG ACTGGAATCT AATAACTACA ATACTTACCG GTCAAGGAAA 181 TACTCCAGTT GGTATGTGGC ACTGAAACGA ACTGGGCAGT ATAAACTTGG ACCCAAAACA 241 GGACCTGGGC AGAAAGCTAT ACTTTTTCTT CCAATGTCTG CTAAGAGC Sloth FGF2 gene coding sequence (aa 14-168) (SEQ ID NO: 188) (Ensembl accession no. EN5CH0T00000011394, which is hereby incorporated by reference in its entirety): 40 A TGGCAGCCGG GAGCATCACC 61 ACGCTGCCCG CCCTGCCCGA GGACGGAGGC AGCGGCGCCT TACCGCCCGG CCACTTCAAA 121 GATCCCAAGC GGCTCTACTG CAAAAACGGG GGCTTCTTCC TGCGTATCCA TCCCGACGGC 181 AGAGTGGACG GGGTCCGGGA GAAGAGCGAC CCCCACATCA AACTACAACT TCAAGCAGAA 241 GAGAGAGGGG TTGTGTCTAT CAAAGGTGTG TGTGCAAACC GATATCTTGC TATGAAGGAA 301 GATGGAAGAT TACAGGCTTC TAAATGTGTA ACGGACGAGT GTTTCTTTTT TGAACGATTG 361 GAATCTAATA ACTACAATAC GTACCGATCA AGGAAATACT CCAGTTGGTA TGTGGCACTG 421 AAACGAACTG GGCAATATAA ACTTGGACCC AAAACAGGAC CTGGGCAGAA AGCCATACTT 481 TTTCTTCCAA TGTCTGCTAA GAGCTGA Water buffalo FGF2 gene coding sequence (aa 1-155) (SEQ ID NO: 189) (GenBank accession no. JQ326277, which is hereby incorporated by reference in its entirety): 1 ATGGCCGCCG GGAGCATCAC CACGCTGCCA CCCCTGCCGG AGGACGGCGG CAGCGGCGCT 61 TTCCCGCCCG GCCACTTCAA GGACCCCAAG CGGCTGTACT GCAAGAACGG GGGCTTCTTC 121 CTGCGCATCC ACCCCGACGG CCGAGTGGAC GGGGTCCGCG AGAAGAGCGA CCCACACATC 181 AAACTACAAC TTCAAGCAGA AGAGAGAGGG GTTGTGTCTA TCAAAGGAGT GTGTGCAAAC 241 CGTTACCTTG CTATGAAAGA AGATGGAAGA TTACTAGCTT CCAAATGTGT TACAGACGAG 301 TGTTTCTTTT TTGAACGATT GGAGTCTAGT AACTACAATA CTTACCGGTC AAGGAAATAC 361 TCCAGTTGGT ATGTGGCACT GAAACGAACT GGGCAGTATA AACTTGGACC CAAAACAGGA 421 CCTGGGCAGA AAGCTATACT TTTTCTTCCA ATGTCTGCTA AGAGCTGA Dog FGF2 gene coding sequence (aa 40-194) (SEQ ID NO: 190) (GenBank accession no. XM_003432481, which is hereby incorporated by reference in its entirety): 118 ATG 121 GCAGCCGGGA GCATCACCAC GCTGCCCGCC CTGCCGGAGG ACGGCGGCAG CGGCGCCTTC 181 CCGCCCGGCC ACTTCAAGGA CCCCAAGAGG CTGTACTGCA AAAAAGGGGG CTTCTTCCTG 241 CGGATCCACC CCGACGGCCG GGTGGACGGG GTCCGGGAGA AGAGCGATCC CCACGTCAAA 301 TTGCAACTTC AAGCAGAAGA GAGAGGCGTT GTGTCCATCA AAGGAGTATG TGCAAATCGC 361 TATCTTGCTA TGAAGGAAGA TGGAAGATTA CTGGCTTCTA AATGTGTTAC TGACGAGTGC 421 TTCTTTTTTG AACGATTGGA ATCTAATAAC TACAATACTT ACCGGTCAAG GAAATACTCC 481 AGTTGGTATG TGGCACTGAA ACGAACTGGG CAGTATAAAC TTGGACCAAA AACAGGACCT 541 GGGCAGAAAG CTATACTTTT TCTTCCAATG TCTGCTAAGA GCTGA Norway rat FGF2 gene coding sequence (aa 1-154) (SEQ ID NO: 191) (GenBank accession no. NM_019305, which is hereby incorporated by reference in its entirety): 533 ATGGCTGC 541 CGGCAGCATC ACTTCGCTTC CCGCACTGCC GGAGGACGGC GGCGGCGCCT TCCCACCCGG 601 CCACTTCAAG GATCCCAAGC GGCTCTACTG CAAGAACGGC GGCTTCTTCC TGCGCATCCA 661 TCCAGACGGC CGCGTGGACG GCGTCCGGGA GAAGAGCGAC CCACACGTCA AACTACAGCT 721 CCAAGCAGAA GAGAGAGGAG TTGTGTCCAT CAAGGGAGTG TGTGCGAACC GGTACCTGGC 781 TATGAAGGAA GATGGACGGC TGCTGGCTTC TAAGTGTGTT ACAGAAGAGT GTTTCTTCTT

841 TGAACGCCTG GAGTCCAATA ACTACAACAC TTACCGGTCA CGGAAATACT CCAGTTGGTA 901 TGTGGCACTG AAACGAACTG GGCAGTATAA ACTCGGATCC AAAACGGGGC CTGGACAGAA 961 GGCCATACTG TTTCTTCCAA TGTCTGCTAA GAGCTGA Naked mole-rat FGF2 gene coding sequence (1-134; partial amino acid sequence corresponding to human FGF2 residues 22 to 155) (SEQ ID NO: 192) (GenBank accession no. JH173674, which is hereby incorporated by reference in its entirety): 378500 C CACCCGGCCA CTTCAAGGAC CCAAAGCGGC 378531 TGTACTGCAA AAACGGGGGC TTCTTCCTGC GCATCCACCC CGACGGCCGC 378581 GTGGACGGGG TCCGGGAGAA GAGCGACCCT CACG 418784 TCAAACT ACAACTTCAA GCAGAAGAGA GAGGAGTTGT GTCTATTAAG 418831 GGAGTGTGTG CGAACCGTTA CCTTGCTATG AAGGAAGATG GAAGATTACT 418881 GGCTTCT 433983 AAATGTGT TACAGATGAG TGTTTCTTTT TTGAACGATT GGAATCTAAT 434031 AACTACAATA CTTATCGGTC AAGGAAATAC TCCAGTTGGT ATGTGGCACT 434081 GAAACGAACT GGACAATATA AACTTGGATC CAAAACAGGA CCGGGGCAGA 434131 AAGCTATACT TTTTCTTCCA ATGTCTGCTA AGAGCTGA Bushbaby FGF2 gene coding sequence (aa 52-206) (SEQ ID NO: 193) (Ensembl accession no. EN50GAT00000025228, which is hereby incorporated by reference in its entirety): 154 ATGGCAG CCGGGAGCAT CACCACGCTG 181 CCCTCCCTGC CCGAGGACGG CGGCAGCGAC GCCTTTCCGC CCGGCCACTT CAAGGACCCC 241 AAGCGACTGT ACTGCAAAAA CGGGGGCTTC TTCCTGCGCA TCCACCCCGA CGGCCGAGTG 301 GACGGGGTCC GGGAGAAGAG CGACCCTTAC ATCAAACTAC AACTTCAAGC AGAAGAGAGA 361 GGAGTTGTGT CTATCAAAGG AGTGTGTGCG AACCGTTACC TTGCTATGAA GGAAGACGGA 421 AGATTGCTGG CTTCTAAATT GATTACAGAC GAGTGCTTCT TTTTTGAACG ACTGGAATCT 481 AATAACTACA ATACTTACCG GTCAAGAAAA TACTCCAGTT GGTATGTGGC ACTGAAACGA 541 ACTGGACAGT ATAAACTTGG ATCCAAAACA GGACCTGGGC AGAAAGCTAT ACTTTTTCTT 601 CCAATGTCTG CTAAGAGCTG A House mouse FGF2 gene coding sequence (aa 1-154) (SEQ ID NO: 194) (GenBank accession no. NM 008006, which is hereby incorporated by reference in its entirety): 198 ATG GCTGCCAGCG GCATCACCTC GCTTCCCGCA CTGCCGGAGG 241 ACGGCGGCGC CGCCTTCCCA CCAGGCCACT TCAAGGACCC CAAGCGGCTC TACTGCAAGA 301 ACGGCGGCTT CTTCCTGCGC ATCCATCCCG ACGGCCGCGT GGATGGCGTC CGCGAGAAGA 361 GCGACCCACA CGTCAAACTA CAACTCCAAG CAGAAGAGAG AGGAGTTGTG TCTATCAAGG 421 GAGTGTGTGC CAACCGGTAC CTTGCTATGA AGGAAGATGG ACGGCTGCTG GCTTCTAAGT 481 GTGTTACAGA AGAGTGTTTC TTCTTTGAAC GACTGGAATC TAATAACTAC AATACTTACC 541 GGTCACGGAA ATACTCCAGT TGGTATGTGG CACTGAAACG AACTGGGCAG TATAAACTCG 601 GATCCAAAAC GGGACCTGGA CAGAAGGCCA TACTGTTTCT TCCAATGTCT GCTAAGAGCT 661 GA Squirrel FGF2 gene coding sequence (1-144; partial amino acid sequence corresponding to human FGF2 residues 12 to 155) (SEQ ID NO: 195) (Ensembl accession no. ENSSTOT00000022105, which is hereby incorporated by reference in its entirety): 1 CTGCCCGAGG ACGGCGGCGG CGGCGCCTTC CCGCCCGGCC ACTTTAAGGA CCCCAAGCGG 61 CTCTACTGCA AAAACGGAGG CTTCTTCCTG CGCATCCACC CCGACGGCCG AGTGGACGGG 121 GTCCGGGAGA AGAGCGACCC CCACATCAAG CTCCAGCTTC AAGCCGAAGA CCGAGGGGTT 181 GTGTCCATCA AGGGAGTGTG TGCAAACCGA TACCTGGCCA TGAAGGAGGA CGGGAGGCTC 241 CTGGCTTCTA AATGTGTTAC GGACGAGTGT TTCTTTTTTG AACGACTGGA ATCAAATAAC 301 TACAATACTT ACCGGTCAAG GAAATACTCC AGTTGGTATG TGGCCCTGAA ACGAACAGGG 361 CAGTATAAAC TTGGATCCAA AACAGGACCT GGGCAGAAAG CTATACTTTT TCTTCCAATG 421 TCTGCTAAGA GC Domestic cat FGF2 gene coding sequence (1-106; partial amino acid sequence corresponding to human FGF2 residues 25 to 130) (SEQ ID NO: 196) (GenBank accession no. EU314952, which is hereby incorporated by reference in its entirety): 1 CCACTTCAAG GACCCCAAGC GTCTGTACTG CAAAAACGGG GGCTTCTTCC TGCGCATCCA 61 CCCCGACGGC CGAGTGGATG GGGTCCGGGA GAAGAGCGAC CCTCACATCA AACTGCAACT 121 TCAGGCAGAA GAGAGAGGGG TTGTGTCCAT CAAAGGAGTC TGTGCAAACC GCTATCTTGC 181 CATGAAGGAA GATGGAAGAT TACTGGCTTC TAAATGTGTT ACGGACGAGT GTTTCTTTTT 241 TGAACGATTG GAATCTAATA ACTACAATAC TTATCGGTCA AGGAAATACT CCAGCTGGTA 301 TGTGGCACTG AAACGAAC Guinea pig FGF2 gene coding sequence (1-96; partial amino acid sequence corresponding to human FGF2 residues 60 to 155) (SEQ ID NO: 197) (Ensembl accession no. ENSCPOT00000005443, which is hereby incorporated by reference in its entirety): 1 GTTAAACTAC AACTTCAAGC CGAAGACAGA GGAGTTGTGT CTATCAAGGG AGTCTGTGCG 61 AACCGTTACC TTGCTATGAA GGAAGACGGA AGATTATTGG CTTCCAAATG TGTTACAGAT 121 GAATGTTTCT TTTTTGAACG ACTGGAATCT AATAACTACA ACACTTACCG GTCAAGGAAA 181 TACTCCAGTT GGTATGTGGC ACTGAAACGA ACTGGACAAT ATAAACTTGG GTCCAAAACA 241 GGACCAGGGC AGAAAGCCAT ACTTTTTCTT CCAATGTCTG CGAAGAGC Tasmanian devil FGF2 gene coding sequence (aa 48-203) (SEQ ID NO: 198) (Ensembl accession no. EN55HAP00000012215, which is hereby incorporated by reference in its entirety): 142 ATGGCCGCG GGCAGCATCA CCACGTTGCC GGCCCTGGCC 181 GGGGATGGAG CCAGCGGGGG CGCCTTTCCC CCGGGCCACT TCCAGGACCC CAAGCGGCTG 241 TACTGCAAGA ACGGAGGCTT CTTCTTGCGC ATCCATCCCG ACGGTCACGT GGACGGCATC 301 CGCGAGAAGA GCGATCCGCA CATTAAACTT CAGCTTCAGG CAGAAGAGAG AGGAGTAGTG 361 TCTATTAAAG GAGTTTGTGC CAACCGCTAT CTTGCCATGA AAGAGGATGG CAGATTACTG 421 GCTCTGAAAT GTGTGACTGA AGAGTGTTTC TTCTTTGAAC GTCTAGAGTC CAACAATTAC 481 AACACTTATC GCTCAAGGAA ATACTCCAAT TGGTATGTGG CATTGAAACG CACAGGCCAG 541 TATAAGCTTG GATCCAAGAC TGGACCAGGG CAGAAAGCCA TCCTTTTCCT TCCCATGTCT 601 GCTAAGAGCT GA Gray short-tailed opossum FGF2 gene coding sequence (aa 1-155) (SEQ ID NO: 199) (GenBank accession no. NM_001033976, which is hereby incorporated by reference in its entirety): 29 AT GGCCGCAGGC AGCATCACCA CGCTGCCAGC 61 CCTGTCCGGG GACGGAGGCG GCGGGGGCGC CTTTCCCCCG GGCCACTTCA AGGACCCCAA 121 GCGGCTGTAC TGCAAGAACG GAGGCTTCTT CCTGCGCATC CACCCCGACG GCCGTGTGGA 181 CGGCATCCGC GAGAAGAGCG ACCCGAACAT TAAACTACAA CTTCAGGCAG AAGAGAGAGG 241 AGTGGTGTCT ATTAAAGGAG TATGTGCCAA TCGCTATCTT GCCATGAAGG AAGATGGAAG 301 ATTATTGGCT TTGAAATATG TGACCGAAGA GTGTTTCTTT TTCGAACGCT TGGAGTCCAA 361 CAACTACAAC ACTTATCGCT CGAGGAAATA TTCCAATTGG TACGTGGCAC TGAAACGAAC 421 GGGGCAGTAC AAGCTTGGAT CCAAGACTGG CCCGGGGCAG AAAGCCATCC TTTTCCTCCC 481 CATGTCTGCT AAGAGCTGA Rabbit FGF2 gene coding sequence (aa 1-155) (SEQ ID NO: 200) (GenBank accession no. XM_002717238, which is hereby incorporated by reference in its entirety): 1 ATGGCAGCCG AGAGCATCAC CACGCTGCCC GCCCTGCCGG AGGATGGAGG CAGCGGCGCC 61 TTCCCGCCCG GCCACTTCAA GGACCCCAAG CGGCTGTACT GCAAAAACGG GGGTTTCTTC 121 CTGCGTATCC ACCCCGACGG CCGCGTGGAC GGGGTCCGGG AGAAGAGCGA CCCACACATC 181 AAATTACAAC TTCAAGCAGA AGAGAGAGGA GTTGTATCCA TCAAAGGTGT GTGTGCAAAC 241 CGTTACCTTG CTATGAAGGA AGATGGAAGA CTGCTGGCTT CTAAATGTGT TACAGACGAG 301 TGCTTCTTTT TTGAACGACT GGAGTCTAAT AACTACAATA CTTACCGGTC AAGGAAATAT 361 TCCAGCTGGT ATGTGGCACT GAAACGAACT GGGCAGTATA AACTTGGATC CAAAACAGGA 421 CCTGGGCAGA AGGCTATACT TTTTCTTCCA ATGTCTGCTA AGAGCTGA Turkey FGF2 gene coding sequence (1-125; partial amino acid sequence corresponding to human FGF2 residues 31 to 155) (SEQ ID NO: 201) (Ensembl accession no. ENSMGAT00000011845, which is hereby incorporated by reference in its entirety): 1 CGGCTCTACT GTAAGAACGG CGGCTTCTTC CTGCGCATCA ATCCCGACGG CAGAGTGGAC 61 GGCGTCCGCG AGAAGAGCGA TCCGCACATC AAACTGCAGC TTCAGGCAGA AGAAAGAGGA 121 GTGGTATCAA TCAAAGGTGT AAGTGCAAAC CGCTTTCTGG CTATGAAGGA GGATGGCAGA 181 TTGCTGGCAC TGAAATGTGC AACAGAAGAA TGTTTCTTTT TTGAGCGTTT GGAATCTAAT 241 AATTATAACA CTTACCGGTC ACGGAAGTAC TCTGATTGGT ATGTGGCACT GAAAAGAACT 301 GGACAGTACA AGCCCGGACC AAAAACTGGA CCTGGACAGA AAGCTATCCT TTTTCTTCCA 361 ATGTCTGCTA AAAGC Gallus gallus FGF2 gene coding sequence (aa 1-158) (SEQ ID NO: 202) (GenBank accession no. NM_205433, which is hereby incorporated by reference in its entirety): 98 ATG GCGGCGGGGG CGGCGGGGAG 121 CATCACCACG CTGCCGGCGC TGCCCGACGA CGGGGGCGGC GGCGCTTTTC CCCCCGGGCA 181 CTTCAAGGAC CCCAAGCGGC TCTACTGCAA GAACGGCGGC TTCTTCCTGC GCATCAACCC 241 CGACGGCAGG GTGGACGGCG TCCGCGAGAA GAGCGATCCG CACATCAAAC TGCAGCTTCA 301 AGCAGAAGAA AGAGGAGTAG TATCAATCAA AGGCGTAAGT GCAAACCGCT TTCTGGCTAT 361 GAAGGAGGAT GGCAGATTGC TGGCACTGAA ATGTGCAACA GAGGAATGTT TCTTTTTCGA 421 GCGCTTGGAA TCTAATAACT ATAACACTTA CCGGTCACGG AAGTACTCTG ATTGGTATGT 481 GGCACTGAAA AGGACTGGAC AGTACAAGCC CGGACCAAAA ACTGGACCTG GACAGAAAGC 541 TATCCTTTTT CTTCCAATGT CTGCTAAAAG CTGA Zebra finch FGF2 gene coding sequence (aa 1-153) (SEQ ID NO: 203) (GenBank accession no. XM_002188361, which is hereby incorporated by reference in its entirety): 1 ATGGCGGCGG CGGGGGGCAT CGCTACGCTG CCCGACGACG GCGGCAGCGG CGCCTTTCCC 61 CCGGGGCACT TCAAGGACCC CAAGCGCCTG TACTGCAAGA ACGGCGGCTT CTTCCTGCGC 121 ATCAACCCCG ACGGGAAGGT GGACGGCGTC CGCGAGAAGA GCGACCCGCA CATCAAGCTG 181 CAGCTTCAGG CGGAGGAACG AGGAGTGGTG TCCATCAAAG GTGTCAGTGC CAATCGCTTC 241 CTGGCCATGA AAGAGGATGG CAGATTGCTG GCCTTGAAAT ATGCAACAGA AGAATGTTTC 301 TTTTTTGAAC GTTTGGAATC CAATAACTAT AACACTTACC GGTCACGGAA ATACTCGGAT 361 TGGTATGTGG CACTGAAAAG AACTGGACAG TACAAACCTG GACCAAAAAC TGGACCTGGA 421 CAGAAAGCTA TCCTTTTCCT TCCTATGTCT GCTAAAAGCT GA Japanese firebelly newt FGF2 gene coding sequence (aa 1-155) (SEQ ID NO: 204) (GenBank accession no. AB064664, which is hereby incorporated by reference in its entirety): 384 ATGGCTG CTGGGAGCAT CACCAGTCTC CCTGCCCTAC 421 CCGAGGACGG GAATGGCGGC ACCTTCACAC CCGGCGGATT CAAAGAGCCG AAGAGGCTGT 481 ACTGCAAGAA CGGGGGCTTC TTTCTCCGGA TCAACTCCGA CGGCAAGGTG GACGGAGCCC 541 GGGAGAAGAG CGACTCCTAC ATTAAACTGC AGCTTCAAGC AGAAGAGCGC GGTGTGGTGT 601 CCATCAAGGG AGTATGTGCA AACCGCTATC TCGCTATGAA GGATGATGGC AGGCTGATGG 661 CGCTGAAATG GATAACCGAT GAATGCTTCT TTTTCGAGCG ACTGGAGTCC AACAACTATA 721 ACACGTATCG ATCACGGAAA TATTCCGATT GGTATGTGGC GCTGAAAAGA ACTGGGCAAT 781 ACAAAAATGG ATCAAAAACC GGAGCAGGAC AGAAAGCAAT CCTTTTTCTA CCCATGTCGG 841 CCAAGAGTTG A African clawed frog FGF2 gene coding sequence (aa 1-155) (SEQ ID NO: 205) (GenBank accession no. NM_001099871, which is hereby incorporated by reference in its entirety): 335 ATGGCG GCAGGGAGCA TCACAACTCT 361 GCCAACTGAA TCCGAGGATG GGGGAAACAC TCCTTTTTCA CCAGGGAGTT TTAAAGACCC 421 CAAGAGGCTC TACTGCAAGA ACGGGGGCTT CTTCCTCAGG ATAAACTCAG ACGGGAGAGT 481 GGACGGGTCA AGGGACAAAA GTGACTCGCA CATAAAATTA CAGCTACAAG CTGTAGAGCG 541 GGGAGTGGTA TCAATAAAGG GAATCACTGC AAATCGCTAC CTTGCCATGA AGGAAGATGG 601 GAGATTAACA TCGCTGAGGT GTATAACAGA TGAATGCTTC TTTTTTGAAC GACTGGAAGC 661 TAATAACTAC AACACTTACC GGTCTCGGAA ATACAGCAGC TGGTATGTGG CACTAAAGCG 721 AACCGGGCAG TACAAAAATG GATCGAGCAC TGGACCGGGA CAAAAAGCTA TTTTATTTCT 781 CCCAATGTCC GCAAAGAGCT GA White-eared opossum FGF2 gene coding sequence (aa 1-156) (SEQ ID NO: 206) (GenBank accession no. EF057322, which is hereby incorporated by reference in its entirety): 1 ATGGCAGCAG GCAGCATCAC CACATTGCCG GCCCTGTCCG GGGACGGAGG CGGCGGGGGA 61 GCCTTTCCTC CAGGCCACTT CAAGGACCCC AAGCGGCTGT ACTGCAAGAA CGGAGGCTTC 121 TTCCTGCGCA TCCACCCCGA CGGCCGCGTG GACGGCATCC GCGAGAAGAG CGACCCGAAC 181 ATTAAACTAC AACTTCAGGC AGAAGAGAGA GGAGTAGTGT CTATTAAAGG AGTATGTGCC 241 AACCGATATC TTGCCATGAA GGAGGATGGC AGATTATTGG CTTTGAAATA TGTGACCGAA 301 GAGTGTTTCT TTTTTGAACG TTTGGAGTCC AACAACTACA ACACTTATCG CTCAAGAAAA 361 TATTCCAATT GGTATGTGGC ACTGAAACGA ACGGGGCAGT ATAAGCTTGG ATCCAAGACT 421 GGCCCGGGGC AGAAAGCCAT CCTTTTCTCC CCATGTCTGC TAAGATGCTG A Microbat FGF2 gene coding sequence (1-96; partial amino acid sequence corresponding to human FGF2 residues 60 to 155) (SEQ ID NO: 207) (Ensembl accession no. ENSMLUT00000027717 , which is hereby incorporated by reference in its entirety): 1 GTCAAACTCC AACTTCAAGC AGAAGAGAGA GGGGTCGTGT CTATCAAAGG AGTGTGTGCC 61 AACCGCTATC TCGCTATGAA GGAGGACGGC CGGTTACAGG CTTCTAAATG TGTTACGGAT 121 GAGTGTTTCT TTTTTGAACG GTTGGAATCC AATAACTACA ACACTTACCG GTCAAGAAAG 181 TACTCCAGTT GGTATGTGGC ATTGAAGCGG AATGGGCAGT ATAAACTTGG ACCCAAAACA 241 GGACCTGGCC AGAAAGCCAT ACTTTTTCTT CCCATGTCTG CTAAGAGC Anole lizard FGF2 gene coding sequence (1-140; partial amino acid sequence corresponding to human FGF2 residues 16 to 155) (SEQ ID NO: 208) (Ensembl accession no. ENSACAT00000011897, which is hereby incorporated by reference in its entirety): 1 GCGGCGGCGG CCTCTTTCCC CCCGGGCCCC TTCAAGGACC CCAAGCGCCT CTACTGCAAG 61 AACGGGGGCT TCTTCCTGCG GATCAACCCC GACGGCGGCG TGGACGGCGT CCGAGAGAAG 121 AGCGACCCCA ACATCAAATT GCTGCTCCAG GCAGAGGAGA GAGGTGTAGT GTCCATCAAA 181 GGTGTATGCG CAAACCGTTT CCTGGCTATG AATGAAGACG GTCGATTGTT AGCACTGAAA 241 TACGTAACAG ATGAATGCTT CTTTTTTGAA CGCTTGGAAT CTAATAATTA CAATACTTAT 301 CGGTCTCGTA AATACCGTGA TTGGTACATT GCACTGAAAC GAACTGGTCA GTACAAACTT 361 GGACCAAAAA CTGGACGAGG CCAGAAAGCT ATCCTTTTCC TTCCAATGTC TGCCAAAAGT Armadillo FGF2 gene coding sequence (124-217; partial amino acid sequence corresponding to human FGF2 residues 1 to 94) (SEQ ID NO: 209) (Ensembl accession no. EN5DN0T00000014647, which is hereby incorporated by reference in its entirety): 361 A TGGCAGCCGG GAGCATCACC ACGCTGCCCG CTCTGCCCGA GGACGGCGGC 421 AGCGGCGCCT TCCCGCCGGG CCACTTCAAG GACCCCAAGC GGCTGTACTG CAAAAACGGG 481 GGCTTCTTCC TGCGCATCCA TCCCGACGGC CGAGTGGACG GGGTCCGGGA GAAGAGCGAC 541 CCTAACATCA AACTACAACT TCAAGCAGAA GAGAGAGGGG TCGTGTCTAT CAAAGGCGTG 601 TGTGCGAACC GTTACCTTGC TATGCGGGAA GACGGAAGAC TCCAGGCGTC T Tree shrew FGF2 gene coding sequence (1-189) (SEQ ID NO: 210) (Ensembl accession no. ENSTBET00000001143, which is hereby incorporated by reference in its entirety): 1 GCGGGGGTTA GAGCTGAGAG GGAGGAGGCA CCGGGGAGCG GTGACAGCCG GGGGACCGAT 61 CCCGCCGCGC GTTCGCTCAT CAGGAGGCCG GATGCTGCAG CGCGAGAGGC GCTTCTTGGA 121 GCCAGGAGCC GGGTTCAGGG CAGCTCCACC TCCTGGCCAG CCTCGTCACG AACCGGGATC 181 AAGTTGCCGG ACGACTCAGG TCAAGGAATG GGCGGCTATC CTCTGGACCG CCCGAGCCGG 241 AGCACAGGGC GAGGGCTGGG CGGTGCCCCG GACCCTGCCG TAAAACTACA GCTTCAAGCG 301 GAAGAGAGAG GGGTCGTGTC TATCAAAGGA GTGTGTGCAA ACCGTTACCT GGCCATGAAG 361 GAGGATGGGC GACTGCTGGC TTCTAAATGT GTTACAGATG AGTGTTTCTT TTTTGAACGA 421 CTGGAATCTA ATAACTACAA TACTTACCGG TCCCGAAAGT ACTCCAGCTG GTATGTGGCA 481 CTGAAACGAA CTGGGCAGTA TAAACTTGGA TCCAAAACAG GACCTGGGCA GAAAGCTATA 541 CTTTTTCTTC CAATGTCTGC TAAAAGC

Western clawed frog FGF2 gene coding sequence (aa 1-154) (SEQ ID NO: 211) (GenBank accession no. NM_001017333, which is hereby incorporated by reference in its entirety): 171 ATGGCAGCAG 181 GAAGCATCAC AACCCTACCA ACCGAATCTG AGGATGGAAA CACTCCTTTC CCACCGGGGA 241 ACTTTAAGGA CCCCAAGAGG CTCTACTGCA AGAATGGGGG CTACTTCCTC AGGATTAACT 301 CAGACGGGAG AGTGGACGGA TCAAGGGATA AAAGTGACTT ACACATAAAA TTACAGCTAC 361 AAGCAGTAGA GCGGGGAGTG GTATCAATAA AGGGAATCAC TGCAAATCGC TACCTTGCCA 421 TGAAGGAAGA TGGGAGATTA ACATCGCTGA AGTGTATAAC AGATGAATGC TTCTTTTATG 481 AACGATTGGA AGCTAATAAC TACAACACTT ACCGGTCTCG GAAAAACAAC AGCTGGTATG 541 TGGCACTAAA GCGAACTGGG CAGTATAAAA ATGGATCGAC CACTGGACCA GGACAAAAAG 601 CTATTTTGTT TCTCCCAATG TCAGCAAAAA GCTGA Coelacanth FGF2 gene coding sequence (aa 1-155) (SEQ ID NO: 212) (Ensembl accession no. ENSLACT00000019333, which is hereby incorporated by reference in its entirety): 1 ATGGCTGCGG GAGGAATCAC TACCCTGCCG GCGGTACCTG 41 AGGATGGAGG CAGCAGCACC TTCCCTCCAG GAAACTTCAA GGAGCCCAAG AGACTTTACT 101 GTAAGAATGG AGGCTATTTC TTAAGGATAA ACCCCGATGG AAGAGTGGAT GGAACAAGGG 161 AGAAAAATGA TCCTTATATA AAATTACAAC TGCAAGCTGA ATCTATAGGA GTGGTGTCGA 221 TAAAGGGAGT TTGTTCAAAC CGTTACCTAG CGATGAATGA AGACTGTAGA CTTTTTGGAT 281 TGAAATATCC AACGGATGAA TGTTTCTTCC ATGAGAGGCT GGAGTCCAAC AACTACAATA 341 CTTATCGTTC AAAGAAGTAT TCGGATTGGT ATGTGGCGCT GAAACGGACT GGTCAGTACA 401 AACCTGGGCC AAAAACTGGA CTGGGACAAA AAGCAATCCT TTTCCTTCCG ATGTCTGCCA 461 AGAGTTGA Spotted green pufferfish FGF2 gene coding sequence (aa 34-188) (SEQ ID NO: 213) (Ensembl accession no. EN5TNIT00000016254, which is hereby incorporated by reference in its entirety): 1 ATGGCCACGG GAGGGATCAC GACGCTTCCA TCCACACCTG AAGACGGCGG CAGCAGCGGC 61 TTTCCTCCCG GCAGCTTCAA GGATCCCAAA AGGCTCTACT GTAAAAACGG AGGTTTCTTC 121 CTGAGGATCA AGTCCGACGG GGTCGTGGAC GGAATCCGGG AGAAGAGTGA CCCCCACATA 181 AAGCTTCAGC TCCAGGCGAC CTCTGTGGGG GAGGTGGTCA TCAAGGGGGT GTGCGCTAAC 241 CGCTATCTGG CCATGAACAG AGATGGACGG CTGTTCGGAA CGAAACGAGC CACGGACGAA 301 TGCCATTTCT TAGAGCGGCT TGAGAGCAAC AACTACAACA CTTACCGCTC CAGGAAGTAC 361 CCAACCATGT TTGTGGGACT GACGCGGACG GGCCAGTACA AGTCTGGGAG CAAAACTGGA 421 CCGGGCCAAA AGGCCATCCT TTTTCTTCCG ATGTCCGCCA AATGCTAA Stickleback FGF2 gene coding sequence (aa 1-155) (SEQ ID NO: 214) (Ensembl accession no. ENSGACT00000022120, which is hereby incorporated by reference in its entirety): 1 AT GGCCACGGCA GGCTTCGCGA CGCTTCCCTC CACGCCCGAA 43 GACGGCGGCA GCGGCGGCTT CACCCCCGGG GGATTCAAGG ATCCCAAGAG GCTGTACTGC 103 AAAAACGGGG GCTTCTTCTT GAGGATCAGG TCCGACGGAG GTGTAGATGG AATCAGGGAG 163 AAGAGCGACG CCCACATAAA GCTCCAAATC CAGGCGACGT CGGTGGGGGA GGTGGTCATC 223 AAAGGAGTCT GTGCCAACCG CTATCTGGCC ATGAACAGAG ACGGCCGGCT GTTCGGAGTG 283 AGACGGGCGA CGGACGAATG CTACTTCCTG GAGCGGCTGG AGAGTAACAA CTACAACACC 343 TACCGCTCCA GGAAGTACCC CGGCATGTAC GTGGCTCTGA AGCGGACCGG CCAGTACAAG 403 TCCGGGAGCA AAACCGGACC CGGTCAAAAG GCCATTCTGT TCCTCCCCAT GTCGGCTAAG 463 TGCTAA Fugu rubripes FGF2 gene coding sequence (aa 1-155) (SEQ ID NO: 215) (Ensembl accession no. ENSTRUT00000022363, which is hereby incorporated by reference in its entirety): 127 ATGG CCACGGGAGG GATCACAACA CTTCCATCCA CACCTGAAGA CGGCGGCAGC 181 GGCGGTTTTC CTCCCGGGAG CTTCAAGGAT CCCAAAAGGC TGTACTGTAA AAACGGCGGC 241 TTCTTCCTGA GGATCAGGTC CGACGGGGCC GTGGACGGAA CCCGGGAGAA GACTGACCCC 301 CACATAAAGC TTCAGCTCCA GGCGACCTCT GTGGGGGAGG TGGTCATCAA GGGGGTTTGT 361 GCTAATCGTT ATCTGGCCAT GAACAGAGAT GGACGACTGT TTGGAATGAA ACGAGCGACG 421 GATGAATGCC ACTTCTTAGA GCGGCTCGAG AGCAACAACT ACAACACCTA CCGCTCCAGG 481 AAGTACCCCA ACATGTTTGT GGGACTGACG CGAACTGGCA ACTACAAGTC TGGGACTAAA 541 ACTGGACCGG GCCAAAAGGC CATCCTCTTT CTTCCGATGT CGGCCAAATA CTAA Rainbow trout FGF2 gene coding sequence (aa 1-155) (SEQ ID NO: 216) (GenBank accession no. NM_001124536, which is hereby incorporated by reference in its entirety): 390 A TGGCCACAGG AGAAATCACC ACTCTACCCG 421 CCACACCTGA AGATGGAGGC AGTGGCGGCT TCCTTCCAGG AAACTTTAAG GAGCCCAAGA 481 GGTTGTACTG TAAAAATGGA GGCTACTTCT TGAGGATAAA CTCTAACGGA AGCGTGGACG 541 GGATCAGAGA TAAGAACGAC CCCCACAATA AGCTTCAACT CCAGGCGACC TCAGTGGGGG 601 AAGTAGTAAT CAAAGGGGTC TCAGCCAACC GCTATCTGGC CATGAATGCA GATGGAAGAC 661 TGTTTGGACC GAGACGGACA ACAGATGAAT GCTACTTCAT GGAGAGGCTG GAGAGTAACA 721 ACTACAACAC CTACCGCTCT CGAAAGTACC CTGAAATGTA TGTGGCACTG AAAAGGACTG 781 GCCAGTACAA GTCAGGATCC AAAACTGGAC CCGGCCAAAA AGCCATCCTC TTCCTCCCCA 841 TGTCAGCCAG ACGCTGA Salmon FGF2 gene coding sequence (1-150) (SEQ ID NO: 217) (GenBank accession no. EU816603, which is hereby incorporated by reference in its entirety): 99402 AT GGCCACA GGAGAAAT CA 99421 CCACTCTACC CGCCACACCT GAAGATGGAG GCAGTGGCGG CTTCCCTCCA GGAAACTTTA 99481 AGGATCCCAA GAGGCTGTAC TGTAAAAACG GGGGCTACTT CTTGAGAATA AACTCTAATG 99541 GAAGCGTGGA CGGGATCCGA GAGAAGAACG ACCCCCACA 100968 AAC AGCCTCAATT 100981 TGTCAGGGCA TGGACTCTTC AAGGTGTCAA ACGTTCCACA GGGATGCTGG CCCATGTTGA 101041 CTCCAACGCT TCCCACAATT GTGTCAAGGT GGCTGGATGT TCTTTGGGAG 101845 AATTTG GCAGTATGTC CAACCGGCCT CATAACCGCA 101881 GACCACGTGT AGCTACACCA GCCCAGGACC TCCACATCCG GCTTCTTCAT CTACGGGATC 101941 GTCTGAAACC AGCCACCCGA ACAGCTGATA AAACTGAGGA GTATTTCTGT CTGTAA Zebrafish FGF2 gene coding sequence (aa 1-154) (SEQ ID NO: 218) (GenBank accession no. AY269790, which is hereby incorporated by reference in its entirety): 43 ATGGCCAC CGGAGGGATC 61 ACCACACTCC CGGCCGCTCC GGACGCCGAA AACAGCAGCT TTCCCGCGGG CAGCTTCAGG 121 GATCCCAAGC GCCTGTACTG CAAAAACGGA GGATTCTTCC TGCGGATCAA CGCGGACGGC 181 CGAGTGGACG GAGCCCGAGA CAAGAGCGAC CCGCACATTC GTCTGCAGCT GCAGGCGACG 241 GCAGTGGGTG AAGTACTCAT TAAAGGCATC TGTACCAACC GTTTCCTTGC CATGAACGCA 301 GACGGACGAC TGTTCGGGAC GAAAAGGACC ACAGATGAAT GTTATTTCCT GGAGCGCCTG 361 GAGTCCAACA ACTACAACAC ATACAGATCC CGCAAGTATC CCGACTGGTA CGTGGCTCTG 421 AAGAGAACCG GCCAGTATAA AAGCGGCTCT AAAACCAGCC CGGGACAGAA GGCCATCCTG 481 TTTCTGCCCA TGTCGGCCAA ATGCTGA Nile tilapia FGF2 gene coding sequence (aa 1-155) (SEQ ID NO: 219) (GenBank accession no. XM_003443364, which is hereby incorporated by reference in its entirety): 1 ATGGCCACGG GAGGAATCAC AACACTTCCC GCTACACCTG AAGACGGCGG CAGCAGCGGC 61 TTTCCTCCTG GGAACTTCAA GGACCCTAAA AGGCTGTACT GTAAAAATGG TGGCTTCTTC 121 TTGAGGATAA AATCTGATGG AGGAGTGGAT GGAATACGAG AGAAAAACGA CCCCCACATA 181 AAGCTTCAAC TCCAGGCGAC CTCAGTGGGA GAAGTGGTCA TCAAAGGGAT TTGTGCAAAC 241 CGATATCTGG CAATGAACAG AGATGGACGA CTGTTTGGAG CGAGAAGAGC AACAGATGAG 301 TGCTACTTCT TAGAGCGGCT CGAGAGCAAC AACTACAACA CCTACCGCTC CAGGAAGTAC 361 CCAAACATGT ACGTGGCGCT GAAGCGGACT GGCCAGTACA AGTCTGGAAG CAAAACTGGA 421 CCGGGTCAAA AGGCAATTCT CTTTCTCCCA ATGTCTGCTA AATGCTAA Medaka FGF2 gene coding sequence (aa 1-155) (SEQ ID NO: 220) (Ensembl accession no. EN50RLT00000025835, which is hereby incorporated by reference in its entirety): 1 ATGGCTACGG GAGAAATCAC AACACTTCCC TCCCCAGCTG AAAACAGCAG AAGCGATGGC 61 TTTCCTCCAG GGAACTACAA GGATCCTAAG AGGCTCTACT GTAAAAATGG AGGTTTGTTT 121 TTGAGGATTA AACCTGATGG AGGAGTGGAT GGAATCCGGG AAAAAAAAGA TCCCCACGTT 181 AAGCTTCGCC TTCAGGCTAC CTCAGCGGGA GAGGTGGTGA TCAAAGGAGT TTGTTCAAAC 241 AGATATCTGG CGATGCATGG AGATGGACGT CTATTTGGAG TGAGACAAGC AACAGAGGAA 301 TGCTACTTCT TGGAGCGACT AGAGAGCAAC AACTATAACA CCTATCGCTC TAAAAAGTAC 361 CCAAACATGT ACGTGGCACT GAAGCGGACA GGCCAGTACA AACCTGGAAA CAAAACTGGA 421 CCAGGTCAAA AGGCCATTCT CTTTCTGCCT ATGTCTGCCA AGTACTAA

As noted above, also encompassed within the present invention are portions of paracrine FGFs other than FGF1 and/or FGF2 (e.g., FGF4, FGF5, FGF6, FGF9, FGF16, and FGF20). The portion of the paracrine FGF may be from human FGF4, FGF5, FGF6, FGF9, FGF16, and/or FGF20 having the amino acid sequences shown in Table 5, or orthologs thereof.

TABLE-US-00009 TABLE 5 Amino acid sequence of human FGF4(SEQ ID NO: 221) (GenBank accession no. NP_001998, which is hereby incorporated by reference in its entirety): 1 MSGPGTAAVA LLPAVLLALL APWAGRGGAA APTAPNGTLE AELERRWESL VALSLARLPV 61 AAQPKEAAVQ SGAGDYLLGI KRLRRLYCNV GIGFHLQALP DGRIGGAHAD TRDSLLELSP 121 VERGVVSIFG VASRFFVAMS SKGKLYGSPF FTDECTFKEI LLPNNYNAYE SYKYPGMFIA 181 LSKNGKTKKG NRVSPTMKVT HFLPRL Amino acid sequence of human FGF5(SEQ ID NO: 222) (GenBank Accession No. NP_004455, which is hereby incorporated by reference in its entirety): 1 MSLSFLLLLF FSHLILSAWA HGEKRLAPKG QPGPAATDRN PRGSSSRQSS SSAMSSSSAS 61 SSPAASLGSQ GSGLEQSSFQ WSPSGRRTGS LYCRVGIGFH LQIYPDGKVN GSHEANMLSV 121 LEIFAVSQGI VGIRGVFSNK FLAMSKKGKL HASAKFTDDC KFRERFQENS YNTYASAIHR 181 TEKTGREWYV ALNKRGKAKR GCSPRVKPQH ISTHFLPRFK QSEQPELSFT VTVPEKKKPP 241 SPIKPKIPLS APRKNTNSVK YRLKFRFG Amino acid sequence of human FGF6(SEQ ID NO: 223) (NP_066276, which is hereby incorporated by reference in its entirety): 1 MALGQKLFIT MSRGAGRLQG TLWALVFLGI LVGMVVPSPA GTRANNTLLD SRGWGTLLSR 61 SRAGLAGEIA GVNWESGYLV GIKRQRRLYC NVGIGFHLQV LPDGRISGTH EENPYSLLEI 121 STVERGVVSL FGVRSALFVA MNSKGRLYAT PSFQEECKFR ETLLPNNYNA YESDLYQGTY 181 IALSKYGRVK RGSKVSPIMT VTHFLPRI Amino acid sequence of human FGF9(SEQ ID NO: 224) (GenBank accession no. NP_002001, which is hereby incorporated by reference in its entirety): 1 MAPLGEVGNY FGVQDAVPFG NVPVLPVDSP VLLSDHLGQS EAGGLPRGPA VTDLDHLKGI 61 LRRRQLYCRT GFHLEIFPNG TIQGTRKDHS RFGILEFISI AVGLVSIRGV DSGLYLGMNE 121 KGELYGSEKL TQECVFREQF EENWYNTYSS NLYKHVDTGR RYYVALNKDG TPREGTRTKR 181 HQKFTHFLPR PVDPDKVPEL YKDILSQS Amino acid sequence of human FGF16(SEQ ID NO: 225) (GenBank accession no. NP_003859, which is hereby incorporated by reference in its entirety): 1 MAEVGGVFAS LDWDLHGFSS SLGNVPLADS PGFLNERLGQ IEGKLQRGSP TDFAHLKGIL 61 RRRQLYCRTG FHLEIFPNGT VHGTRHDHSR FGILEFISLA VGLISIRGVD SGLYLGMNER 121 GELYGSKKLT RECVFREQFE ENWYNTYAST LYKHSDSERQ YYVALNKDGS PREGYRTKRH 181 QKFTHFLPRP VDPSKLPSMS RDLFHYR Amino acid sequence of human FGF20(SEQ ID NO: 226) (GenBank accession no. NP_062825, which is hereby incorporated by reference in its entirety): 1 MAPLAEVGGF LGGLEGLGQQ VGSHFLLPPA GERPPLLGER RSAAERSARG GPGAAQLAHL 61 HGILRRRQLY CRTGFHLQIL PDGSVQGTRQ DHSLFGILEF ISVAVGLVSI RGVDSGLYLG 121 MNDKGELYGS EKLTSECIFR EQFEENWYNT YSSNIYKHGD TGRRYFVALN KDGTPRDGAR 181 SKRHQKFTHF LPRPVDPERV PELYKDLLMY T

It will be understood that the portion of the paracrine FGF according to the present invention may be derived from a nucleotide sequence that encodes human FGF4, FGF5, FGF6, FGF9, FGF16, and/or FGF20 having the nucleotide sequences shown in Table 6, or orthologs thereof.

TABLE-US-00010 TABLE 6 Human FGF4 gene coding sequence (1-206) (SEQ ID NO: 227) (GenBank accession no. NM_002007, which is hereby incorporated by reference in its entirety): 320 A TGTCGGGGCC CGGGACGGCC GCGGTAGCGC TGCTCCCGGC 361 GGTCCTGCTG GCCTTGCTGG CGCCCTGGGC GGGCCGAGGG GGCGCCGCCG CACCCACTGC 421 ACCCAACGGC ACGCTGGAGG CCGAGCTGGA GCGCCGCTGG GAGAGCCTGG TGGCGCTCTC 481 GTTGGCGCGC CTGCCGGTGG CAGCGCAGCC CAAGGAGGCG GCCGTCCAGA GCGGCGCCGG 541 CGACTACCTG CTGGGCATCA AGCGGCTGCG GCGGCTCTAC TGCAACGTGG GCATCGGCTT 601 CCACCTCCAG GCGCTCCCCG ACGGCCGCAT CGGCGGCGCG CACGCGGACA CCCGCGACAG 661 CCTGCTGGAG CTCTCGCCCG TGGAGCGGGG CGTGGTGAGC ATCTTCGGCG TGGCCAGCCG 721 GTTCTTCGTG GCCATGAGCA GCAAGGGCAA GCTCTATGGC TCGCCCTTCT TCACCGATGA 781 GTGCACGTTC AAGGAGATTC TCCTTCCCAA CAACTACAAC GCCTACGAGT CCTACAAGTA 841 CCCCGGCATG TTCATCGCCC TGAGCAAGAA TGGGAAGACC AAGAAGGGGA ACCGAGTGTC 901 GCCCACCATG AAGGTCACCC ACTTCCTCCC CAGGCTGTGA Human FGF5 gene coding sequence (1-268) (SEQ ID NO: 228) (GenBank Accession No. NM_004464, which is hereby incorporated by reference in its entirety): 238 ATG 241 AGCTTGTCCT TCCTCCTCCT CCTCTTCTTC AGCCACCTGA TCCTCAGCGC CTGGGCTCAC 301 GGGGAGAAGC GTCTCGCCCC CAAAGGGCAA CCCGGACCCG CTGCCACTGA TAGGAACCCT 361 AGAGGCTCCA GCAGCAGACA GAGCAGCAGT AGCGCTATGT CTTCCTCTTC TGCCTCCTCC 421 TCCCCCGCAG CTTCTCTGGG CAGCCAAGGA AGTGGCTTGG AGCAGAGCAG TTTCCAGTGG 481 AGCCCCTCGG GGCGCCGGAC CGGCAGCCTC TACTGCAGAG TGGGCATCGG TTTCCATCTG 541 CAGATCTACC CGGATGGCAA AGTCAATGGA TCCCACGAAG CCAATATGTT AAGTGTTTTG 601 GAAATATTTG CTGTGTCTCA GGGGATTGTA GGAATACGAG GAGTTTTCAG CAACAAATTT 661 TTAGCGATGT CAAAAAAAGG AAAACTCCAT GCAAGTGCCA AGTTCACAGA TGACTGCAAG 721 TTCAGGGAGC GTTTTCAAGA AAATAGCTAT AATACCTATG CCTCAGCAAT ACATAGAACT 781 GAAAAAACAG GGCGGGAGTG GTATGTGGCC CTGAATAAAA GAGGAAAAGC CAAACGAGGG 841 TGCAGCCCCC GGGTTAAACC CCAGCATATC TCTACCCATT TTCTGCCAAG ATTCAAGCAG 901 TCGGAGCAGC CAGAACTTTC TTTCACGGTT ACTGTTCCTG AAAAGAAAAA GCCACCTAGC 961 CCTATCAAGC CAAAGATTCC CCTTTCTGCA CCTCGGAAAA ATACCAACTC AGTGAAATAC 1021 AGACTCAAGT TTCGCTTTGG ATAA Human FGF6 gene coding sequence (1-208) (SEQ ID NO: 229) (NM_020996, which is hereby incorporated by reference in its entirety): 45 ATGGCC CTGGGACAGA 61 AACTGTTCAT CACTATGTCC CGGGGAGCAG GACGTCTGCA GGGCACGCTG TGGGCTCTCG 121 TCTTCCTAGG CATCCTAGTG GGCATGGTGG TGCCCTCGCC TGCAGGCACC CGTGCCAACA 181 ACACGCTGCT GGACTCGAGG GGCTGGGGCA CCCTGCTGTC CAGGTCTCGC GCGGGGCTAG 241 CTGGAGAGAT TGCCGGGGTG AACTGGGAAA GTGGCTATTT GGTGGGGATC AAGCGGCAGC 301 GGAGGCTCTA CTGCAACGTG GGCATCGGCT TTCACCTCCA GGTGCTCCCC GACGGCCGGA 361 TCAGCGGGAC CCACGAGGAG AACCCCTACA GCCTGCTGGA AATTTCCACT GTGGAGCGAG 421 GCGTGGTGAG TCTCTTTGGA GTGAGAAGTG CCCTCTTCGT TGCCATGAAC AGTAAAGGAA 481 GATTGTACGC AACGCCCAGC TTCCAAGAAG AATGCAAGTT CAGAGAAACC CTCCTGCCCA 541 ACAATTACAA TGCCTACGAG TCAGACTTGT ACCAAGGGAC CTACATTGCC CTGAGCAAAT 601 ACGGACGGGT AAAGCGGGGC AGCAAGGTGT CCCCGATCAT GACTGTCACT CATTTCCTTC 661 CCAGGATCTA A Human FGF9 gene coding sequence (1-208)(SEQ ID NO: 230) (GenBank accession no. NM_002010, which is hereby incorporated by reference in its entirety): 838 ATG 841 GCTCCCTTAG GTGAAGTTGG GAACTATTTC GGTGTGCAGG ATGCGGTACC GTTTGGGAAT 901 GTGCCCGTGT TGCCGGTGGA CAGCCCGGTT TTGTTAAGTG ACCACCTGGG TCAGTCCGAA 961 GCAGGGGGGC TCCCCAGGGG ACCCGCAGTC ACGGACTTGG ATCATTTAAA GGGGATTCTC 1021 AGGCGGAGGC AGCTATACTG CAGGACTGGA TTTCACTTAG AAATCTTCCC CAATGGTACT 1081 ATCCAGGGAA CCAGGAAAGA CCACAGCCGA TTTGGCATTC TGGAATTTAT CAGTATAGCA 1141 GTGGGCCTGG TCAGCATTCG AGGCGTGGAC AGTGGACTCT ACCTCGGGAT GAATGAGAAG 1201 GGGGAGCTGT ATGGATCAGA AAAACTAACC CAAGAGTGTG TATTCAGAGA ACAGTTCGAA 1261 GAAAACTGGT ATAATACGTA CTCATCAAAC CTATATAAGC ACGTGGACAC TGGAAGGCGA 1321 TACTATGTTG CATTAAATAA AGATGGGACC CCGAGAGAAG GGACTAGGAC TAAACGGCAC 1381 CAGAAATTCA CACATTTTTT ACCTAGACCA GTGGACCCCG ACAAAGTACC TGAACTGTAT 1441 AAGGATATTC TAAGCCAAAG TTGA Human FGF16 gene coding sequence (1-207) (SEQ ID NO: 231) (GenBank accession no. NM_003868, which is hereby incorporated by reference in its entirety): 1 ATGGCAGAGG TGGGGGGCGT CTTCGCCTCC TTGGACTGGG ATCTACACGG CTTCTCCTCG 61 TCTCTGGGGA ACGTGCCCTT AGCTGACTCC CCAGGTTTCC TGAACGAGCG CCTGGGCCAA 121 ATCGAGGGGA AGCTGCAGCG TGGCTCACCC ACAGACTTCG CCCACCTGAA GGGGATCCTG 181 CGGCGCCGCC AGCTCTACTG CCGCACCGGC TTCCACCTGG AGATCTTCCC CAACGGCACG 241 GTGCACGGGA CCCGCCACGA CCACAGCCGC TTCGGAATCC TGGAGTTTAT CAGCCTGGCT 301 GTGGGGCTGA TCAGCATCCG GGGAGTGGAC TCTGGCCTGT ACCTAGGAAT GAATGAGCGA 361 GGAGAACTCT ATGGGTCGAA GAAACTCACA CGTGAATGTG TTTTCCGGGA ACAGTTTGAA 421 GAAAACTGGT ACAACACCTA TGCCTCAACC TTGTACAAAC ATTCGGACTC AGAGAGACAG 481 TATTACGTGG CCCTGAACAA AGATGGCTCA CCCCGGGAGG GATACAGGAC TAAACGACAC 541 CAGAAATTCA CTCACTTTTT ACCCAGGCCT GTAGATCCTT CTAAGTTGCC CTCCATGTCC 601 AGAGACCTCT TTCACTATAG GTAA Human FGF20 gene coding sequence (1-211) (SEQ ID NO: 232) (GenBank accession no. NM_019851, which is hereby incorporated by reference in its entirety): 134 ATGGCTC CCTTAGCCGA AGTCGGGGGC TTTCTGGGCG GCCTGGAGGG 181 CTTGGGCCAG CAGGTGGGTT CGCATTTCCT GTTGCCTCCT GCCGGGGAGC GGCCGCCGCT 241 GCTGGGCGAG CGCAGGAGCG CGGCGGAGCG GAGCGCGCGC GGCGGGCCGG GGGCTGCGCA 301 GCTGGCGCAC CTGCACGGCA TCCTGCGCCG CCGGCAGCTC TATTGCCGCA CCGGCTTCCA 361 CCTGCAGATC CTGCCCGACG GCAGCGTGCA GGGCACCCGG CAGGACCACA GCCTCTTCGG 421 TATCTTGGAA TTCATCAGTG TGGCAGTGGG ACTGGTCAGT ATTAGAGGTG TGGACAGTGG 481 TCTCTATCTT GGAATGAATG ACAAAGGAGA ACTCTATGGA TCAGAGAAAC TTACTTCCGA 541 ATGCATCTTT AGGGAGCAGT TTGAAGAGAA CTGGTATAAC ACCTATTCAT CTAACATATA 601 TAAACATGGA GACACTGGCC GCAGGTATTT TGTGGCACTT AACAAAGACG GAACTCCAAG 661 AGATGGCGCC AGGTCCAAGA GGCATCAGAA ATTTACACAT TTCTTACCTA GACCAGTGGA 721 TCCAGAAAGA GTTCCAGAAT TGTACAAGGA CCTACTGATG TACACTTGA

As noted above, the chimeric protein includes a portion of a paracrine FGF coupled to a C-terminal region derived from an FGF21 molecule. FGF21 is an endocrine FGF expressed primarily by the pancreas (Fon Tacer et al., "Research Resource: Comprehensive Expression Atlas of the Fibroblast Growth Factor System in Adult Mouse," Mol Endocrinol 24(10):2050-2063 (2010), which is hereby incorporated by reference in its entirety) and has metabolic effects similar to that of FGF19, such as increased energy metabolism, weight loss, lowered blood glucose levels, and resistance to obesity and diabetes (Kharitonenkov et al., "FGF-21 as a Novel Metabolic Regulator," J Clin Invest 115(6), 1627-1635 (2005); Coskun et al., "Fibroblast growth factor 21 corrects obesity in mice," Endocrinology 149(12):6018-6027 (2008), which are hereby incorporated by reference in their entirety). Transgenic mice overexpressing FGF21 are also resistant to diet-induced obesity (Kharitonenkov et al., "FGF-21 as a Novel Metabolic Regulator," J Clin Invest 115(6), 1627-1635 (2005), which is hereby incorporated by reference in its entirety). Moreover, in diabetic rodent models, FGF21 administration lowers blood glucose and triglyceride levels (Kharitonenkov et al., "FGF-21 as a Novel Metabolic Regulator," J Clin Invest 115(6), 1627-1635 (2005), which is hereby incorporated by reference in its entirety).

In one embodiment, the C-terminal portion of FGF21 of the chimeric protein of the present invention is from human FGF21 having the amino acid sequence of SEQ ID NO: 233 (GenBank Accession No. NP_061986, which is hereby incorporated by reference in its entirety), as follows:

TABLE-US-00011 1 MDSDETGFEH SGLWVSVLAG LLLGACQAHP IPDSSPLLQF GGQVRQRYLY TDDAQQTEAH 61 LEIREDGTVG GAADQSPESL LQLKALKPGV IQILGVKTSR FLCQRPDGAL YGSLHFDPEA 121 CSFRELLLED GYNVYQSEAH GLPLHLPGNK SPHRDPAPRG PARFLPLPGL PPALPEPPGI 181 LAPQPPDVGS SDPLSMVGPS QGRSPSYAS.

In one embodiment, the C-terminal portion of FGF21 of the chimeric protein of the present invention includes a .beta.-Klotho co-receptor binding domain.

In one embodiment, the C-terminal portion of FGF21 of the chimeric protein of the present invention includes amino acid residues 168-209 of SEQ ID NO: 233.

In one embodiment, the C-terminal portion of FGF21 of the chimeric protein further includes one or more substitutions, deletions, or additions. In one embodiment, the C-terminal portion of FGF21 of the chimeric protein further includes one or more substitutions, deletions, or additions while retaining the ability to bind .beta.-Klotho. In one embodiment, the C-terminal portion of FGF21 of the chimeric protein further includes one or more substitutions, deletions, or additions while retaining the ability to selectively bind .beta.-Klotho. In one embodiment, the C-terminal portion of FGF21 of the chimeric protein further includes one or more substitutions, additions, or deletions to enhance binding affinity for .beta.-Klotho.

In one embodiment of the present invention, the C-terminal portion of the chimeric protein according to the present invention is or is derived from a mammalian FGF21. In one embodiment of the present invention, the C-terminal portion of the chimeric protein according to the present invention is or is derived from a vertebrate FGF21. In one embodiment, the C-terminal portion of the chimeric protein according to the present invention is derived from a non-human vertebrate FGF21. It will be understood that this includes orthologs of human FGF21, or a polypeptide or protein obtained from one species that is the functional counterpart of a polypeptide or protein from a different species. In one embodiment of the present invention, the C-terminal portion of FGF21 of the chimeric protein according to the present invention is derived from human, pongo abelii, pan troglodytes, canis lupus familiaris, bos taurus, equus caballus, ailuropoda melanoleuca, oryctolagus cuniculus, gorilla gorilla, nomascus leucogenys, procavia capensis, cavia porcellus, tupaia belangeri, sorex araneus, ictidomys tridecemlineatus, loxodonta africana, sus scrofa, felis catus, otolemur garnettii, rattus norvegicus, mus musculus, vicugna pacos, anolis carolinensis, gadus morhua, latimeria chalumnae, tursiops truncatus, mustela putorius furo, takifugu rubripes, dipodomys ordii, echinops telfairi, macaca mulatta, microcebus murinus, ochotona princeps, xiphophorus maculatus, gasterosteus aculeatus, sarcophilus harrisii, macropus eugenii, xenopus tropicalis, danio rerio, bos grunniens mutus, saimiri boliviensis boliviensis, callithrix jacchus, tupaia chinensis, papio anubis, pteropus alecto, heterocephalus glaber, cricetulus griseus, ovies aries, pan paniscus, macaca fascicularis, mesocricetus auratus, or oreochromis niloticus.

In one embodiment of the present invention, the portion of FGF21 of the chimeric protein of the present invention is from an ortholog of human FGF21 having an amino acid sequence as shown in Table 7. The portions of an ortholog of human FGF21 of a chimeric protein according to the present invention include portions corresponding to the above-identified amino acid sequences of human FGF21. Corresponding portions may be determined by, for example, sequence analysis and structural analysis.

TABLE-US-00012 TABLE 7 Pongo abelii (Sumatran orangutan) FGF21 (GenBank Accession No. XP_002829565, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 234) 1 MDSDETGFEH SGLWVPVLAG LLLGACQAHP IPDSSPLLQF GGQVRQRYLY TDDAQQTEAH 61 LEIREDGTVG GAADQSPESL LQLKALKPGV IQILGVKTSR FLCQRPDGAL YGSLHFDPEA 121 CSFRELLLED GYNVYQSEAH GLPLHLPGNK SPHRDPAPRG aARFLPLPGL PPAPPEPPGI 181 LAPQPPDVGS SDPLSMVGPS QGRSPSYAS Pan troglodytes (chimpanzee) FGF21 (GenBank Accession No. XP_524333, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 235) 1 MDSDETGFEH SGLWVSVLAG LLLGACQAHP IPDSSPLLQF GGQVRQRYLY TDDAQQTEAH 61 LEIREDGTVG GAADQSPESL LQLKALKPGV IQILGVKTSR FLCQRPDGAL YGSLHFDPEA 121 CSFRELLLED GYNVYQSEAH GLPLHLPGNK SPHRDPAPRG aARFLPLPGL PPAPPEPPGI 181 LAPQPPDVGS SDPLSMVGPS QGRSPSYTS Canis lupus familiaris (dog) FGF21 (GenBank Accession No. XP_541510, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 236) 1 MGWAEAGFEH LGLWVPVLAV LLLEACRAHP IPDSSPLLQF GGQVRQRYLY TDDAQETEAH 61 LEIRADGTVV GAARQSPESL LELKALKPGV IQILGVKTSR FLCQGPDGTL YGSLHFDPVA 121 CSFRELLLED GYNIYHSETL GLPLRLRPHN SAYRDLAPRG aARFLPLPGL LPAPPEPPGI 181 LAPEPPDVGS SDPLSMVGPS QGRSPSYAS Bos taurus (bovine) FGF21 (GenBank Accession No. XP_001789639, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 237) 1 MGWDEAKFKH LGLWVPVLAV LLLGTCRAHP IPDSSPLLQF GGQVRQRYLY TDDAQETEAH 61 LEIRADGTVV GAARQSPESL LELKALKPGV IQILGVKTSR FLCQGPDGKL YGSLHFDPKA 121 CSFRELLLED GYNVYQSETL GLPLRLPPQR SSNRDPAPRG PARFLPLPGL PAAPPDPPGI 181 LAPEPPDVGS SDPLSMVGPS YGRSPSYTS Equus caballus (horse) FGF21 (GenBank Accession No. XP_001489202, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 238) 1 MDWDKTGFKY QGLWVPVLAV LLLGACQSHP IPDSSPLLQF GGQVRQRHLY TDDAQETEAH 61 LEIRADGTVA GAVHRSPESL LELKALKPGV IQILGVKTSR FLCQGPDGTL YGSLHFDPVA 121 CSFRELLLED GYNVYQSETL GLPLRLPHHS SPYQDPAPRA PARFLPLPGF PPAPPEPPGI 181 PAPEPPDVGS SDPLSMVGPS RSRSPSYTS Ailuropoda melanoleuca (giant panda) FGF21 (GenBank Accession No. XP_002917910, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 239) 1 MGWDEARSEQ LGLWVPVLAV LLLEACQAHP IPDSSPLLQF GGQVRQRYLY TDDAQETEAH 61 LAIRADGTVV GAASRSPESL LELKALKPGV IQILGVKTSR FLCQGPDGTL YGSVRFDPVA 121 CSFRELLLED GYNIYHSETL GLPLRLPAHN SPYRDSAPRG PARFLPLPGL LPVPPDPPGI 181 LGPEPPDVGS SDPLSMVGPS QGRSPSYAS Oryctolagus cuniculus (rabbit) FGF21 (GenBank Accession No. XP_002723745, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 240) 1 MDWGKAKCRP PGLWVPALAA LLLGACQAHP IPDSSPLLQF GDQVRQQHLY TDDAQETEAH 61 LEIRADGTVV GAARRSPESL LQMKALQPGI IQILGVQTSR FLCQRPDGTL YGSLHFDREA 121 CSFRELLRED GYNVYLSEAL GLPLRLSPGS SPRRAPAPRG PARFLPLPGL PPDLPEPPGL 181 LAAAPPDVDS PDPLSMVQPA LDQSPSYTS Gorilla gorilla (gorilla) FGF21 (Ensembl Accession No. ENSGGOP00000001229, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 241) 1 MDSDETGFEH SGLWVSVLAG LLLGACQAHP IPDSSPLLQF GGQVRQRYLY TDDAQQTEAH 61 LEIREDGTVG GAADQSPESL LQLKALKPGV IQILGVKTSR FLCQRPDGAL YGSLHFDPEA 121 CSFRELLLED GYNVYQSEAH GLPLHLPGNK SPHRDPAPRG PARFLPLPGL PPAPPEPPGI 181 LAPQPPDVGS SDPLSMVGPS QGRSPSYAS Nomascus leucogenys (Northern white-cheeked gibbon) FGF21 (Ensembl Accession No. ENSNLEP00000005639, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 242) 1 MDSDETGFEH SGLWVPVLAG LLLGACQAHP IPDSSPLLQF GGQVRQRYLY TDDAQQTEAH 61 LEIREDGTVG GAADQSPESL LQLKALKPGV IQILGVKTSR FLCQRPDGAL YGSLHFDPEA 121 CSFRELLLED GYNVYQSEAH GLPLHLPGNK SPHRDPAPRG PARFLPLPGL PPAPPEPPGI 181 LAPQPPDVGS SDPLSMVGPS QGRSPSYAS Procavia capensis (hyrax) FGF21 (Ensembl Accession No. ENSOGAG00000001210, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 243) 1 MDWAKFGIEH PGLWVPVMAV LLLGACQGYP IPDSSPLLQF GGQVRQRYLY TDDAQETEAH 61 LEIRADGTVV GAAHRSPESL LELKALKPGI IQILGVKTSR FLCQGPDGVL YGSLRFDPVA 121 CSFRELLLED GYNVYQSEAH GLPLRLPSHN SPQRDLASRV PARFLPLPGR LTVLPEPSGV 181 LGPEPPDVDS SDPLSMVGPS QGRSPSYAS Cavia porcellus (guinea pig) FGF21 (Ensembl Accession No. ENSCPOP00000000237, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 244) 1 MDWARTECER PRLWVSMLAI LLVGACQAHP IPDSSPLLQF GGQVRQRYLY TDDAQDTEVH 61 LEIRADGSVR GIAHRSPESL LELKALKPGV IQILGIRTSR FLCQRPDGSL YGSLHFDPEA 121 CSFRELLLAD GYNVYKSEAH GLPLHLLRGD SLSQEPAPPG PARFLPLPGL PATPPEPPRM 181 LPPGPPDVGS SDPLSMVGPL WDRSPSYTS Tupaia belangeri (tree shrew) FGF21 (Ensembl Accession No. ENSTBEP00000013946, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 245) 1 MGWDKARFEH LGAWAPVLAV LLLGACQAYP IPDSSPLLQF GGQVRQRYLY TDDTQDTEAH 61 LEIRADGTVV GAAHQSPESL LELKALKPGV IQILGVKTSR FLCQRPDGAL YGSLHFDPEA 121 CSFRELLLED GYNIYQSEAR GLPLRLPPHD SPHRDRTPRG PARFLPLPGL PLVPPELPGV 181 LALEPPDVGS SDPLSMMGPS QGQSPSYAS Sorex araneus (shrew) FGF21 (Ensembl Accession No. ENSSARP00000002784, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 246) 1 MVWDKARGQQ LGLWAPMLLG LLLGACQAHP LPDSSPLLQF GGQVRLRFLY TDDAQRTGAH 61 LEIRADGTVQ GAAHRTPECL LELKALKPGV IQILGVSTSR FLCQRPDGVL YGSLRFDPEA 121 CSFRELLLQD GYNVYQSEAL GLPLYLHPPS APVSQEPASR GAVRFLPLPG LPPASLEPPR 181 PPAPVPPDVG SSDPLSMVGP PERHSPSYTS Ictidomys tridecemlineatus (squirrel) FGF21 (SEQ ID NO: 247) 1 MDWVKAKLEP LGLWVLVLAA LVLGACQAYP IPDSSPLLQF GGQVRQRYLY TDDAQETEAH 61 LEIRADGTVV GAAHQSPESL LELKALKPGV IQILGVKTSR FLCQRPDGVL YGSLHFDPEA 121 CSFREQLLED GYNVYQSESH GLPVRLPPNS PYRDPAPPGP ARFLPLPGLP PAALEPPGIL 181 GPEPPDVGSS DPLSMVGPLQ GRSPSYAS Loxodonta africana (elephant) FGF21 (Ensembl Accession No. ENSLAFP00000016854, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 248) 1 MDWAKFGLE HPGLWVPVMA VLLLGACQGH PIPDSSPLLQ FGGQVRQRYL YTDDQETEAH 60 LEIRADGTVA GAAHRSSESL LELKALKPGI IQILGVKTSR FLCQGPDGVL YGSLHFDPAA 120 CSFRELLLED GYNVYWSEAH GLPIRLPSHN SPYRDPASRV PARFLPLPGL LPMLQEPPGV 180 LAPEPPDVDS SDPLSMVGPS QGRSPSYAS Sus scrofa (pig) FGF21 (GenBank Accession No. NP_001156882, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 249) 1 MGWAEAKFER LGLWVPVLAV LLGACQARPI PDSSPLLQFG GQVRQRYLYT DDAQETEAHL 61 EIRADGTVAG VARQSPESLL ELKALKPGVI QILGVQTSRF LCQGPDGRLY GSLHFDPEAC 121 SFRELLLEDG YNVYQSEALG LPLRLPPHRS SNRDLAPRGP ARFLPLPGLP PAPPEPPGIL 181 APEPPDVGSS DPLSMVGPSH GRSPSYTS Felis catus (cat) FGF21 (Ensembl Accession No. ENSFCAP00000006832, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 250) 1 MDWDEAGSQ RLGLWVVLGV LLPEACQAHP IPDSSPLLQF GGQVRQRFLY TDDAQETEVH 60 LEIKADGTVV GTARRSPESL LELKALKPGV IQILGVKTSR FLCQGPDGTL YGSLRFDPAA 120 CSFRELLLED GYNIYHSETL GLPLRLPPHN SPYRDLAPRA PARFLPLPGL LPAPPEPPGI 180 LAPEPPDVGS SDPLSMVGPS QGRSPSYAS Otolemur garnettii (bushbaby) FGF21 (Ensembl Accession No. ENSOGAG00000003581, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 251) 1 DKARTGFKH PGPWFPLLAV LLLGACQAHP IPDSSPLLQF GGQVRQRYLY TDDAQETEAH 60 LEIREDGTVV GAAQQSPESL LELKALKPGV IQILGVKTSR FLCQRPDGGL YGSLYFDPKA 120 CSFRELLLED GYNVYWSETY GLPLHLPPAN SPYWGPSLRS PARFLPLPGP PAASPELPGI 180 LALEPPDVGS SDPLSMVGPS QGRSPSYAS Rattus norvegicus (Norway rat) FGF21 (GenBank Accession No. NP_570108, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 252) 1 MDWMKSRVGA PGLWVCLLLP VFLLGVCEAY PISDSSPLLQ FGGQVRQRYL YTDDDQDTEA 61 HLEIREDGTV VGTAHRSPES LLELKALKPG VIQILGVKAS RFLCQQPDGT LYGSPHFDPE 121 ACSFRELLLK DGYNVYQSEA HGLPLRLPQK DSQDPATRGP VRFLPMPGLP HEPQEQPGVL 181 PPEPPDVGSS DPLSMVEPLQ GRSPSYAS Mus musculus (house mouse) FGF21 (GenBank Accession No. NP_064397, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 253) 1 MEWMRSRVGT LGLWVRLLLA VFLLGVYQAY PIPDSSPLLQ FGGQVRQRYL YTDDDQDTEA 61 HLEIREDGTV VGAAHRSPES LLELKALKPG VIQILGVKAS RFLCQQPDGA LYGSPHFDPE 121 ACSFRELLLE DGYNVYQSEA HGLPLRLPQK DSPNQDATSW GPVRFLPMPG LLHEPQDQAG 181 FLPPEPPDVG SSDPLSMVEP LQGRSPSYAS Vicugna pacos (alpaca) FGF21 (Ensembl Accession No. ENSVPAP00000005562, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 254); partial sequence corresponding to human FGF21 residues 1 to 78, 169 to 171, and 183 to 209 1 MDWDEAKFEH RGLWVPVLTV LLLGACQARP IPDSSPLLQF GGQVRQRYLY TDDAQETEAH 61 LEIRADGTVV GVARQPE--- ---------- ---------- ---------- ---------- 121 ---------- ---------- ---------- ---------- --------GI P--------- 181 --PEPPDVGS SDPLSMVGPS YSRSPSYTS Anolis carolinensis (anole lizard) FGF21 (Ensembl Accession No. ENSACAP00000016895, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 255) 1 CKSKGGGKGG ERMWVDLVFW AALLRTAPAL PLRNSNPIYQ FDGQVRLRHL YTADEQTHLH 61 LEILPDGTVG GSRFQNPFSL MEIKAVKPGV IRMQAKKTSR FLCMKPNGRL YGSLFYSEEA 121 CNFHEKVLSD GYNLYYSENY NIPVSLSSAG NLGQSRQLPP FSQFLPLVNK IPLEPVLEDF 181 DFYGHQLDVE SADPLSILGQ NPGFMSPSYV F Gadus morhua (cod) FGF21 (Ensembl Accession No. ENSGMOP00000013789, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 256) 1 LLLATLLHIG LSFYVPDSGP LLWLGDQVRE RHLYTAESHR RGLFLEMSPD GQVTGSAAQT 61 PLSVLELRSV RAGDTVIRAR LSSLYLCVDR AGHLTGQRQY TESDCTFREV ILEDGYTHFL 121 SVHHGLPISL APRHSPGRQG LRFSRFLPLR SSLSEDRVAE PPDSPLNLDS EDPLGMGLGS 181 LLSPAFSM Latimeria chalumnae (coelacanth) FGF21 (Ensembl Accession No. ENSLACP00000003781, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 257) 1 MLCQSFVILS QKFIFGLFLT GLGLTGLAWT RPFQDSNPIL QYSDSIRLRH LYTASESRHL 61 HLQINSDGQV GGTTKQSPYS LLEMKAVKTG FVVIRGKKSA RYLCMERSGR LYGSLQYTEK 121 DCTFKEVVLA DGYNLYVSEE HQATVTLSPM RARIAQGKKI PPFSHFLPMV NKVPVEDVAA 181 EMEFVQVLRE MTADVDSPDP FGMTWEESVH SPSFFA Tursiops truncatus (dolphin) FGF21 (Ensembl Accession No. ENSTTRP00000013808, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 258) 1 MGWDKTKLEH LGLWVPVLAV LLGPCQAHPI PDSSPLLQFG GQVRQRYLYT DDAQETEAHL 61 EIRADGTVVG TARRSPEGVK TSRFLCQGPE GRLYGSLHFN PQACSFRELL LEDGYNVYQS 121 EALGIPLRLP PHRSSNWDLA PRGPARFLPL PGFLPPPLEP PGILAPEPPN VGSSDPLSMV 181 GPSHGRSPSY TS Mustela putorius furo (ferret) FGF21 (Ensembl Accession No. ENSMPUP00000003687, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 259) 1 MGWEEARSEH LGLWVPVLAV LLLGACQAYP IPDSSPLLQF GGQVRQRYLY TDDAQETEAH 61 LEIRADGTVV GAARRSPESL LELKALKPGV IQILGVKTSR FLCQGPNGTL YGSFHFDPVA 121 CSFREVLLED GYNIYHSETL GLPLRLPPHN SPHRDLAPRG PARFLPLPGL LPATPESRGI 181 PAPEPPNVGS SDPLSMVGPL QGQSPSYTS Takifugu rubripes (fugu) FGF21 (Ensembl Accession No. ENSTRUP00000033950, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 260) 1 FIYLFIQTAL FSPSKWFNFY LPDSNPLLSF DSHGRGIHLY TDNQRRGMYL QMSTDGSVSG 61 SDVQTANSVL ELKSVRNGHV VIRGKSSSLF LCMDSRGRLW GQRHPTEADC TFREVLLADG 121 YTRFLSLHNG TPVSLAPKQS PDQHTVPFTR FLPLRNTLAE ESMSEPPSNQ QRYFNIDSDD 181 LLGMDLNAMV SPQFSGDK Dipodomys ordii (kangaroo rat) FGF21 (Ensembl Accession No. ENSDORP00000001155, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 261) 1 MDQAKTRVGA RGLGGLVLAV IILGACKARP IPDSSPLLQF GGQVRLRHLY TDDTQETEAH 61 LEIRADGTVV GTAHRSPESL LELKALKPGV IQILGIKTSR FLCQRPDGTL YGSLHFDPEV 121 CSFQELLLED GYNIYRSEAL GLPLRLSPDP APWGPARFLP LPGVPPAPPE PPGILAPEPP 181 DVGSSDPLSM VGLLQGRSPS YAS Echinops telfairi (lesser hedgehog tenrec) FGF21 (Ensembl Accession No. ENSETEP00000008707, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 262) 1 MGCTKSGWKS PGLWVPVLAS LLLGGCGAHP IPDSSPLLQF GGQVRQRYLY TDDAQTTEAH 61 LEIRADGTVG GVAHQSPEKF LSQWREKPLR SLHFDPAACS FREKLLEDGY NLYHSETHGL 121 PLRLPPRGGD PSSQPGARFP PLPGQLPQLQ ETPGVLAPEP PDVGSSDPLS MVGPWRGQSP 181 SYAS Macaca mulatta (rhesus monkey) FGF21 (Ensembl Accession No. ENSMMUP00000031540, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 263) 1 MDSDETGFEH SGLWVPVLAG LLLGACQAHP IPDSSPLLQF GGQVRQRYLY TDDAQQTEAH 61 LEIREDGTVG GAAHQSPESE CGPEPGSEGG GAVGGAEGPG LLGLREAGLG PGSWLHFDPE 121 ACSFRELLLE NGYNVYQSEA HGLPLHLPGN KSPHRDPASQ GPARFLPLPG LPPAPPEPPG 181 ILAPQPPDVG SSDPLSMVGP SQARSPSYAS Microcebus murinus (mouse lemur) FGF21 (Ensembl Accession No. ENSMICP00000012089, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 264) 1 MGWDEAGAGF EHPGLWFPML GVLLLGACQA YPIPDSSPLL QFGGQVRQRH LYTDDIQETE 61 AHLEIRADGT VVGAARQSPE LELKALKPGV IQILGVKTSR FLCQRPDGAL YGSLHFDPEC 121 SFRELLLEDG YNVYCPYLPL HLSPRIELAG SRSALPLPPA PERRILAPEP PDGSSDPLSM 181 VGPSQGRSPS YAS Ochotona princeps (pika) FGF21 (Ensembl Accession No. ENSOPRP00000006754, which is hereby incorporated by reference in its

entirety) (SEQ ID NO: 265) 1 KDMDGLQPPG LRVPVLAALL LGVGQARPIP DSSPLLQFGG QVRQRHLYTD DAQESEVHLE 61 IRADGTVAGT ARRSPESLLE MKALKPGVIQ ILGVHTSRFL CQRPDGTLYG SLHFDHKACS 121 FREQLLEDGY NVYHSETHGL PLRLSPDRAP RGPARFLPLP GPPPDLLVPP LPPDVLAPEP 181 PDVDSPDPLS MVGPLQGQSP SYTS Xiphophorus maculatus (platyfish) FGF21 (Ensembl Accession No. ENSXMAP00000001576, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 266) 1 CPFPFLFLIL SLPFFSSSFY IPESNPIFAF RNQLREVHLY TENHRRGLYV EIHLDGRVTG 61 SDAQSPYSVL QIKSVKPGHV VIKGQTSSLF LCMDDSGNLR GQTTYDEADC SFRELLLADG 121 YTRFLNSQHG VPLSLASRNS PDRHSVPFTR FLPLRNTLTV SEESTKTQRD FNLDSDDLLG 181 MG Gasterosteus aculeatus (stickleback) FGF21 (Ensembl Accession No. ENSGACP00000010703, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 267) 1 SLLLMVPLPF CSSFYLTDSS PLLPFNNQVK EVHLYTAENH RRAMYLQIAL DGSVSGSDAR 61 STYSVLQLKS IQPGHVVIRG KASSMFLCVD SGGRLRGQGP YSEADCSFRE LLLGDGYTRF 121 LSSQHGSPLS LASRPSPDPN SVPFTRFLPI RTAPEAESVI EEPPSNQRYV NVDSEDLLGM 181 GLNTVVSPQF SA Sarcophilus harrisii (tasmanian devil) FGF21 (Ensembl Accession No. ENSSHAP00000005963, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 268); partial sequence corresponding to human FGF21 residues 3 to 172 1 VSAMGLRERA PRYLAPLLSL LLACRASGHP LPDSSPMLLF GGQVRLRHLY TDVGQEAEAH 61 VELASDGTVR AAARRSPNSL LELKAVKPGI VRILAVHSSR FLCMRPNGEL YGAIHYDPSA 121 CNFRERLLGD GYNVYESEAH GRTLRLPPKA APGPAGPSRF LPLPG Macropus eugenii (wallaby) FGF21 (Ensembl Accession No. ENSMEUP00000013936, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 269) 1 TEEPSTGSRH LGQWAPGLPG PLLSLLLAYR GWGSPIPDSS PMLLFGGQVR LRHLYTDDGQ 61 DTEAHVELGP DGVVRAVAER SPNSLLELKA VKPGVIRILA VQSSRFLCMR PNGELYGAVH 121 YDPSACNFRE HLLGDGYNVY ESETHRRTLR LSPSLGQAGP SRFLPLPGDW LPGPDPPWAQ 181 GPEPPDVGSA DPLSMVGAVQ GLSPSYSS Xenopus tropicalis (Western clawed frog) FGF21 (Ensembl Accession No. ENSXETP00000009917, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 270); partial sequence corresponding to human FGF21 residues 1 to 169 1 RGGRTKKKTL LRKWLCLLAI MLSRSRFSLA NPIQNSNPIL SNDNQVRTQY LYTDNNNMHL 61 YLQITHNGVV TGTEEKNDYG VLEIKAVKAG VVVIKGIRSN LYLCMDSRHQ LYASAYDKDD 121 CHFHEKITPD NYNMYSSEKH SEYVSLAPLK GSQMARFLPI Danio rerio (zebrafish) FGF21 (Ensembl Accession No. ENSDARP00000094287, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 271) 1 MLLACFFIFF ALFPHLRWCM YVPAQNVLLQ FGTQVRERLL YTDGLFLEMN PDGSVKGSPE 61 KNLNCVLELR SVKAGETVIQ SAATSLYLCV DDQDKLKGQH HYSALDCTFQ ELLLDGYSFF 121 LSPHTNLPVS LLSKRQKHGN PLSRFLPVSR AEDSRTQEVK QYIQDINLDS DDPLGMGHRS 181 HLQTVFSPSL HTKK Bos grunniens mutus (yak) FGF21 (GenBank Accession No. ELR56628, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 272) 1 MGWDEAKFKH LGLWVPVLAV LLLGTCRAHP IPDSSPLLQF GGQVRQRYLY TDDAQETEAH 61 LEIRADGTVV GAARQSPESL LELKALKPGV IQILGVKTSR FLCQGPDGKL YGSLHFDPKA 121 CSFRELLLED GYNVYQSETL GLPLRLPPQR SSNRDPAPRG PARFLPLPGL PAEPPDPPGI 181 LAPEPPDVGS SDPLSMVGPS YGRSPSYTS Saimiri boliviensis boliviensis (Bolivian squirrel monkey) FGF21 (GenBank Accession No. XP_003940375, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 273) 1 MGSEEVALER PALWVSVLAG LLLGTCQAYP IPDSSPLLQF GGQVRQRYLY TDDAQQTEAH 61 LEIREDGTVA GAAHQSPESL LQLKALKPGV IQILGVKTSR FLCQRPDGAL YGSLYFDPEA 121 CSFRELLLED GYNVYQSVAH SLPLHLPGGR SPPWDPAPRG PARFLPLPGL PPEPPEAPGI 181 LAPEPPDVGS SDPLSMVGPS QGQSPSYTS Callithrix jacchus (white-tufted-ear marmoset) FGF21 (GenBank Accession No. XP_003735669, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 274) 1 MGSEEVGLEH PALWVSVLAG LLLGTCQAHP IPDSSPLLQF GGQVRQRYLY TDDAQQKEAH 61 LEIXEDGTVA GAATKVPKVS LLQLKALKPG VIQILGVKTS RFLCQRPDGA LYGSLHFDPE 121 ACSFRELLLE DGYNVYQSVA HGLPLHLPES RSPPRDPAPR GPARFLPLPG LPPEPPEPPG 181 ILAPEPPDVG SSDPLSMVGP SQGQSPSYAS Tupaia chinensis (Chinese tree shrew) FGF21 (GenBank Accession No. ELW47159, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 275) 1 MGWDKARFEH LGAWAPVLAV LLLGACQAYP IPDSSPLLQF GGQVRQRYLY TDDTQDTEAH 61 LEIRADGTVV GAAHQSPESL LELKALKPGV IQILGVKTSR FLCQRPDGAL YGSLHFDPEA 121 CSFRELLLED GYNIYQSEAR GLPLRLPPHD SPHRDRTPQG PARFLPLPGL PLVPPELPGV 181 LALEPPDVGS SDPLSMMGPS QGQSPSYAS Papio anubis (olive baboon) FGF21 (GenBank Accession No. XP_003915900, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 276) 1 MDSDETGFEH SGLWVPVLAG LLLGACQAHP IPDSSPLLQF GGQVRQRYLY TDDAQQTEAH 61 LEIREDGTVG GAAHQSPESK CGPEPGSEGG GALHFDPEAC SFRELLLENG YNVYQSEAHG 121 LPLHLPGNKS PHRDPASRGP ARFLPLPGLP PAPPEPPGIL APQPPDVGSS DPLSMVGPSQ 181 ARSPSYAS Pteropus alecto (black flying fox) FGF21 (GenBank Accession No. ELK18566, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 277) 1 MGWGKARLQH PGLWGPVLAV LLGACQAHPI LDSSPLFQFG SQVRRRYLYT DDAQDTEAHL 61 EIRADGTVAG AARRSPESLL ELKALKPGVI QVLGVKTSRF LCQRPDGTLY GSLHFDPAAC 121 SFRELLLKDG YNVYQSEALA RPLRLPPYSS PSSDPARRGP ARFLPLPGPP PEPPQPPGRL 181 APEPPDVGSS DPLSMVWPSR GRSPSYTS Heterocephalus glaber (naked mole-rat) FGF21 (GenBank Accession No. EHB06286, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 278) 1 MDWARAESER PGLWVPAVLA VLLLGACQAH PIPDSSPLLQ FGGQVRQRHL YTDDAQDTEV 61 HLEIRADGSV GGAAHRSPES LLELKALKPG VIQILGVRTS RFLCQRPDGT LYGSLHFDPE 121 ACSFRELLLA DGYNIYQSEA YGLPLRMLPS DSASRDPVPP GPARFLPLPG LHPPPLEPPG 181 MLPPEPPDVG SSDPLSMVGP LQGRSPSYAF Cricetulus griseus (Chinese hamster) FGF21 (GenBank Accession No. XP_003508726, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 279) 1 MDWMKSGVGV PGLWVPLLPI FLLGVSQAHP IPDSSPLLQF GGQVRHRHLY TDDNQETEVH 61 LEIRQDGTVI GTTHRSPESL LELKALKPEV IPVLGVKASR FLCQQPDGTL YGSPHFDPEA 121 CSFRELLLED GYNVYQSEVH GLPLRLPQRD SPNQAPASWG PVPPLPVPGL LHQPQELPGF 181 LAPEPPDVGS SDPLSMVGPL QGRSPSYAS Ovis aries (sheep) FGF21 (GenBank Accession No. XP_004015845, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 280) 1 MGWDEAKFKH LGLWVPVLAV LLLGTCRAHP IPDSSPLLQF GGQVRQRYLY TDDAQETEAH 61 LEIRADGTVV GAARQSPESL LELKALKPGV IQIFGVKTSR FLCQGPDGKL YGSLHFDPKA 121 CSFRELLLED GYNVYQSETL GLPLRLPPQR SSNRDPAPRG PPKPQLHFLK TSAVQYWPRY 181 EKVPAFLHPF PG Pan paniscus (pygmy chimpanzee) FGF21 (GenBank Accession No. XP_003814163, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 281); partial sequence corresponding to human FGF21 residues 1 to 116 and 195 to 201 1 MDSDETGFEH SGLWVSVLAG LLLGACQAHP IPDSSPLLQF GGQVRQRYLY TDDAQQTEAH 61 LEIREDGTVG GAADQSPESL LQLKALKPGV IQILGVKTSR FLCQRPDGAL YGSVSF---- 121 ---------- ---------- ---------- ----Q----- ---------- -----DPP-- 181 --HHPP---C S---SYMSPS Q---PG--- Macaca fascicularis (crab-eating macaque) FGF21 (GenBank Accession No. EHH59757, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 282); partial sequence corresponding to human FGF21 residues 1 to 116 1 MDSDETGFEH SGLWVPVLAG LLLGACQAHP IPDSSPLLQF GGQVRQRYLY TDDAQQTEAH 61 LEIREDGTVG GAAHQSPESL LQLKALKPGV IQILGVKTSR FLCQKPDGAL YGSVSF Mesocricetus auratus (golden hamster) FGF21 (GenBank Accession No. ACB30542, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 283); partial sequence corresponding to human FGF21 residues 90 to 193 1 VIQILGVKAA RFPCQQPDGS LYGSPHFDPE ACSFRELLLE DGYNVYQSEA HGLPLRLPQR 61 DAPSQPPASW GPVRFLPVPG LFQPPHDLPG RPAPEPPDVG SSDP Oreochromis niloticus (Nile tilapia) FGF21 (GenBank Accession No. XP_003438516, which is hereby incorporated by reference in its entirety) (SEQ ID NO: 284); partial sequence corresponding to human FGF21 residues 59 to 209 1 MYLQMNMDGR VTGSDAQTPY SLMQLKSVKP GHVIIKGPSS SLFLCVDSEG NLRGQSHYSE 61 TSCTFREMLL ADGYTRFISS QYGFPMSLAS RHSPDRHALP FTRFLPLRNN LKTDSVSEQL 121 PNNQRLFNVD SDDLLGMGLN SMGSPQFSMD K

In certain embodiments according to the present invention, the C-terminal portion of FGF21 of the chimeric protein of the present invention includes a polypeptide sequence that has at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% amino acid sequence identity to amino acid residues 168-209 of SEQ ID NO: 233. In certain embodiments according to the present invention, the C-terminal portion of FGF21 of the chimeric protein of the present invention includes a polypeptide sequence that has at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, or at least 99% amino acid sequence homology to amino acid residues 168-209 of SEQ ID NO: 233.

It will be understood that the portion of FGF21 of the chimeric protein of the present invention may be derived from a nucleotide sequence that encodes a vertebrate or a non-vertebrate FGF21 protein. In one embodiment, the portion of FGF21 of the chimeric protein of the present invention may be derived from a nucleotide sequence that encodes a mammalian FGF21 protein. Nucleotide sequences encoding a vertebrate FGF21 protein according to the present invention may include, but are not limited to, those shown in Table 8. The portion of FGF21 of the chimeric protein of the present invention derived from an ortholog of human FGF21 include portions corresponding to the above-identified amino acid sequences of FGF21. Corresponding portions may be determined by, for example, sequence analysis and structural analysis.

TABLE-US-00013 TABLE 8 Human FGF21 gene coding sequence (SEQ ID NO: 285) (GenBank Accession No. NM_019113, which is hereby incorporated by reference in its entirety) 151 ATGGACTCGG ACGAGACCGG GTTCGAGCAC TCAGGACTGT GGGTTTCTGT GCTGGCTGGT 211 CTTCTGCTGG GAGCCTGCCA GGCACACCCC ATCCCTGACT CCAGTCCTCT CCTGCAATTC 271 GGGGGCCAAG TCCGGCAGCG GTACCTCTAC ACAGATGATG CCCAGCAGAC AGAAGCCCAC 331 CTGGAGATCA GGGAGGATGG GACGGTGGGG GGCGCTGCTG ACCAGAGCCC CGAAAGTCTC 391 CTGCAGCTGA AAGCCTTGAA GCCGGGAGTT ATTCAAATCT TGGGAGTCAA GACATCCAGG 451 TTCCTGTGCC AGCGGCCAGA TGGGGCCCTG TATGGATCGC TCCACTTTGA CCCTGAGGCC 511 TGCAGCTTCC GGGAGCTGCT TCTTGAGGAC GGATACAATG TTTACCAGTC CGAAGCCCAC 571 GGCCTCCCGC TGCACCTGCC AGGGAACAAG TCCCCACACC GGGACCCTGC ACCCCGAGGA 631 CCAGCTCGCT TCCTGCCACT ACCAGGCCTG CCCCCCGCAC TCCCGGAGCC ACCCGGAATC 691 CTGGCCCCCC AGCCCCCCGA TGTGGGCTCC TCGGACCCTC TGAGCATGGT GGGACCTTCC 751 CAGGGCCGAA GCCCCAGCTA CGCTTCCTGA Pongo abelii (Sumatran orangutan) FGF21 gene coding sequence (SEQ ID NO: 286) (GenBank Accession No. XM_002829519, which is hereby incorporated by reference in its entirety) 165 ATGGAC TCGGACGAGA CCGGGTTCGA GCACTCAGGA CTGTGGGTTC CTGTGCTGGC 221 TGGTCTTCTG CTGGGAGCCT GCCAGGCACA CCCCATCCCT GACTCCAGTC CTCTCCTGCA 281 ATTCGGGGGC CAAGTCCGGC AGCGGTACCT CTACACAGAT GATGCCCAGC AGACAGAAGC 341 CCACCTGGAG ATCAGGGAGG ATGGGACGGT GGGGGGCGCT GCTGACCAGA GCCCCGAAAG 401 TCTCCTGCAG CTGAAAGCCT TGAAGCCGGG AGTTATTCAA ATCTTGGGAG TCAAGACATC 461 CAGGTTCCTG TGCCAGAGGC CAGATGGGGC CCTGTATGGA TCGCTCCACT TTGACCCTGA 521 GGCCTGCAGC TTCCGGGAGC TGCTTCTTGA GGACGGATAC AATGTTTATC AGTCCGAGGC 581 CCATGGCCTC CCGCTGCACC TGCCGGGAAA CAAGTCCCCA CACCGGGACC CTGCACCCCG 641 AGGACCAGCT CGCTTCCTGC CACTACCAGG CCTGCCCCCC GCACCCCCAG AGCCGCCCGG 701 AATCCTGGCC CCCCAGCCCC CCGATGTGGG CTCCTCGGAC CCTCTGAGCA TGGTGGGACC 761 TTCCCAGGGC CGAAGCCCCA GCTATGCTTC CTGA Pan troglodytes (chimpanzee) FGF21 gene coding sequence (SEQ ID NO: 287) (GenBank Accession No. XM_524333, which is hereby incorporated by reference in its entirety) 573 ATGGACTC GGACGAGACC GGGTTCGAGC ACTCAGGACT GTGGGTTTCT GTGCTGGCTG 631 GTCTTCTGCT AGGAGCCTGC CAGGCACACC CCATCCCTGA CTCCAGTCCT CTCCTGCAAT 691 TCGGGGGCCA AGTCCGGCAG CGGTACCTCT ACACAGATGA TGCCCAGCAG ACAGAAGCCC 751 ACCTGGAGAT CAGGGAGGAT GGGACGGTGG GGGGCGCTGC TGACCAGAGC CCCGAAAGTC 811 TCCTGCAGCT GAAAGCCTTG AAGCCGGGAG TTATTCAAAT CTTGGGAGTC AAGACATCCA 871 GGTTCCTGTG CCAGAGGCCA GATGGGGCCC TGTATGGATC GCTCCACTTT GACCCTGAGG 931 CCTGCAGCTT CCGGGAGCTG CTTCTTGAGG ACGGATACAA TGTTTACCAG TCCGAGGCCC 991 ACGGCCTCCC GCTGCACCTG CCGGGGAACA AGTCCCCACA CCGGGACCCT GCACCCCGAG 1051 GACCAGCTCG CTTCCTGCCA CTACCAGGCC TGCCCCCCGC ACCCCCGGAG CCACCCGGAA 1111 TCCTGGCCCC CCAGCCCCCC GATGTGGGCT CCTCAGACCC TCTGAGCATG GTGGGACCTT 1171 CCCAGGGCCG AAGCCCCAGC TACACTTCCT GA Canis lupus familiaris (dog) FGF21 gene coding sequence (SEQ ID NO: 288) (GenBank Accession No. XM_541510, which is hereby incorporated by reference in its entirety) 1 ATGGGCTGGG CCGAGGCCGG GTTCGAGCAC CTGGGACTGT GGGTCCCTGT GCTGGCTGTG 61 CTTTTGCTGG AAGCCTGCCG GGCACATCCG ATCCCTGACT CCAGCCCCCT CCTACAATTT 121 GGAGGTCAAG TTCGACAGCG GTACCTCTAC ACCGACGATG CCCAGGAGAC AGAGGCCCAC 181 CTAGAGATCA GGGCCGATGG CACAGTGGTG GGGGCTGCCC GCCAGAGCCC TGAAAGTCTC 241 CTGGAGCTGA AAGCCCTAAA GCCAGGGGTC ATTCAAATCT TGGGAGTCAA AACATCCAGG 301 TTCCTGTGCC AGGGCCCAGA TGGGACACTA TATGGCTCGC TCCATTTCGA CCCTGTGGCC 361 TGCAGTTTCC GAGAACTGCT TCTTGAGGAT GGGTACAACA TCTACCACTC CGAGACCCTT 421 GGTCTCCCGC TTCGCCTGCG CCCCCACAAC TCCGCATACC GGGACTTGGC ACCCCGCGGG 481 CCTGCCCGCT TCCTGCCACT GCCAGGCCTG CTTCCAGCAC CCCCAGAGCC TCCAGGGATC 541 CTGGCCCCGG AGCCTCCTGA CGTGGGCTCC TCGGACCCTC TGAGCATGGT GGGGCCTTCA 601 CAGGGCCGGA GTCCCAGCTA TGCTTCCTAA Bos taurus (bovine) FGF21 gene coding sequence (SEQ ID NO: 289) (GenBank Accession No. XP_001789587, which is hereby incorporated by reference in its entirety) 1 ATGGGCTGGG ACGAGGCCAA GTTCAAGCAC TTGGGACTGT GGGTCCCTGT GCTGGCTGTC 61 CTCCTGCTAG GAACCTGCCG GGCGCATCCC ATTCCAGACT CCAGCCCCCT CCTCCAGTTT 121 GGGGGCCAAG TCCGCCAGCG GTACCTCTAC ACGGATGATG CCCAGGAGAC AGAGGCCCAC 181 CTGGAGATCA GGGCCGATGG CACAGTGGTG GGGGCAGCCC GCCAGAGCCC CGAAAGTCTC 241 TTGGAGCTGA AAGCCCTGAA GCCAGGCGTC ATTCAGATCT TGGGAGTTAA AACATCCAGG 301 TTTCTCTGCC AGGGGCCAGA TGGGAAGCTG TACGGATCGC TGCACTTTGA CCCCAAAGCC 361 TGCAGCTTTC GGGAGCTGCT TCTTGAAGAT GGATACAACG TCTACCAGTC GGAGACCCTG 421 GGCCTTCCAC TCCGCCTGCC CCCCCAGCGC TCGTCCAACC GGGACCCGGC CCCGCGGGGA 481 CCTGCTCGCT TCCTTCCACT GCCGGGCCTG CCCGCGGCGC CCCCGGATCC TCCAGGGATC 541 TTGGCCCCCG AGCCTCCCGA CGTGGGCTCC TCGGATCCCC TGAGTATGGT GGGACCCTCG 601 TATGGCCGAA GCCCCAGCTA CACTTCTTGA Equus caballus (horse) FGF21 gene coding sequence (SEQ ID NO: 290) (GenBank Accession No. XM_001489152, which is hereby incorporated by reference in its entirety) 1 ATGGACTGGG ACAAGACGGG GTTCAAGTAC CAGGGACTGT GGGTCCCTGT GCTGGCTGTC 61 CTTCTGCTGG GAGCCTGCCA GTCACACCCC ATCCCTGACT CCAGTCCCCT CCTCCAATTC 121 GGGGGCCAAG TCAGGCAGCG CCACCTCTAC ACAGATGATG CCCAGGAGAC AGAGGCGCAC 181 CTGGAGATCA GGGCTGACGG CACTGTGGCA GGGGCTGTCC ACCGGAGCCC AGAAAGTCTC 241 TTGGAGCTGA AAGCCCTGAA GCCAGGGGTA ATTCAAATCT TGGGAGTCAA GACATCCAGG 301 TTTCTGTGCC AGGGGCCAGA CGGGACGCTG TACGGATCGC TCCACTTCGA CCCCGTGGCC 361 TGCAGCTTCC GGGAGCTGCT TCTCGAAGAC GGCTACAACG TTTACCAGTC TGAGACCCTT 421 GGCCTCCCAC TCCGCCTGCC CCACCACAGC TCCCCATACC AGGATCCGGC CCCTCGGGCA 481 CCCGCCCGCT TCCTGCCGCT GCCAGGCTTT CCCCCAGCAC CCCCGGAGCC TCCAGGGATC 541 CCGGCCCCCG AGCCCCCGGA CGTGGGCTCC TCGGACCCCC TGAGCATGGT GGGGCCTTCA 601 CGCAGCCGGA GCCCCAGCTA CACTTCCTGA Ailuropoda melanoleuca (giant panda) FGF21 gene coding sequence (SEQ ID NO: 291) (GenBank Accession No. XM_002917864, which is hereby incorporated by reference in its entirety) 1 ATGGGCTGGG ACGAGGCCAG GTCCGAGCAG CTGGGGCTGT GGGTCCCTGT GCTGGCTGTC 61 CTTTTGCTGG AAGCTTGCCA GGCACACCCT ATCCCTGACT CCAGCCCCCT CCTCCAATTC 121 GGAGGCCAAG TTCGACAGCG GTACCTCTAC ACGGACGATG CCCAGGAGAC AGAGGCCCAC 181 CTAGCGATCA GGGCTGATGG CACAGTGGTG GGGGCTGCCA GCCGGAGCCC AGAAAGTCTC 241 TTGGAGCTGA AAGCCCTGAA ACCGGGGGTC ATTCAAATCC TGGGAGTGAA AACATCTAGG 301 TTCCTGTGCC AGGGCCCAGA TGGGACACTG TACGGATCGG TCCGCTTCGA CCCCGTAGCC 361 TGCAGCTTCC GGGAACTGCT CCTGGAGGAT GGGTACAACA TCTACCACTC TGAGACCCTC 421 GGCCTCCCAC TTCGCCTGCC CGCCCACAAC TCTCCATACC GGGACTCGGC GCCCCGGGGG 481 CCTGCCCGCT TCCTGCCCCT GCCAGGCCTG CTTCCGGTCC CCCCGGACCC CCCAGGGATC 541 CTGGGCCCCG AGCCTCCCGA CGTGGGCTCC TCGGACCCCC TGAGCATGGT GGGGCCTTCA 601 CAGGGCCGAA GTCCCAGCTA CGCTTCCTGA Oryctolagus cuniculus (rabbit) FGF21 gene coding sequence (SEQ ID NO: 292) (GenBank Accession No. XM_002723699, which is hereby incorporated by reference in its entirety) 1 ATGGACTGGG GCAAGGCCAA GTGCCGGCCC CCGGGGCTGT GGGTCCCCGC GCTCGCTGCC 61 CTGCTGCTGG GGGCCTGCCA GGCACACCCC ATCCCCGACT CCAGCCCCCT CCTCCAGTTT 121 GGGGACCAAG TGCGGCAGCA GCACCTGTAC ACGGACGATG CGCAGGAAAC AGAAGCCCAC 181 CTGGAGATCA GGGCGGATGG CACGGTGGTG GGGGCTGCCC GGAGGAGCCC AGAAAGTCTC 241 TTGCAGATGA AAGCCTTACA ACCGGGGATC ATTCAGATCT TGGGGGTCCA GACGTCCAGG 301 TTCCTCTGCC AGAGGCCGGA TGGCACGCTC TACGGCTCGC TCCACTTCGA CCGCGAGGCC 361 TGCAGCTTCC GGGAGCTGCT GCGTGAGGAT GGGTACAACG TTTACCTCTC GGAGGCCCTG 421 GGCCTGCCCC TGCGCCTGTC CCCCGGCAGC TCCCCACGCA GGGCGCCGGC CCCCCGGGGA 481 CCAGCCCGCT TCCTGCCGCT GCCCGGCCTG CCGCCAGACC TTCCGGAACC GCCAGGCCTC 541 CTGGCCGCCG CGCCCCCCGA TGTCGACTCC CCGGACCCCC TGAGCATGGT GCAGCCTGCG 601 CTGGACCAGA GCCCCAGCTA CACCTCCTGA Gorilla gorilla (gorilla) FGF21 gene coding sequence (SEQ ID NO: 293) (Ensembl Accession No. ENSGGOT00000001253, which is hereby incorporated by reference in its entirety) 151 ATGGACTCGG ACGAGACCGG GTTCGAGCAC TCAGGACTGT GGGTTTCTGT GCTGGCTGGT 211 CTTCTGCTGG GAGCCTGCCA GGCACACCCC ATCCCTGACT CCAGTCCTCT CCTGCAATTC 271 GGGGGCCAAG TCCGGCAGCG GTACCTCTAC ACAGATGATG CCCAGCAGAC AGAAGCCCAC 331 CTGGAGATCA GGGAGGATGG GACGGTGGGG GGTGCTGCTG ACCAGAGCCC TGAAAGTCTC 391 CTGCAGCTGA AAGCCTTGAA GCCGGGAGTT ATTCAAATCT TGGGAGTCAA GACATCCAGG 451 TTCCTGTGCC AGAGGCCAGA TGGGGCCCTG TATGGATCGC TCCACTTTGA CCCTGAGGCC 511 TGCAGCTTCC GGGAGCTGCT TCTTGAGGAC GGATACAATG TTTACCAGTC CGAGGCCCAC 571 GGCCTCCCGC TGCACCTGCC GGGGAACAAG TCCCCACACC GGGACCCTGC ACCCCGAGGA 631 CCAGCTCGCT TCCTGCCACT ACCAGGCCTG CCCCCCGCAC CCCCGGAGCC ACCCGGAATC 691 CTGGCCCCCC AGCCCCCCGA TGTGGGCTCC TCGGACCCTC TGAGCATGGT GGGACCTTCC 751 CAGGGCCGAA GCCCCAGCTA CGCTTCCTGA Nomascus leucogenys (Northern white-cheeked gibbon) FGF21 gene coding sequence (SEQ ID NO: 294) (Ensembl Accession No. ENSNLET00000005931, which is hereby incorporated by reference in its entirety) 587 ATGG ACTCGGACGA GACCGGGTTC GAGCACTCAG GACTGTGGGT TCCTGTGCTG 647 GCTGGTCTTC TGCTGGGAGC CTGCCAGGCA CACCCCATCC CTGACTCCAG TCCTCTCCTG 707 CAATTCGGGG GCCAAGTCCG GCAGCGGTAC CTCTACACAG ATGATGCCCA GCAGACAGAA 767 GCCCACCTGG AGATCAGGGA GGATGGGACG GTGGGGGGCG CTGCTGACCA GAGCCCTGAA 831 AGTCTCCTGC AGCTGAAAGC CTTGAAGCCG GGAGTTATTC AAATCTTGGG AGTCAAGACA 891 TCCAGGTTCC TATGCCAGAG GCCAGATGGG GCCCTGTATG GATCGCTCCA CTTTGACCCT 951 GAGGCCTGCA GCTTCCGGGA GCTGCTTCTT GAGGACGGAT ACAATGTTTA CCAGTCCGAG 1011 GCCCATGGCC TCCCGCTGCA CCTGCCGGGG AACAAGTCCC CACACCGGGA CCCTGCACCC 1071 CGAGGACCAG CTCGCTTCCT GCCACTACCA GGCCTGCCCC CTGCACCCCC AGAGCCGCCC 1131 GGAATCCTGG CCCCCCAGCC CCCCGATGTG GGCTCCTCGG ACCCTCTGAG CATGGTGGGA 1191 CCTTCCCAGG GCCGAAGCCC CAGCTACGCT TCCTGA Procavia capensis (hyrax) FGF21 gene coding sequence (SEQ ID NO: 295) (Ensembl Accession No. ENSPCAT00000001288, which is hereby incorporated by reference in its entirety) 1 ATGGACTGGG CCAAGTTTGG GATCGAGCAC CCGGGACTGT GGGTCCCGGT GATGGCAGTA 61 CTTCTGCTGG GAGCCTGCCA AGGATACCCT ATTCCTGACT CCAGCCCCCT TCTCCAATTC 121 GGAGGCCAGG TCCGGCAACG TTACCTCTAC ACAGATGACG CGCAGGAGAC CGAGGCCCAC 181 CTGGAGATCC GAGCAGACGG CACGGTGGTG GGGGCTGCCC ACCGGAGCCC CGAGAGTCTC 241 TTGGAGCTGA AAGCTTTGAA GCCCGGCATA ATTCAGATCT TGGGAGTCAA GACATCCAGA 301 TTCCTCTGCC AGGGTCCTGA TGGGGTGCTG TATGGATCGC TCCGTTTTGA CCCAGTGGCC 361 TGCAGCTTCC GGGAGCTGCT TCTTGAAGAT GGATACAATG TTTACCAGTC TGAGGCCCAC 421 GGCCTCCCGC TTCGCCTACC ATCCCACAAT TCCCCACAGA GGGACCTGGC GTCCCGGGTG 481 CCAGCCCGCT TCCTGCCACT GCCAGGCCGG CTCACGGTGC TCCCAGAACC TTCGGGGGTC 541 CTGGGCCCTG AGCCCCCCGA TGTGGACTCC TCAGACCCCC TGAGCATGGT GGGGCCTTCG 601 CAGGGCCGAA GCCCCAGTTA CGCCTCCTGA Cavia porcellus (guinea pig) FGF21 gene coding sequence (SEQ ID NO: 296) (Ensembl Accession No. ENSCPOT00000000273, which is hereby incorporated by reference in its entirety) 1 ATGGACTGGG CCCGGACTGA GTGTGAGCGC CCAAGGCTGT GGGTCTCCAT GCTGGCCATC 61 CTTCTGGTGG GAGCCTGCCA GGCACACCCT ATCCCTGACT CCAGCCCCCT CCTCCAGTTT 121 GGGGGCCAGG TCCGGCAGCG GTACCTCTAC ACAGATGATG CTCAGGACAC TGAAGTGCAC 181 CTGGAGATCA GGGCCGATGG CTCAGTACGG GGCATTGCCC ACAGGAGCCC TGAAAGTCTC 241 CTGGAGCTGA AAGCCTTGAA GCCAGGAGTC ATTCAGATCT TGGGAATCAG GACTTCCAGG 301 TTCCTGTGCC AGAGGCCCGA TGGGAGTCTG TATGGATCAC TCCACTTTGA TCCTGAGGCC 361 TGCAGCTTCC GGGAGCTGCT GCTTGCTGAT GGCTACAATG TCTACAAGTC TGAAGCCCAC 421 GGCCTCCCTC TGCACCTGCT GCGCGGTGAC TCTCTATCGC AGGAACCAGC ACCCCCAGGA 481 CCAGCCCGAT TTCTGCCACT ACCAGGCCTG CCCGCAACAC CCCCGGAGCC ACCCAGGATG 541 CTGCCCCCAG GGCCCCCAGA TGTGGGCTCC TCGGACCCTT TGAGCATGGT GGGGCCTTTA 601 TGGGACCGAA GCCCCAGCTA TACTTCCTGA Tupaia belangeri (tree shrew) FGF21 gene coding sequence (SEQ ID NO: 297) (Ensembl Accession No. ENSTBET00000016056, which is hereby incorporated by reference in its entirety) 1 ATGGGCTGGG ACAAGGCCCG GTTCGAGCAC CTGGGAGCGT GGGCTCCTGT GCTGGCTGTC 61 CTCCTCCTGG GAGCCTGCCA GGCATACCCC ATCCCTGACT CCAGCCCCCT CCTACAATTC 121 GGGGGCCAGG TCCGGCAGCG GTACCTCTAC ACGGACGACA CGCAGGACAC AGAAGCCCAC 181 CTTGAGATCA GGGCCGACGG CACCGTGGTG GGGGCCGCCC ACCAAAGCCC GGAAAGTCTC 241 CTGGAGCTGA AAGCCTTGAA GCCGGGGGTC ATTCAAATCC TGGGAGTCAA GACCTCCAGG 301 TTCCTGTGCC AGAGGCCAGA CGGGGCCCTG TACGGGTCGC TTCACTTCGA CCCCGAGGCC 361 TGCAGCTTCC GGGAGCTGCT TCTCGAGGAT GGATACAACA TTTACCAGTC TGAGGCTCGT 421 GGCCTCCCCC TGCGCCTGCC GCCCCACGAC TCCCCACATC GGGACCGGAC CCCTCGGGGA 481 CCAGCTCGTT TCCTGCCGCT GCCTGGCCTG CCCCTGGTTC CTCCAGAGCT GCCAGGGGTC 541 CTGGCCCTTG AGCCCCCCGA CGTGGGCTCC TCAGACCCGC TGA Sorex araneus (shrew) FGF21 gene coding sequence (SEQ ID NO: 298) (Ensembl Accession No. ENSSART00000003074, which is hereby incorporated by reference in its entirety) 1 ATGGTCTGGG ACAAGGCCAG GGGGCAGCAG TTGGGACTGT GGGCCCCCAT GCTGCTGGGC 61 TTGCTGCTGG GTGCCTGCCA GGCACACCCC CTCCCTGACT CCAGCCCCCT CCTCCAATTT 121 GGGGGCCAAG TCCGACTGAG GTTCCTGTAC ACCGACGATG CCCAGAGGAC AGGGGCGCAC 181 CTGGAGATCA GGGCCGACGG CACAGTGCAG GGTGCGGCCC ACAGGACCCC AGAATGTCTC 241 CTGGAGCTGA AAGCCTTGAA GCCAGGCGTA ATTCAAATCC TTGGGGTCAG CACATCCAGA 301 TTCCTGTGCC AGCGGCCCGA TGGGGTCCTG TATGGATCGC TTCGCTTTGA CCCAGAGGCC 361 TGCAGTTTCC GGGAACTTCT TCTCCAGGAT GGATATAACG TTTACCAGTC TGAGGCCCTG 421 GGTCTCCCGC TCTACCTACA CCCGCCCAGT GCCCCAGTGT CCCAGGAACC AGCCTCACGG 481 GGCGCCGTCC GCTTCCTGCC ACTGCCAGGA CTGCCACCTG CCTCCCTGGA GCCCCCCAGG 541 CCCCCCGCCC CGGTGCCTCC AGACGTGGGT TCCTCAGACC CCCTGA Ictidomys tridecemlineatus (squirrel) FGF21 gene coding sequence (SEQ ID NO: 299) 1 ATGTACCCCA TCCCTGACTC AAGCCCCCTC CTCCAATTTG GGGGCCAAGT CCGGCAGCGG 61 TACCTGTACA CAGATGATGC CCAGGAGACT GAGGCCCACC TGGAGATCAG GGCTGATGGC 121 ACCGTGGTGG GGGCTGCCCA TCAAAGCCCG GAAAGTCTCT TGGAACTGAA AGCCTTGAAG 181 CCTGGGGTCA TTCAAATCTT GGGGGTCAAA ACATCCAGGT TCCTGTGCCA GAGGCCAGAT 241 GGAGTGCTGT ATGGATCGCT CCACTTTGAC CCTGAGGCCT GCAGCTTCCG GGAGCAGCTT 301 CTGGAGGACG GGTACAACGT TTACCAGTCA GAATCCCACG GCCTCCCCGT GCGCCTGCCC 361 CCTAACTCAC CATACCGGGA CCCAGCGCCG CCAGGACCAG CCCGCTTCCT TCCACTGCCA 421 GGCCTGCCCC CAGCAGCCCT GGAGCCGCCA GGGATCCTGG GCCCTGAGCC CCCTGATGTG 481 GGCTCCTCCG ACCCACTCAG CATGGTGGGG CCTTTGCAGG GCCGAAGCCC CAGTTACGCT 541 TCCTGA Loxodonta africana (elephant) FGF21 gene coding sequence (SEQ ID NO: 300) (Ensembl Accession No. ENSLAFT00000022429, which is hereby incorporated by reference in its entirety) 1 ATGGACTGGG CCAAGTTTGG GTTGGAGCAC CCAGGACTGT GGGTCCCTGT GATGGCTGTC 61 CTTCTGCTGG GAGCCTGCCA GGGACACCCC ATCCCTGACT CCAGCCCCCT CCTCCAATTC 121 GGGGGCCAGG TCCGGCAACG TTACCTCTAC ACAGATGATC AGGAGACCGA GGCCCACCTG 181 GAGATCAGAG CAGATGGCAC AGTGGCGGGA GCCGCTCACC GGAGCTCTGA GAGTCTCTTG 241 GAGCTGAAAG CTTTGAAGCC TGGAATAATT CAGATCTTGG GGGTCAAGAC ATCCCGGTTC 301 CTGTGCCAGG GGCCTGATGG GGTGCTGTAC GGATCGCTCC ATTTCGACCC AGCCGCCTGC 361 AGCTTCCGGG AGCTGCTTCT TGAAGATGGA TACAATGTTT ACTGGTCCGA GGCCCATGGA 421 CTCCCAATCC GCCTGCCCTC CCACAACTCC CCATATAGGG ACCCAGCATC CCGGGTACCA 481 GCCCGCTTCC TGCCACTGCC AGGCCTGCTC CCAATGCTCC AAGAACCTCC AGGGGTCCTG 541 GCCCCTGAGC CCCCTGATGT GGACTCCTCA GACCCCCTGA GCATGGTGGG GCCTTCACAG 601 GGCCGAAGCC CCAGCTATGC CTCCTGA Sus scrofa (pig) FGF21 gene coding sequence (SEQ ID NO: 301) (GenBank Accession No. NM_001163410, which is hereby incorporated by reference in its entirety 131 ATGGGCTGGG CCGAGGCCAA GTTCGAGCGC TTGGGACTGT GGGTCCCTGT GCTGGCTGTC 191 CTGCTGGGAG CCTGCCAGGC ACGTCCCATT CCTGACTCCA GCCCCCTCCT CCAATTTGGG 251 GGCCAAGTGC GCCAACGATA CCTCTACACG GATGATGCCC AGGAAACTGA AGCCCACCTG 311 GAGATCAGAG CTGATGGCAC CGTGGCAGGG GTAGCCCGCC AGAGCCCTGA AAGTCTCTTG 371 GAGCTGAAAG CCCTGAAGCC AGGGGTCATT CAAATTTTGG GAGTCCAGAC ATCCCGGTTC 431 CTGTGCCAGG GGCCAGACGG GAGACTGTAC GGATCGCTCC ACTTCGACCC TGAGGCCTGC 491 AGCTTCCGGG AGCTGCTTCT TGAGGATGGC TACAACGTTT ACCAGTCTGA GGCCCTTGGC 551 CTCCCACTCC GGCTGCCTCC GCACCGCTCC TCCAACCGGG ACCTGGCCCC CCGGGGACCT

611 GCTCGCTTCC TGCCACTGCC AGGCCTGCCC CCGGCACCCC CGGAGCCGCC AGGGATCTTG 671 GCCCCTGAAC CTCCCGACGT GGGCTCCTCG GACCCCCTGA GCATGGTGGG GCCTTCACAC 731 GGCCGGAGCC CCAGCTACAC TTCTTGA Felis catus (cat) FGF21 gene coding sequence (SEQ ID NO: 302) (Ensembl Accession No. ENSFCAT00000007367, which is hereby incorporated by reference in its entirety) 1 ATGGGCTGGG ACGAGGCCGG GTCCCAGCGC CTGGGACTGT GGGTCGTGCT GGGGGTCCTT 61 TTGCCGGAAG CCTGCCAGGC ACACCCTATC CCTGACTCCA GCCCCCTCCT CCAATTCGGG 121 GGCCAAGTTC GACAGCGGTT CCTCTACACG GACGACGCCC AGGAGACAGA GGTCCACCTC 181 GAGATCAAGG CTGATGGCAC AGTGGTGGGG ACCGCTCGCC GGAGCCCTGA GAGTCTCTTG 241 GAGCTAAAAG CCCTGAAGCC GGGGGTAATT CAAATCTTGG GGGTCAAAAC GTCCAGGTTC 301 CTGTGCCAGG GCCCAGATGG GACACTGTAT GGATCGCTCC GCTTTGACCC CGCAGCCTGC 361 AGCTTCCGGG AACTGCTCCT GGAGGACGGA TACAACATCT ACCACTCGGA GACCCTCGGG 421 CTCCCACTCC GCCTGCCCCC CCACAACTCC CCATACCGGG ACTTGGCCCC CCGGGCACCT 481 GCCCGCTTCC TGCCGCTGCC AGGCCTGCTT CCGGCACCCC CGGAGCCTCC AGGGATCCTG 541 GCCCCCGAGC CCCCGGACGT GGGCTCCTCG GACCCTCTGA GCATGGTGGG GCCTTCCCAG 601 GGCCGAAGTC CCAGCTACGC TTCCTGA Otolemur garnettii (bushbaby) FGF21 gene coding sequence (SEQ ID NO: 303) (Ensembl Accession No. ENSOGAT00000003585, which is hereby incorporated by reference in its entirety) 1 GACAAGGCCA GGACTGGGTT CAAGCACCCA GGACCATGGT TTCCCCTGCT GGCTGTACTT 61 TTGTTGGGAG CCTGCCAGGC ACACCCTATC CCTGACTCCA GCCCCCTACT CCAGTTTGGT 121 GGCCAAGTCC GGCAGCGGTA CCTCTACACA GATGATGCCC AGGAGACAGA AGCCCACCTG 181 GAGATCAGGG AAGATGGCAC AGTGGTGGGG GCTGCACAAC AGAGCCCTGA AAGTCTCTTG 241 GAGCTGAAAG CTTTAAAGCC AGGGGTCATT CAAATCTTGG GAGTCAAGAC ATCCAGGTTC 301 CTGTGCCAGA GGCCAGATGG GGGCCTATAT GGATCGCTCT ACTTTGACCC CAAGGCCTGC 361 AGTTTCCGGG AGCTGCTTCT TGAGGATGGA TACAACGTTT ACTGGTCTGA GACCTATGGC 421 CTCCCACTGC ACCTGCCTCC TGCCAATTCC CCATACTGGG GCCCATCCCT TCGGAGCCCA 481 GCCCGCTTCC TGCCACTGCC AGGCCCTCCT GCAGCATCCC CAGAGCTGCC GGGGATCTTG 541 GCCCTGGAAC CCCCCGATGT GGGCTCCTCG GACCCTCTGA GCATGGTGGG GCCTTCGCAG 601 GGCCGAAGCC CCAGCTATGC TTCCTGA Rattus norvegicus (Norway rat) FGF21 gene coding sequence (SEQ ID NO: 304) (GenBank Accession No. NM_130752, which is hereby incorporated by reference in its entirety) 1 ATGGACTGGA TGAAATCTAG AGTTGGGGCC CCGGGACTGT GGGTCTGTCT CCTGCTGCCT 61 GTCTTCCTGC TGGGGGTGTG CGAGGCATAC CCCATCTCTG ACTCCAGCCC CCTCCTCCAG 121 TTTGGGGGTC AAGTCCGACA GAGGTATCTC TACACAGATG ACGACCAGGA CACCGAAGCC 181 CACCTGGAGA TCAGGGAGGA CGGAACAGTG GTGGGCACAG CACACCGCAG TCCAGAAAGT 241 CTCCTGGAGC TCAAAGCCTT GAAGCCAGGG GTCATTCAAA TCCTGGGTGT CAAAGCCTCT 301 AGGTTTCTTT GCCAACAACC AGATGGAACT CTCTATGGAT CGCCTCACTT TGATCCTGAG 361 GCCTGCAGTT TCAGAGAGCT GCTGCTTAAG GACGGATACA ATGTGTACCA GTCTGAGGCC 421 CATGGCCTGC CCCTGCGTCT GCCCCAGAAG GACTCCCAGG ATCCAGCAAC CCGGGGACCT 481 GTGCGCTTCC TGCCCATGCC AGGCCTGCCC CACGAGCCCC AAGAGCAACC AGGAGTCCTT 541 CCCCCAGAGC CCCCAGATGT GGGTTCCTCC GACCCCCTGA GCATGGTAGA GCCTTTGCAA 601 GGCCGAAGCC CCAGCTATGC ATCTTGA Mus musculus (house mouse) FGF21 gene coding sequence (SEQ ID NO: 305) (GenBank Accession No. NM_020013, which is hereby incorporated by reference in its entirety) 185 ATGGAA TGGATGAGAT CTAGAGTTGG GACCCTGGGA CTGTGGGTCC GACTGCTGCT 241 GGCTGTCTTC CTGCTGGGGG TCTACCAAGC ATACCCCATC CCTGACTCCA GCCCCCTCCT 301 CCAGTTTGGG GGTCAAGTCC GGCAGAGGTA CCTCTACACA GATGACGACC AAGACACTGA 361 AGCCCACCTG GAGATCAGGG AGGATGGAAC AGTGGTAGGC GCAGCACACC GCAGTCCAGA 421 AAGTCTCCTG GAGCTCAAAG CCTTGAAGCC AGGGGTCATT CAAATCCTGG GTGTCAAAGC 481 CTCTAGGTTT CTTTGCCAAC AGCCAGATGG AGCTCTCTAT GGATCGCCTC ACTTTGATCC 541 TGAGGCCTGC AGCTTCAGAG AACTGCTGCT GGAGGACGGT TACAATGTGT ACCAGTCTGA 601 AGCCCATGGC CTGCCCCTGC GTCTGCCTCA GAAGGACTCC CCAAACCAGG ATGCAACATC 661 CTGGGGACCT GTGCGCTTCC TGCCCATGCC AGGCCTGCTC CACGAGCCCC AAGACCAAGC 721 AGGATTCCTG CCCCCAGAGC CCCCAGATGT GGGCTCCTCT GACCCCCTGA GCATGGTAGA 781 GCCTTTACAG GGCCGAAGCC CCAGCTATGC GTCCTGA Vicugna pacos (alpaca) FGF21 gene coding sequence (SEQ ID NO: 306) (Ensembl accession no. ENSVPAT00000005993, which is hereby incorporated by reference in its entirety) (1-209, excluding 79-168 and 172-182) 1 ATGGACTGGG ACGAGGCCAA GTTCGAGCAT CGGGGACTGT GGGTCCCAGT GCTCACTGTC 61 CTTCTGCTGG GAGCCTGCCA GGCACGCCCC ATTCCTGACT CCAGCCCCCT CCTCCAATTC 121 GGGGGCCAAG TCCGGCAGCG GTACCTCTAC ACGGATGACG CCCAGGAGAC AGAAGCCCAC 181 CTGGAGATCA GGGCTGATGG CACAGTGGTG GGGGTGGCCC GCCAG---CC CGAA------ 241 ---------- ---------- ---------- ---------- ---------- ---------- 301 ---------- ---------- ---------- ---------- ---------- ---------- 361 ---------- ---------- ---------- ---------- ---------- ---------- 421 ---------- ---------- ---------- ---------- ---------- ---------- 481 ---------- ---------- ----GGAATT CCT------- ---------- ---------- 541 ------CCCG AGCCTCCTGA CGTGGGCTCC TCAGACCCCC TGAGCATGGT GGGGCCTTCA 601 TACAGCAGAA GCCCCAGCTA CACTTCCTGA Anolis carolinensis (anole lizard) FGF21 gene coding sequence (SEQ ID NO: 307) (Ensembl accession no. ENSACAT00000017230, which is hereby incorporated by reference in its entirety) 1 TGTAAAAGCA AGGGAGGAGG GAAGGGGGGA GAGAGGATGT GGGTAGACCT AGTTTTCTGG 61 GCTGCCTTGC TCCGCACAGC TCCTGCTCTT CCCTTGCGGA ATTCCAACCC CATCTACCAA 121 TTTGATGGGC AGGTCCGGCT TCGGCACCTC TACACAGCAG ATGAACAGAC GCACCTCCAC 181 TTGGAGATCT TGCCAGACGG TACCGTGGGT GGATCCAGGT TTCAGAATCC CTTCAGTTTG 241 ATGGAGATCA AAGCTGTGAA GCCAGGAGTC ATTCGCATGC AGGCCAAGAA GACCTCTAGA 301 TTTCTCTGTA TGAAACCCAA TGGACGACTG TATGGCTCGC TGTTCTACTC TGAGGAGGCA 361 TGCAACTTCC ATGAGAAGGT TCTCAGCGAT GGCTACAACC TCTACTATTC TGAAAACTAC 421 AACATACCTG TCAGCCTCAG CTCGGCAGGG AACCTGGGTC AGAGCCGTCA GTTGCCTCCC 481 TTCTCCCAAT TCCTGCCGTT AGTCAACAAA ATTCCTCTTG AGCCTGTGCT TGAAGACTTT 541 GACTTCTATG GACATCAATT GGATGTTGAA TCAGCTGATC CTTTGAGCAT TTTAGGACAA 601 AACCCTGGTT TCATGAGTCC GAGCTATGTC TTC Gadus morhua (cod) FGF21 gene coding sequence (SEQ ID NO: 308) (Ensembl accession no. ENSGMOT00000014151, which is hereby incorporated by reference in its entirety) 1 CTCCTCCTCG CCACCCTCCT CCACATCGGC CTCTCCTTCT ACGTCCCCGA CTCCGGCCCC 61 CTGCTGTGGC TGGGCGACCA GGTCAGGGAG AGACACCTCT ACACAGCAGA GAGCCACCGG 121 AGGGGGCTGT TCCTGGAGAT GAGCCCGGAC GGTCAGGTGA CAGGAAGTGC TGCTCAGACG 181 CCGCTCAGTG TTCTGGAGCT GAGGTCGGTC AGAGCAGGAG ATACGGTCAT CAGAGCGCGC 241 CTCTCCTCTC TCTACCTGTG TGTGGACAGG GCAGGTCACC TGACAGGACA GAGACAGTAC 301 ACAGAGTCCG ACTGCACCTT CAGAGAGGTC ATCCTTGAGG ACGGCTACAC CCACTTCCTG 361 TCCGTGCACC ACGGACTTCC TATTTCGCTG GCGCCGAGAC ACTCCCCAGG GAGACAGGGG 421 CTGCGCTTCA GCAGGTTCCT CCCGCTGAGG AGCAGTCTGT CAGAGGATAG GGTCGCCGAG 481 CCCCCAGACA GCCCACTGAA CCTGGACTCT GAAGACCCCC TGGGGATGGG TCTGGGTTCG 541 CTCCTCAGCC CGGCCTTCTC CATG Latimeria chalumnae (coelacanth) FGF21 gene coding sequence (SEQ ID NO: 309) (Ensembl accession no. ENSLACT00000003815, which is hereby incorporated by reference in its entirety) 1 ATGTTATGCC AGAGTTTTGT GATATTAAGT CAGAAATTCA TTTTTGGGCT CTTTTTGACT 61 GGATTGGGGC TAACAGGATT GGCTTGGACA AGGCCCTTCC AGGATTCCAA TCCCATCCTG 121 CAGTATTCCG ATTCCATCCG GCTCCGACAT CTGTACACTG CCAGTGAGAG TCGGCACCTT 181 CACCTACAAA TCAACTCGGA TGGACAGGTG GGAGGGACAA CCAAGCAAAG CCCTTACAGT 241 CTGTTGGAGA TGAAGGCGGT GAAGACAGGT TTTGTGGTCA TCAGGGGCAA GAAAAGCGCC 301 CGTTACCTCT GTATGGAACG TAGTGGACGG CTCTATGGAT CGCTGCAGTA TACAGAAAAA 361 GACTGCACCT TCAAAGAGGT TGTGTTGGCA GATGGATACA ACCTGTATGT CTCAGAGGAA 421 CACCAGGCCA CAGTGACGCT GAGCCCCATG AGGGCGAGGA TAGCGCAAGG GAAAAAGATC 481 CCACCCTTTT CCCATTTCCT TCCAATGGTG AACAAGGTGC CTGTGGAGGA TGTTGCCGCT 541 GAGATGGAGT TTGTCCAGGT GCTGCGGGAA ATGACGGCCG ACGTGGACTC TCCGGATCCC 601 TTTGGAATGA CCTGGGAAGA ATCGGTTCAC AGTCCGAGCT TTTTTGCC Tursiops truncatus (dolphin) FGF21 gene coding sequence (SEQ ID NO: 310) (Ensembl accession no. ENSTTRT00000014561, which is hereby incorporated by reference in its entirety) 1 ATGGGCTGGG ACAAGACCAA ACTCGAGCAC CTGGGACTGT GGGTCCCTGT GCTAGCTGTC 61 CTGCTGGGAC CCTGCCAGGC ACATCCCATT CCTGACTCCA GCCCCCTCCT CCAATTTGGG 121 GGCCAAGTCC GCCAGCGATA CCTCTACACG GATGACGCCC AGGAGACGGA GGCCCACCTG 181 GAGATCAGGG CTGATGGCAC AGTGGTGGGG ACGGCCCGCC GGAGCCCCGA AGGAGTTAAA 241 ACATCCAGGT TCCTGTGCCA GGGGCCAGAG GGGAGGCTGT ATGGATCGCT CCACTTCAAC 301 CCCCAGGCCT GCAGCTTCCG GGAGCTGCTT CTTGAGGATG GATACAACGT TTACCAGTCT 361 GAGGCTCTTG GCATTCCCCT CCGCCTGCCC CCGCACCGCT CCTCCAACTG GGACCTGGCC 421 CCCCGGGGAC CTGCTCGCTT CCTGCCGCTG CCAGGCTTCC TCCCGCCACC CCTGGAGCCT 481 CCAGGGATCT TGGCCCCCGA GCCTCCCAAC GTAGGTTCCT CGGACCCCTT GAGCATGGTG 541 GGACCTTCAC ATGGCCGAAG CCCCAGCTAC ACTTCCTGA Mustela putorius furo (ferret) FGF21 gene coding sequence (SEQ ID NO: 311) (Ensembl accession no. ENSMPUT00000003755, which is hereby incorporated by reference in its entirety) 188 ATG GGCTGGGAAG AGGCCAGGTC CGAGCACCTG GGGCTGTGGG TCCCTGTGCT 241 GGCGGTCCTT TTGCTGGGAG CCTGCCAGGC ATACCCTATT CCTGACTCCA GCCCCCTCCT 301 CCAATTTGGA GGCCAAGTTC GACAGCGGTA CCTCTACACA GACGACGCTC AGGAGACGGA 361 GGCCCACCTA GAGATCAGGG CTGATGGCAC GGTGGTGGGG GCTGCCCGCC GGAGCCCCGA 421 AAGTCTCTTG GAGCTGAAAG CCCTGAAGCC AGGGGTCATT CAGATCTTGG GAGTGAAAAC 481 ATCCAGGTTC CTGTGCCAGG GCCCGAATGG GACACTGTAC GGATCGTTCC ACTTCGACCC 541 CGTAGCCTGC AGCTTCCGGG AAGTGCTTCT GGAAGATGGA TACAACATCT ACCACTCTGA 601 GACCCTGGGC CTCCCACTGC GCCTGCCCCC CCACAACTCC CCACACAGGG ACCTGGCGCC 661 CCGGGGGCCT GCCCGCTTCC TGCCCCTGCC AGGCCTGCTT CCGGCCACCC CGGAGTCCCG 721 GGGGATCCCA GCCCCCGAGC CTCCCAACGT GGGCTCCTCA GACCCCCTGA GCATGGTGGG 781 GCCTTTGCAG GGTCAAAGTC CCAGCTACAC TTCCTGA Takifugu rubripes (fugu) FGF21 gene coding sequence (SEQ ID NO: 312) (Ensembl accession no. ENSTRUT00000034076, which is hereby incorporated by reference in its entirety) 1 TTTATTTATT TATTTATTCA AACTGCACTT TTTTCCCCTT CCAAATGGTT CAACTTTTAT 61 CTCCCTGACT CCAACCCGCT CTTATCCTTT GACAGTCATG GCAGAGGCAT CCACCTCTAC 121 ACAGATAATC AAAGGCGAGG GATGTATCTG CAGATGAGCA CAGATGGAAG CGTTTCCGGG 181 AGTGATGTCC AGACGGCGAA CAGTGTGCTG GAACTGAAGT CAGTCAGAAA CGGCCACGTC 241 GTCATCCGAG GAAAATCGTC TTCTCTGTTT CTCTGTATGG ACAGCAGAGG CCGTTTATGG 301 GGGCAGAGGC ACCCCACTGA GGCCGACTGC ACTTTCAGGG AAGTGTTGCT GGCAGATGGA 361 TACACTCGCT TCCTGTCCCT GCACAACGGA ACTCCTGTGT CTCTGGCACC TAAACAATCT 421 CCAGACCAGC ACACAGTCCC CTTCACTCGT TTCCTGCCGC TCAGGAATAC ACTGGCAGAG 481 GAGAGCATGT CTGAACCACC ATCAAACCAA CAGAGATATT TTAACATTGA CTCTGATGAT 541 CTTCTTGGAA TGGATTTAAA TGCGATGGTC AGTCCTCAGT TTTCAGGGGA CAAGTGA Dipodomys ordii (kangaroo rat) FGF21 gene coding sequence (SEQ ID NO: 313) (Ensembl accession no. ENSDORT00000001234, which is hereby incorporated by reference in its entirety) 1 ATGGACCAGG CAAAGACCAG GGTTGGGGCC CGGGGGCTGG GGGGCCTTGT GCTGGCTGTC 61 ATAATTCTGG GAGCATGCAA GGCACGGCCT ATCCCTGACT CCAGCCCCCT CCTCCAATTT 121 GGGGGTCAAG TTCGGCTTCG GCACCTCTAC ACAGATGACA CTCAGGAGAC GGAAGCCCAT 181 CTGGAGATCA GGGCAGATGG CACGGTAGTG GGGACTGCCC ACCGGAGCCC TGAAAGTCTC 241 TTGGAGCTGA AAGCCTTGAA GCCAGGAGTC ATTCAAATCT TAGGGATCAA GACATCCAGA 301 TTCTTATGCC AGAGACCAGA CGGGACACTG TATGGATCAC TCCACTTTGA CCCTGAGGTT 361 TGCAGCTTCC AGGAGCTGCT TCTGGAAGAT GGATACAACA TTTACCGTTC TGAAGCCCTG 421 GGTCTCCCCC TGCGCCTGTC CCCAGATCCA GCACCCTGGG GGCCAGCCCG CTTCCTGCCC 481 CTGCCTGGTG TGCCCCCCGC ACCGCCGGAG CCCCCCGGGA TCCTGGCTCC CGAACCCCCT 541 GATGTCGGCT CCTCCGACCC TCTGAGTATG GTGGGACTGT TGCAGGGCCG AAGCCCCAGC 601 TATGCATCCT GA Echinops telfairi (lesser hedgehog tenrec) FGF21 gene coding sequence (SEQ ID NO: 314) (Ensembl accession no. ENSETET00000010721, which is hereby incorporated by reference in its entirety) 1 ATGGGTTGCA CCAAATCTGG GTGGAAGTCC CCGGGACTGT GGGTCCCTGT GCTGGCCAGC 61 CTTCTGCTGG GAGGCTGCGG AGCACACCCC ATCCCTGACT CCAGCCCCCT CCTCCAATTC 121 GGGGGCCAAG TCCGGCAGCG ATACCTCTAT ACGGATGACG CCCAGACCAC CGAGGCCCAC 181 CTGGAGATCA GAGCGGATGG CACAGTGGGG GGCGTCGCCC ACCAGAGCCC AGAGAAGTTC 241 CTGAGTCAAT GGCGTGAAAA GCCCCTGAGA TCACTCCATT TCGACCCAGC CGCCTGCAGC 301 TTCCGGGAGA AGCTTCTAGA AGACGGATAC AACTTGTACC ACTCTGAGAC CCACGGCCTC 361 CCCCTCCGCC TCCCACCCCG TGGGGGCGAC CCCTCTTCTC AGCCTGGGGC CCGCTTCCCA 421 CCGCTGCCGG GCCAGCTCCC ACAACTCCAA GAGACGCCAG GGGTCCTCGC CCCCGAACCC 481 CCCGACGTGG GCTCTTCAGA CCCCCTGAGC ATGGTGGGGC CTTGGCGAGG GCAAAGTCCC 541 AGTTATGCCT CCTGA Macaca mulatta (rhesus monkey) FGF21 gene coding sequence (SEQ ID NO: 315) (Ensembl accession no. ENSMMUT00000038440, which is hereby incorporated by reference in its entirety) 1 ATGGACTCGG ACGAGACCGG GTTCGAGCAC TCAGGACTGT GGGTTCCTGT GCTGGCTGGT 61 CTTCTGCTGG GAGCCTGCCA GGCACACCCC ATCCCTGACT CCAGTCCTCT CCTGCAATTC 121 GGGGGCCAAG TCCGGCAACG GTACCTCTAC ACAGATGATG CCCAGCAGAC AGAAGCCCAC 181 CTGGAGATCA GGGAGGATGG GACAGTGGGG GGCGCTGCTC ACCAGAGCCC CGAAAGTGAG 241 TGTGGGCCAG AGCCTGGGTC TGAGGGAGGA GGGGCTGTGG GAGGTGCTGA GGGACCTGGA 301 CTCCTGGGTC TGAGGGAGGC AGGGCTGGGG CCTGGATCCT GGCTCCACTT TGACCCTGAG 361 GCCTGCAGCT TCCGGGAGCT GCTTCTTGAG AACGGATACA ATGTTTACCA GTCCGAGGCC 421 CACGGCCTCC CACTGCACCT GCCGGGAAAC AAGTCCCCAC ACCGGGACCC TGCATCCCAA 481 GGACCAGCTC GCTTCCTGCC ACTACCAGGC CTGCCCCCCG CACCCCCGGA GCCGCCAGGA 541 ATCCTCGCCC CCCAGCCCCC CGATGTGGGC TCCTCGGACC CTCTGAGCAT GGTGGGACCT 601 TCCCAGGCCC GAAGCCCCAG CTATGCTTCC TGA Microcebus murinus (mouse lemur) FGF21 gene coding sequence (SEQ ID NO: 316) (Ensembl accession no. EN5MICT00000013258, which is hereby incorporated by reference in its entirety) 1 ATGGGCTGGG ACGAGGCCGG CGCCGGGTTC GAGCACCCAG GACTGTGGTT TCCCATGCTG 61 GGTGTCCTGC TGCTGGGAGC CTGCCAGGCG TACCCCATCC CTGACTCCAG CCCCCTCCTC 121 CAATTTGGCG GCCAAGTCCG GCAGCGGCAC CTCTACACAG ACGATATCCA GGAGACAGAA 181 GCCCACCTGG AGATCAGGGC GGACGGCACA GTGGTGGGGG CCGCCCGACA GAGCCCTGAG 241 TTGGAGCTGA AAGCCTTAAA GCCAGGGGTC ATTCAAATCT TGGGAGTCAA GACCTCCAGG 301 TTCCTGTGCC AGAGGCCAGA CGGGGCCCTG TACGGATCGC TCCACTTTGA CCCCGAGTGC 361 AGCTTCCGGG AGCTGCTTCT TGAGGATGGA TACAACGTCT ACTGTCCCTA CCTCCCGCTG 421 CACCTGTCCC CACGCATCGA ACTGGCCGGA TCACGCTCTG CGCTGCCACT GCCCCCAGCA 481 CCTGAACGCA GGATTTTGGC CCCGGAGCCC CCGGATGGCT CCTCGGACCC TCTGAGCATG 541 GTGGGGCCTT CGCAGGGCCG AAGTCCCAGC TATGCTTCCT GA Ochotona princeps (pika) FGF21 gene coding sequence (SEQ ID NO: 317) (Ensembl accession no. ENSOPRT00000007373, which is hereby incorporated by reference in its entirety) 1 AAAGACATGG ACGGGCTCCA GCCTCCGGGG CTGCGGGTTC CTGTGCTGGC TGCCCTGCTT 61 TTGGGAGTTG GCCAGGCACG CCCCATCCCT GATTCTAGCC CTCTCCTCCA ATTCGGGGGC 121 CAGGTCCGGC AGAGGCACCT CTACACGGAT GACGCCCAGG AATCGGAAGT ACACCTGGAG 181 ATCCGGGCAG ACGGCACCGT GGCAGGGACT GCCCGCCGGA GCCCTGAAAG TCTCTTAGAA 241 ATGAAAGCGT TGAAGCCAGG CGTCATTCAG ATCCTGGGGG TCCACACATC CAGGTTCCTG 301 TGCCAGAGAC CAGACGGGAC GCTGTACGGC TCGCTCCACT TCGACCACAA GGCCTGCAGC 361 TTCCGGGAGC AGCTGCTGGA GGATGGGTAC AACGTGTACC ACTCAGAGAC ACACGGCCTC 421 CCGCTGCGCC TGTCTCCAGA CCGAGCCCCC CGGGGCCCAG CCCGCTTCCT GCCACTGCCA 481 GGCCCTCCTC CTGACCTCCT GGTGCCACCC CTGCCACCGG ACGTCCTAGC CCCTGAGCCC 541 CCCGACGTGG ACTCCCCAGA CCCCCTGAGC ATGGTGGGGC CCTTGCAGGG CCAAAGCCCC 601 AGCTACACTT CCTGA Xiphophorus maculatus (platyfish) FGF21 gene coding sequence (SEQ ID NO: 318) (Ensembl accession no. ENSXMAT00000001579, which is hereby incorporated by reference in its entirety) 1 TGCCCGTTCC CCTTCCTTTT CTTAATCCTC TCTCTTCCCT TTTTCTCTTC CTCGTTTTAC 61 ATCCCAGAAT CCAACCCAAT CTTTGCCTTC AGGAATCAGC TCAGAGAGGT GCATCTCTAC 121 ACAGAAAATC ACAGACGGGG TTTGTATGTG GAGATACATC TGGATGGGAG AGTGACTGGA 181 AGTGATGCTC AGAGTCCTTA TAGTGTGTTG CAGATAAAGT CTGTTAAACC GGGTCATGTG 241 GTCATAAAGG GACAGACATC GTCCCTGTTC CTCTGCATGG ACGACTCCGG GAATCTAAGA 301 GGACAGACAA CCTATGACGA GGCTGACTGC TCCTTCAGGG AACTGCTGCT GGCCGATGGC 361 TACACCCGTT TCCTGAACTC ACAACATGGC GTTCCTTTAT CACTGGCATC CAGAAACTCT 421 CCAGATCGAC ACTCCGTTCC TTTCACAAGA TTTTTACCTC TCAGGAATAC TTTAACGGTT

481 TCAGAAGAAT CAACAAAAAC TCAGAGGGAC TTCAACCTGG ACTCGGACGA CCTTCTCGGG 541 ATGGGA Gasterosteus aculeatus (stickleback) FGF21 gene coding sequence (SEQ ID NO: 319) (Ensembl accession no. ENSGACT00000010725, which is hereby incorporated by reference in its entirety) 1 TCTCTCCTCC TCATGGTCCC ACTTCCTTTC TGTTCATCCT TTTATCTCAC TGACTCCAGC 61 CCACTTCTAC CCTTCAATAA TCAAGTCAAA GAGGTGCACC TCTACACAGC AGAGAATCAC 121 AGAAGAGCGA TGTACCTGCA GATCGCTCTG GACGGGAGCG TGTCGGGAAG CGACGCTCGG 181 TCCACTTACA GTGTGCTGCA GCTGAAATCT ATCCAGCCGG GCCACGTGGT CATCAGAGGG 241 AAGGCCTCCT CCATGTTCCT CTGCGTGGAC AGCGGGGGCC GTTTGAGAGG ACAGGGGCCG 301 TACTCAGAGG CCGACTGCAG CTTCAGGGAG CTGCTGCTGG GGGATGGCTA CACCCGGTTC 361 CTGTCCTCGC AGCACGGGTC CCCGCTGTCT CTGGCGTCGA GGCCTTCCCC GGATCCCAAC 421 TCGGTGCCCT TCACTCGATT CCTACCCATC CGGACCGCCC CCGAGGCTGA GAGCGTGATC 481 GAAGAGCCAC CGAGCAATCA GAGATACGTC AACGTGGACT CCGAGGATCT TCTTGGAATG 541 GGCCTGAACA CTGTGGTCAG TCCTCAGTTC TCGGCG Sarcophilus harrisii (Tasmanian devil) FGF21 gene coding sequence (SEQ ID NO: 320) (Ensembl accession no. ENSSHAT00000006017, which is hereby incorporated by reference in its entirety) (1-209, excluding 1-2 and 173-209) 132 GTGTCTGCC ATGGGCCTGA GGGAGCGAGC TCCCAGGTAC CTGGCCCCGC 181 TGCTGTCCTT GCTCTTGGCC TGCAGGGCCT CGGGTCACCC CCTCCCGGAT TCCAGCCCCA 241 TGCTCCTGTT TGGGGGGCAG GTCCGCCTCC GGCACCTCTA CACGGATGTG GGCCAGGAGG 301 CCGAGGCCCA CGTGGAACTG GCGTCCGACG GCACAGTCCG GGCGGCAGCG CGGAGGAGTC 361 CCAACAGTCT CCTGGAGCTG AAGGCTGTGA AGCCGGGCAT CGTCCGAATC CTGGCCGTCC 421 ACAGCTCTCG GTTTCTGTGT ATGAGGCCCA ACGGGGAGCT GTACGGAGCG ATACACTACG 481 ACCCTTCCGC CTGCAACTTT CGGGAGCGCC TGCTGGGGGA CGGCTACAAC GTGTACGAGT 541 CCGAGGCTCA CGGGAGGACC CTCCGCCTGC CCCCCAAGGC CGCACCGGGA CCCGCCGGAC 601 CTTCTCGCTT CCTGCCGCTC CCCGGC Macropus eugenii (wallaby) FGF21 gene coding sequence (SEQ ID NO: 321) (Ensembl accession no. ENSMEUT00000015309, which is hereby incorporated by reference in its entirety) 1 ACAGAGGAGC CTTCTACTGG GTCCAGGCAC CTGGGACAAT GGGCTCCCGG GCTGCCTGGT 61 CCTCTGCTGT CCTTGCTCCT GGCCTACAGG GGCTGGGGCT CCCCCATCCC TGATTCCAGC 121 CCCATGCTCC TGTTTGGTGG CCAGGTCCGC CTCCGACACC TGTACACAGA TGATGGCCAG 181 GACACGGAGG CCCATGTGGA GCTGGGGCCA GATGGAGTGG TTCGAGCTGT GGCTGAGAGG 241 AGCCCCAACA GTCTTCTGGA ACTGAAGGCG GTGAAGCCTG GAGTCATCCG AATCCTCGCT 301 GTCCAGAGCT CTCGGTTTCT GTGTATGAGG CCCAACGGGG AACTGTATGG AGCGGTACAC 361 TATGACCCTT CTGCCTGCAA CTTTCGGGAA CATCTGCTGG GGGATGGTTA TAATGTGTAT 421 GAATCAGAGA CTCACAGAAG GACCCTCCGT CTGTCCCCAT CCCTGGGTCA GGCTGGCCCC 481 TCTCGCTTCC TGCCACTTCC AGGCGACTGG CTGCCCGGCC CTGATCCACC TTGGGCACAG 541 GGCCCTGAGC CCCCAGACGT GGGCTCTGCA GACCCCCTGA GCATGGTGGG GGCCGTGCAG 601 GGCCTCAGCC CCAGCTACTC CTCCTGA Xenopus tropicalis (Western clawed frog) FGF21 gene coding sequence (SEQ ID NO: 322) (Ensembl accession no. ENSXETT00000009917, which is hereby incorporated by reference in its entirety) (1-209, excluding 170-209) 1 AGAGGGGGTA GGACCAAAAA AAAGACGTTA CTCAGGAAAT GGCTTTGCCT TTTAGCCATT 61 ATGTTGAGTA GGTCAAGGTT TTCTTTAGCA AATCCTATCC AGAATTCGAA CCCAATCTTA 121 TCCAACGACA ACCAAGTACG GACTCAGTAT TTATACACAG ATAACAATAA CATGCACCTG 181 TATCTTCAGA TCACCCACAA TGGAGTAGTA ACTGGTACCG AAGAAAAGAA TGACTATGGT 241 GTGCTGGAAA TAAAGGCAGT AAAAGCTGGG GTTGTAGTTA TAAAAGGAAT TCGAAGCAAT 301 CTCTACCTAT GCATGGATTC TAGACACCAA TTGTATGCGT CGGCATATGA TAAAGATGAC 361 TGCCATTTCC ATGAAAAGAT CACACCAGAT AATTACAACA TGTATAGCTC AGAGAAGCAT 421 TCAGAATACG TGTCCTTAGC TCCATTAAAA GGAAGCCAGA TGGCTCGTTT TCTACCTATA Danio rerio (zebrafish) FGF21 gene coding sequence (SEQ ID NO: 323) (Ensembl accession no. ENSDART00000103511, which is hereby incorporated by reference in its entirety) 30 A TGCTTCTTGC CTGCTTTTTT ATATTTTTTG 61 CTCTTTTTCC TCATCTTCGG TGGTGTATGT ATGTTCCTGC ACAGAACGTG CTTCTGCAGT 121 TTGGCACACA AGTCAGGGAA CGCCTGCTTT ACACAGATGG GTTGTTTCTT GAAATGAATC 181 CAGATGGCTC CGTCAAAGGC TCTCCTGAAA AGAATCTAAA TTGTGTGCTG GAGCTGCGTT 241 CAGTCAAAGC GGGTGAAACC GTCATCCAGA GTGCAGCTAC ATCTCTCTAC CTCTGCGTCG 301 ATGATCAAGA CAAGCTGAAA GGACAGCATC ATTACTCTGC ACTAGACTGC ACCTTTCAGG 361 AATTGCTACT GGATGGATAT TCGTTTTTCC TTTCTCCACA CACTAATCTT CCCGTATCGC 421 TCCTCTCGAA ACGTCAGAAA CACGGCAATC CTCTTTCTCG CTTCCTCCCT GTTAGCAGAG 481 CAGAGGACAG CCGGACACAG GAGGTGAAAC AGTATATTCA GGATATAAAC CTGGACTCTG 541 ACGACCCACT AGGAATGGGA CATCGGTCAC ACTTACAGAC CGTCTTCAGT CCCAGTCTGC 572 ATACTAAAAA ATGA Tupaia chinensis (Chinese tree shrew) FGF21 gene coding sequence (SEQ ID NO: 327)(generated using SMS Reverse Translate tool on the ExPASy Bioinformatics Resource website (www.expasy.org)) 1 ATGGGCTGGG ATAAAGCGCG CTTTGAACAT CTGGGCGCGT GGGCGCCGGT GCTGGCGGTG 61 CTGCTGCTGG GCGCGTGCCA GGCGTATCCG ATTCCGGATA GCAGCCCGCT GCTGCAGTTT 121 GGCGGCCAGG TGCGCCAGCG CTATCTGTAT ACCGATGATA CCCAGGATAC CGAAGCGCAT 181 CTGGAAATTC GCGCGGATGG CACCGTGGTG GGCGCGGCGC ATCAGAGCCC GGAAAGCCTG 241 CTGGAACTGA AAGCGCTGAA ACCGGGCGTG ATTCAGATTC TGGGCGTGAA AACCAGCCGC 301 TTTCTGTGCC AGCGCCCGGA TGGCGCGCTG TATGGCAGCC TGCATTTTGA TCCGGAAGCG 361 TGCAGCTTTC GCGAACTGCT GCTGGAAGAT GGCTATAACA TTTATCAGAG CGAAGCGCGC 421 GGCCTGCCGC TGCGCCTGCC GCCGCATGAT AGCCCGCATC GCGATCGCAC CCCGCAGGGC 481 CCGGCGCGCT TTCTGCCGCT GCCGGGCCTG CCGCTGGTGC CGCCGGAACT GCCGGGCGTG 541 CTGGCGCTGG AACCGCCGGA TGTGGGCAGC AGCGATCCGC TGAGCATGAT GGGCCCGAGC 601 CAGGGCCAGA GCCCGAGCTA TGCGAGCTAA Papio anubis (olive baboon) FGF21 gene coding sequence (SEQ ID NO: 328) (GenBank accession no. XM_003915851, which is hereby incorporated by reference in its entirety) 1 ATGGACTCGG ACGAGACCGG GTTCGAGCAC TCAGGACTGT GGGTTCCTGT GCTGGCTGGT 61 CTTCTGCTGG GAGCCTGCCA GGCACACCCC ATCCCTGACT CCAGTCCTCT CCTGCAATTC 121 GGGGGCCAAG TCCGGCAACG GTACCTCTAC ACAGATGATG CCCAGCAGAC AGAAGCCCAC 181 CTGGAGATCA GGGAGGATGG GACAGTGGGG GGCGCTGCTC ACCAGAGCCC CGAAAGTAAG 241 TGTGGGCCAG AGCCTGGGTC TGAGGGAGGA GGGGCTCTCC ACTTTGACCC TGAGGCCTGC 301 AGCTTCCGCG AGCTGCTTCT TGAGAACGGA TACAATGTTT ACCAGTCCGA GGCCCACGGC 361 CTCCCACTGC ACCTGCCGGG AAACAAGTCC CCACACCGGG ACCCTGCATC CCGAGGACCA 421 GCTCGCTTCC TGCCACTACC AGGCCTGCCC CCCGCACCCC CAGAGCCACC AGGAATCCTC 481 GCCCCCCAGC CCCCCGATGT GGGCTCCTCG GACCCTCTGA GCATGGTGGG ACCTTCCCAG 541 GCCCGAAGCC CTAGCTACGC TTCCTGA Pteropus alecto (black flying fox) FGF21 gene coding sequence (SEQ ID NO: 329) (generated using SMS Reverse Translate tool on the ExPASy Bioinformatics Resource website (www.expasy.org)) 1 ATGGGCTGGG GCAAAGCGCG CCTGCAGCAT CCGGGCCTGT GGGGCCCGGT GCTGGCGGTG 61 CTGCTGGGCG CGTGCCAGGC GCATCCGATT CTGGATAGCA GCCCGCTGTT TCAGTTTGGC 121 AGCCAGGTGC GCCGCCGCTA TCTGTATACC GATGATGCGC AGGATACCGA AGCGCATCTG 181 GAAATTCGCG CGGATGGCAC CGTGGCGGGC GCGGCGCGCC GCAGCCCGGA AAGCCTGCTG 241 GAACTGAAAG CGCTGAAACC GGGCGTGATT CAGGTGCTGG GCGTGAAAAC CAGCCGCTTT 301 CTGTGCCAGC GCCCGGATGG CACCCTGTAT GGCAGCCTGC ATTTTGATCC GGCGGCGTGC 361 AGCTTTCGCG AACTGCTGCT GAAAGATGGC TATAACGTGT ATCAGAGCGA AGCGCTGGCG 421 CGCCCGCTGC GCCTGCCGCC GTATAGCAGC CCGAGCAGCG ATCCGGCGCG CCGCGGCCCG 481 GCGCGCTTTC TGCCGCTGCC GGGCCCGCCG CCGGAACCGC CGCAGCCGCC GGGCCGCCTG 541 GCGCCGGAAC CGCCGGATGT GGGCAGCAGC GATCCGCTGA GCATGGTGTG GCCGAGCCGC 601 GGCCGCAGCC CGAGCTATAC CAGCTAA Heterocephalus glaber (naked mole-rat) FGF21 gene coding sequence (SEQ ID NO: 330) (generated using SMS Reverse Translate tool on the ExPASy Bioinformatics Resource website (www.expasy.org)) 1 ATGGATTGGG CGCGCGCGGA AAGCGAACGC CCGGGCCTGT GGGTGCCGGC GGTGCTGGCG 61 GTGCTGCTGC TGGGCGCGTG CCAGGCGCAT CCGATTCCGG ATAGCAGCCC GCTGCTGCAG 121 TTTGGCGGCC AGGTGCGCCA GCGCCATCTG TATACCGATG ATGCGCAGGA TACCGAAGTG 181 CATCTGGAAA TTCGCGCGGA TGGCAGCGTG GGCGGCGCGG CGCATCGCAG CCCGGAAAGC 241 CTGCTGGAAC TGAAAGCGCT GAAACCGGGC GTGATTCAGA TTCTGGGCGT GCGCACCAGC 301 CGCTTTCTGT GCCAGCGCCC GGATGGCACC CTGTATGGCA GCCTGCATTT TGATCCGGAA 361 GCGTGCAGCT TTCGCGAACT GCTGCTGGCG GATGGCTATA ACATTTATCA GAGCGAAGCG 421 TATGGCCTGC CGCTGCGCAT GCTGCCGAGC GATAGCGCGA GCCGCGATCC GGTGCCGCCG 481 GGCCCGGCGC GCTTTCTGCC GCTGCCGGGC CTGCATCCGC CGCCGCTGGA ACCGCCGGGC 541 ATGCTGCCGC CGGAACCGCC GGATGTGGGC AGCAGCGATC CGCTGAGCAT GGTGGGCCCG 601 CTGCAGGGCC GCAGCCCGAG CTATGCGTTT TAA Cricetulus griseus (Chinese hamster) FGF21 gene coding sequence (SEQ ID NO: 331) (GenBank accession no. XM_003508678, which is hereby incorporated by reference in its entirety) 1 ATGGACTGGA TGAAATCTGG AGTTGGGGTC CCGGGACTGT GGGTCCCTCT GCTGCCTATC 61 TTCCTGCTGG GGGTCTCCCA GGCACACCCC ATCCCTGACT CCAGCCCCCT CCTCCAGTTT 121 GGGGGTCAAG TCCGGCACAG GCACCTCTAC ACAGATGACA ACCAGGAAAC TGAAGTCCAC 181 CTGGAGATTA GGCAGGATGG CACGGTGATA GGGACCACAC ACCGCAGCCC AGAAAGTCTC 241 CTGGAGCTCA AAGCCTTGAA GCCAGAGGTC ATCCCAGTGC TGGGTGTCAA GGCCTCCAGG 301 TTTCTTTGCC AACAACCAGA CGGAACCCTG TATGGATCGC CTCACTTTGA TCCTGAGGCC 361 TGCAGTTTCA GGGAGCTCTT GCTTGAGGAT GGATACAATG TGTACCAATC TGAAGTCCAT 421 GGCCTGCCCC TGCGCCTGCC CCAGAGGGAC TCTCCAAACC AGGCCCCAGC ATCCTGGGGA 481 CCTGTGCCCC CCCTGCCAGT GCCAGGACTG CTCCACCAGC CCCAGGAGCT ACCAGGGTTC 541 CTGGCCCCAG AACCTCCAGA TGTGGGCTCC TCTGACCCAC TGAGCATGGT GGGACCTTTG 601 CAGGGCCGAA GCCCCAGCTA TGCTTCCTGA Ovis aries (sheep) FGF21 gene coding sequence (SEQ ID NO: 332) (GenBank accession no. XM_004015796, which is hereby incorporated by reference in its entirety) 1 ATGGGCTGGG ACGAGGCCAA GTTCAAGCAC TTGGGACTGT GGGTCCCTGT GCTGGCTGTC 61 CTCCTGCTAG GAACCTGCCG GGCGCATCCA ATTCCAGACT CCAGCCCCCT CCTCCAGTTT 121 GGGGGCCAAG TCCGCCAGCG GTACCTCTAC ACGGATGATG CCCAGGAGAC AGAGGCCCAC 181 CTGGAGATCA GGGCCGATGG CACAGTGGTG GGGGCGGCCC GCCAGAGTCC CGAAAGTCTC 241 TTGGAGCTGA AAGCCCTGAA GCCAGGAGTC ATTCAGATCT TTGGAGTTAA AACATCCAGG 301 TTCCTGTGCC AGGGGCCAGA TGGGAAGCTG TATGGATCGC TGCACTTTGA CCCCAAAGCC 361 TGCAGCTTCC GGGAGCTGCT TCTTGAAGAT GGGTACAATG TCTACCAGTC GGAGACCCTG 421 GGCCTTCCAC TCCGCCTGCC GCCGCAGCGC TCATCCAACC GGGACCCGGC CCCGCGGGGA 481 CCTCCGAAGC CCCAGCTACA CTTCTTGAAG ACGTCCGCTG TGCAGTACTG GCCACGTTAT 541 GAGAAGGTCC CAGCTTTTCT GCACCCCTTC CCCGGCTGA Pan paniscus (pygmy chimpanzee) FGF21 gene coding sequence (SEQ ID NO: 333) (GenBank accession no. XM_003814115, which is hereby incorporated by reference in its entirety) (1-209, excluding 117-194 and 202-209) 573 ATGGACTC GGACGAGACC GGGTTCGAGC 601 ACTCAGGACT GTGGGTTTCT GTGCTGGCTG GTCTTCTGCT GGGAGCCTGC CAGGCACACC 661 CCATCCCTGA CTCCAGTCCT CTCCTGCAAT TCGGGGGCCA AGTCCGGCAG CGGTACCTCT 721 ACACAGATGA TGCCCAGCAG ACAGAAGCCC ACCTGGAGAT CAGGGAGGAT GGGACGGTGG 781 GGGGCGCTGC TGACCAGAGC CCCGAAAGTC TCCTGCAGCT GAAAGCCTTG AAGCCGGGAG 841 TTATTCAAAT CTTGGGAGTC AAGACATCCA GGTTCCTGTG CCAGAGGCCA GATGGGGCCC 901 TGTATGGATC GGTGAGTTTC ---------- ---------- ---------- ---------- ---------- ---------- ---------- ---------- ---------- ---------- 921 ---------- ----CAG--- ---------- ---------- ---------- ---------- 924 ---------- -------GAC CCTCCT---- --------CA CCACCCACCA ---------T 946 GCTCC----- ----TCCTAT ATGTCGCCCTCACAG------ ---CCTGGG Macaca fascicularis (crab-eating macaque) FGF21 gene coding sequence (SEQ ID NO: 334) (generated using SMS Reverse Translate tool on the ExPASy Bioinformatics Resource website (www.expasy.org)) (1-209, excluding 117-209) 1 ATGGATAGCG ATGAAACCGG CTTTGAACAT AGCGGCCTGT GGGTGCCGGT GCTGGCGGGC 61 CTGCTGCTGG GCGCGTGCCA GGCGCATCCG ATTCCGGATA GCAGCCCGCT GCTGCAGTTT 121 GGCGGCCAGG TGCGCCAGCG CTATCTGTAT ACCGATGATG CGCAGCAGAC CGAAGCGCAT 181 CTGGAAATTC GCGAAGATGG CACCGTGGGC GGCGCGGCGC ATCAGAGCCC GGAAAGCCTG 241 CTGCAGCTGA AAGCGCTGAA ACCGGGCGTG ATTCAGATTC TGGGCGTGAA AACCAGCCGC 301 TTTCTGTGCC AGAAACCGGA TGGCGCGCTG TATGGCAGCG TGAGCTTTTA A Mesocricetus auratus (golden hamster) FGF21 gene coding sequence (SEQ ID NO: 335) (GenBank accession no. EU497769, which is hereby incorporated by reference in its entirety) (1-209, excluding 1-89 and 194-209) 1 GGTCATCCAA ATCCTGGGTG TCAAGGCTGC TAGGTTTCCT TGCCAGCAAC CAGACGGAAG 61 CCTGTACGGA TCGCCTCACT TCGATCCCGA GGCCTGCAGT TTCCGGGAGC TCCTGCTTGA 121 GGATGGATAC AATGTGTACC AGTCGGAAGC CCACGGCCTG CCCCTGCGCC TGCCCCAGAG 181 GGACGCTCCG AGCCAGCCCC CAGCATCCTG GGGACCGGTG CGCTTCCTGC CAGTGCCCGG 241 ACTGTTCCAG CCGCCCCACG ACCTCCCAGG GCGCCCGGCC CCAGAGCCTC CGGACGTGGG 301 CTCCTCCGAC CCAC Nile tilapia FGF21 gene coding sequence (SEQ ID NO: 336) (GenBank accession no. XM_003438468, which is hereby incorporated by reference in its entirety) (1-209, excluding 1-58) 1 ATGTATTTGC AGATGAACAT GGATGGGAGA GTCACAGGAA GTGATGCTCA GACACCTTAC 61 AGTTTGATGC AGCTGAAATC AGTTAAACCA GGCCATGTAA TCATTAAAGG ACCATCATCA 121 TCTCTTTTTC TCTGTGTGGA CAGCGAAGGC AATCTGAGAG GGCAGAGTCA CTACTCAGAA 181 ACCAGCTGCA CCTTCAGAGA AATGCTGCTG GCTGACGGAT ACACCCGTTT CATTTCCTCA 241 CAATATGGAT TTCCCATGTC ACTGGCATCA AGACATTCCC CAGATCGACA CGCGCTTCCC 301 TTTACGCGGT TCCTACCACT GAGGAATAAC TTGAAAACGG ATAGCGTATC AGAGCAGCTG 361 CCAAACAATC AGAGACTCTT CAACGTGGAC TCTGATGACC TTCTTGGAAT GGGTCTAAAT 421 TCTATGGGCA GTCCTCAGTT TTCTATGGAC AAATAA

In one embodiment of the present invention, the chimeric protein may include one or more substitutions for or additions of amino acids from another FGF. In one embodiment, the C-terminal portion from FGF21 includes a modification that includes a substitution for or addition of amino acid residues from an FGF19 (including a human FGF19 and orthologs of human FGF19). In one embodiment the FGF19 is a human FGF19 protein having an amino acid sequence of SEQ ID NO: 337 (GenBank Accession No. NP_005108, which is hereby incorporated by reference in its entirety) or a portion or ortholog thereof, as follows:

TABLE-US-00014 1 MRSGCVVVHV WILAGLWLAV AGRPLAFSDA GPHVHYGWGD PIRLRHLYTS GPHGLSSCFL 61 RIRADGVVDC ARGQSAHSLL EIKAVALRTV AIKGVHSVRY LCMGADGKMQ GLLQYSEEDC 121 AFEEEIRPDG YNVYRSEKHR LPVSLSSAKQ RQLYKNRGFL PLSHFLPMLP MVPEEPEDLR 181 GHLESDMFSS PLETDSMDPF GLVTGLEAVR SPSFEK

Exemplary substitutions and additions of such residues are shown in FIGS. 12 and 13.

In one embodiment, the C-terminal portion from FGF21 includes a modification that includes a substitution of amino acid residues from an FGF19 molecule. In one embodiment, the modification includes a substitution for or addition of amino acid residues 169 to 216 of SEQ ID NO: 337 (FGF19). In one embodiment, the modification is a substitution of amino acid residues from SEQ ID NO: 337 (FGF19) for corresponding amino acid residues of SEQ ID NO: 233 (FGF21). The corresponding residues of FGFs may be identified by sequence analysis and/or structural analysis. See FIGS. 2, 11, 12, and 13. In one embodiment, the modification includes a substitution of a contiguous stretch of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 amino acid residues 169 to 216 of SEQ ID NO: 337 (FGF19) for the corresponding contiguous stretch of amino acid residues of SEQ ID NO: 233 (FGF21). In one embodiment, amino acid residues 168 to 209, 191 to 209, or 198 to 209 of SEQ ID NO: 233 (FGF21) are substituted with the corresponding amino acid residues selected from the sequence including amino acid residues 169 to 216 of SEQ ID NO: 337 (FGF19).

In one embodiment, the modification includes a substitution of one or more individual amino acid residues from residues 169 to 216 of SEQ ID NO: 337 (FGF19) for the corresponding amino acid residues of SEQ ID NO: 233 (FGF21). In one embodiment, the C-terminal portion includes substitutions of one or more of amino acid residues 168, 169, 170, 171, 173, 174, 177, 178, 179, 180, 181, 182, 183, 184, 186, 187, 188, 189, 191, 194, 195, 196, 199, 200, 201, 202, 207, 208, or 209 of SEQ ID NO: 233 (FGF21) for the corresponding amino acid residues of SEQ ID NO:337 (FGF19).

In one embodiment of the present invention, the C-terminal portion from FGF21 includes a modification that includes an addition of amino acid residues that are present in the corresponding C-terminal portion from FGF19. As shown in FIGS. 11, 12, and 13, FGF19 residues that are absent in the corresponding C-terminal portion of FGF21 may be identified by sequence analysis and/or structural analysis. In one embodiment, the modification includes an addition of amino acid residues selected from residues 204 to 216, 197 to 216, 174 to 216, or 169 to 216 of SEQ ID NO: 337 (FGF19). In one embodiment, the modification includes an addition of amino acid residue 204 of SEQ ID NO: 337 (FGF19). In one embodiment, the modification includes an addition of amino acid residues 178, 179, 180, 181, and/or 182 of SEQ ID NO: 337 (FGF19) individually or in combination.

It will be understood that the C-terminal portion from FGF21 that includes a substitution of amino acid residues from an FGF19 molecule may be derived using a nucleotide sequence that encodes a human FGF19 protein having a nucleotide sequence of SEQ ID NO: 338 (Human FGF19 gene coding sequence (1-216); GenBank Accession No. NM_005117, which is hereby incorporated by reference in its entirety) or a portion or ortholog thereof, as follows:

TABLE-US-00015 464 ATGCGGA GCGGGTGTGT GGTGGTCCAC GTATGGATCC TGGCCGGCCT CTGGCTGGCC 521 GTGGCCGGGC GCCCCCTCGC CTTCTCGGAC GCGGGGCCCC ACGTGCACTA CGGCTGGGGC 581 GACCCCATCC GCCTGCGGCA CCTGTACACC TCCGGCCCCC ACGGGCTCTC CAGCTGCTTC 641 CTGCGCATCC GTGCCGACGG CGTCGTGGAC TGCGCGCGGG GCCAGAGCGC GCACAGTTTG 701 CTGGAGATCA AGGCAGTCGC TCTGCGGACC GTGGCCATCA AGGGCGTGCA CAGCGTGCGG 761 TACCTCTGCA TGGGCGCCGA CGGCAAGATG CAGGGGCTGC TTCAGTACTC GGAGGAAGAC 821 TGTGCTTTCG AGGAGGAGAT CCGCCCAGAT GGCTACAATG TGTACCGATC CGAGAAGCAC 881 CGCCTCCCGG TCTCCCTGAG CAGTGCCAAA CAGCGGCAGC TGTACAAGAA CAGAGGCTTT 941 CTTCCACTCT CTCATTTCCT GCCCATGCTG CCCATGGTCC CAGAGGAGCC TGAGGACCTC 1001 AGGGGCCACT TGGAATCTGA CATGTTCTCT TCGCCCCTGG AGACCGACAG CATGGACCCA 1061 TTTGGGCTTG TCACCGGACT GGAGGCCGTG AGGAGTCCCA GCTTTGAGAA GTAA

In one embodiment, the chimeric protein of the present invention includes the amino acid sequence of SEQ ID NO: 339, SEQ ID NO: 340, SEQ ID NO: 341, or SEQ ID NO: 342, as shown in Table 9.

TABLE-US-00016 TABLE 9 Description of Chimeric Protein Sequence Amino acid sequence of a SEQ ID NO: 339 FGF1/FGF21 chimera composed MAEGEITTFT ALTEKFNLPP GNYKKPKLLY of residues M1 to L150 of human CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ FGF1 harboring LSAESVGEVY IKSTETGQYL AMDTDGLLYG K127D/K128Q/K133V triple SQTPNEECLF LERLEENHYN TYISKKHAEK mutation (bold) and residues P168 NWFVGLDQNG SCVRGPRTHY GQKAILFLPL to S209 of human FGF21 (bold) PGLPPALPEP PGILAPQPPD VGSSDPLSMV GPSQGRSPSY AS Amino acid sequence of a SEQ ID NO: 340 FGF1/FGF21 chimera composed KPKLLY of residues K25 to L150 of human CSNGGHFLRI LPDGTVDGTR DRSDQHIQLQ FGF1 harboring LSAESVGEVY IKSTETGQYL AMDTDGLLYG K127D/K128Q/K133V triple SQTPNEECLF LERLEENHYN TYISKKHAEK mutation (bold) and residues P168 NWFVGLDQNG SCVRGPRTHY GQKAILFLPL to S209 of human FGF21 (bold) PGLPPALPEP PGILAPQPPD VGSSDPLSMV GPSQGRSPSY AS Amino acid sequence of a SEQ ID NO: 341 FGF2/FGF21 chimera composed MAAGSITTLP ALPEDGGSGA FPPGHFKDPK of residues M1 to M151 of human RLYCKNGGFF LRIHPDGRVD GVREKSDPHI FGF2 harboring KLQLQAEERG VVSIKGVCAN RYLAMKEDGR K128D/R129Q/K134V triple LLASKCVTDE CFFFERLESN NYNTYRSRKY mutation (bold) and residues P168 TSWYVALDQT GQYVLGSKTG PGQKAILFLP to S209 of human FGF21 (bold) MPGLPPALPE PPGILAPQPP DVGSSDPLSM VGPSQGRSPS YAS Amino acid sequence of a SEQ ID NO: 342 FGF2/FGF21 chimera composed HFKDPK of residues H25 to M151 of RLYCKNGGFF LRIHPDGRVD GVREKSDPHI human FGF2 harboring KLQLQAEERG VVSIKGVCAN RYLAMKEDGR K128D/R129Q/K134V triple LLASKCVTDE CFFFERLESN NYNTYRSRKY mutation (bold) and residues P168 TSWYVALDQT GQYVLGSKTG PGQKAILFLP to S209 of human FGF21 (bold) MPGLPPALPE PPGILAPQPP DVGSSDPLSM VGPSQGRSPS YAS

Chimeric proteins according to the present invention may be isolated proteins or polypeptides. The isolated chimeric proteins of the present invention may be prepared for use in accordance with the present invention using standard methods of synthesis known in the art, including solid phase peptide synthesis (Fmoc or Boc strategies) or solution phase peptide synthesis. Alternatively, peptides of the present invention may be prepared using recombinant expression systems.

Accordingly, another aspect of the present invention relates to an isolated nucleic acid molecule encoding a chimeric protein according to the present invention. In one embodiment, the nucleic acid molecule includes the nucleotide sequence of SEQ ID NO: 343, SEQ ID NO: 344, SEQ ID NO: 345, or SEQ ID NO: 346 (as shown in Table 10).

TABLE-US-00017 TABLE 10 Description of Chimeric Protein Sequence Nucleotide SEQ ID NO: 343 sequence of a ATGGCTGAAG GGGAAATCAC CACCTTCACA FGF1/FGF21 GCCCTGACCG AGAAGTTTAA TCTGCCTCCA chimera composed GGGAATTACA AGAAGCCCAA ACTCCTCTAC of residues M1 TGTAGCAACG GGGGCCACTT CCTGAGGATC to L150 of CTTCCGGATG GCACAGTGGA TGGGACAAGG human FGF1 GACAGGAGCG ACCAGCACAT TCAGCTGCAG harboring K127D/ CTCAGTGCGG AAAGCGTGGG GGAGGTGTAT K128Q/K133V ATAAAGAGTA CCGAGACTGG CCAGTACTTG triple mutation GCCATGGACA CCGACGGGCT TTTATACGGC (bold) and TCACAGACAC CAAATGAGGA ATGTTTGTTC residues P168 to CTGGAAAGGC TGGAGGAGAA CCATTACAAC S209 of human ACCTATATAT CCAAGAAGCA TGCAGAGAAG FGF21 (bold) AATTGGTTTG TTGGCCTCGA TCAGAATGGG AGCTGCGTTC GCGGTCCTCG GACTCACTAT GGCCAGAAAG CAATCTTGTT TCTCCCCCTG CCAGGCCTGC CCCCCGCACT CCCGGAGCCA CCCGGAATCC TGGCCCCCCA GCCCCCCGAT GTGGGCTCCT CGGACCCTCT GAGCATGGTG GGACCTTCCC AGGGCCGAAG CCCCAGCTAC GCTTCC Nucleotide SEQ ID NO: 344 sequence of a AAGCCCAA ACTCCTCTAC FGF1/FGF21 TGTAGCAACG GGGGCCACTT CCTGAGGATC chimera composed CTTCCGGATG GCACAGTGGA TGGGACAAGG of residues 1 GACAGGAGCG ACCAGCACAT TCAGCTGCAG (25 to L150 CTCAGTGCGG AAAGCGTGGG GGAGGTGTAT of human FGF1 ATAAAGAGTA CCGAGACTGG CCAGTACTTG harboring K127D/ GCCATGGACA CCGACGGGCT TTTATACGGC K128Q/K133V TCACAGACAC CAAATGAGGA ATGTTTGTTC triple mutation CTGGAAAGGC TGGAGGAGAA CCATTACAAC (bold) and ACCTATATAT CCAAGAAGCA TGCAGAGAAG residues P168 AATTGGTTTG TTGGCCTCGA TCAGAATGGG to S209 AGCTGCGTTC GCGGTCCTCG GACTCACTAT of human GGCCAGAAAG CAATCTTGTT TCTCCCCCTG FGF21 (bold) CCAGGCCTGC CCCCCGCACT CCCGGAGCCA CCCGGAATCC TGGCCCCCCA GCCCCCCGAT GTGGGCTCCT CGGACCCTCT GAGCATGGTG GGACCTTCCC AGGGCCGAAG CCCCAGCTAC GCTTCC Nucleotide SEQ ID NO: 345 sequence of a ATG GCAGCCGGGA FGF2/FGF21 GCATCACCAC GCTGCCCGCC TTGCCCGAGG chimera composed ATGGCGGCAG CGGCGCCTTC CCGCCCGGCC of residues ACTTCAAGGA CCCCAAGCGG CTGTACTGCA M1 to M151 of AAAACGGGGG CTTCTTCCTG CGCATCCACC human FGF2 CCGACGGCCG AGTTGACGGG GTCCGGGAGA harboring K128D/ AGAGCGACCC TCACATCAAG CTACAACTTC R129Q/K134V AAGCAGAAGA GAGAGGAGTT GTGTCTATCA triple mutation AAGGAGTGTG TGCTAACCGT TACCTGGCTA (bold) and TGAAGGAAGA TGGAAGATTA CTGGCTTCTA residues P168 to AATGTGTTAC GGATGAGTGT TTCTTTTTTG S209 of human AACGATTGGA ATCTAATAAC TACAATACTT FGF21 (bold) ACCGGTCAAG GAAATACACC AGTTGGTATG TGGCACTGGA TCAGACTGGG CAGTATGTTC TTGGATCCAA AACAGGACCT GGGCAGAAAG CTATACTTTT TCTTCCAATG CCAGGCCTGC CCCCCGCACT CCCGGAGCCA CCCGGAATCC TGGCCCCCCA GCCCCCCGAT GTGGGCTCCT CGGACCCTCT GAGCATGGTG GGACCTTCCC AGGGCCGAAG CCCCAGCTAC GCTTCC Nucleotide SEQ ID NO: 346 sequence of C a FGF2/FGF21 ACTTCAAGGA CCCCAAGCGG CTGTACTGCA chimera composed AAAACGGGGG CTTCTTCCTG CGCATCCACC of residues M1 CCGACGGCCG AGTTGACGGG GTCCGGGAGA to M151 of human AGAGCGACCC TCACATCAAG CTACAACTTC FGF2 harboring AAGCAGAAGA GAGAGGAGTT GTGTCTATCA K128D/R129Q/ AAGGAGTGTG TGCTAACCGT TACCTGGCTA K134V triple TGAAGGAAGA TGGAAGATTA CTGGCTTCTA mutation (bold) AATGTGTTAC GGATGAGTGT TTCTTTTTTG and residues AACGATTGGA ATCTAATAAC TACAATACTT P168 to S209 ACCGGTCAAG GAAATACACC AGTTGGTATG of human TGGCACTGGA TCAGACTGGG CAGTATGTTC FGF21 (bold) TTGGATCCAA AACAGGACCT GGGCAGAAAG CTATACTTTT TCTTCCAATG CCAGGCCTGC CCCCCGCACT CCCGGAGCCA CCCGGAATCC TGGCCCCCCA GCCCCCCGAT GTGGGCTCCT CGGACCCTCT GAGCATGGTG GGACCTTCCC AGGGCCGAAG CCCCAGCTAC GCTTCC

Another aspect of the present invention relates to a nucleic acid construct including a nucleic acid molecule encoding a chimeric protein according to the present invention, a 5' DNA promoter sequence, and a 3' terminator sequence. The nucleic acid molecule, the promoter, and the terminator are operatively coupled to permit transcription of the nucleic acid molecule.

Also encompassed are vectors or expression vectors including such nucleic acid molecules and host cells including such nucleic acid molecules. Nucleic acid molecules according to the present invention can be expressed in a host cell, and the encoded polynucleotides isolated, according to techniques that are known in the art.

Generally, the use of recombinant expression systems involves inserting the nucleic acid molecule encoding the amino acid sequence of the desired peptide into an expression system to which the molecule is heterologous (i.e., not normally present). One or more desired nucleic acid molecules encoding a peptide of the invention may be inserted into the vector. When multiple nucleic acid molecules are inserted, the multiple nucleic acid molecules may encode the same or different peptides. The heterologous nucleic acid molecule is inserted into the expression system or vector in proper sense (5'.fwdarw.3') orientation relative to the promoter and any other 5' regulatory molecules, and correct reading frame.

The preparation of the nucleic acid constructs can be carried out using standard cloning procedures well known in the art as described by Joseph Sambrook et al., MOLECULAR CLONING: A LABORATORY MANUAL (Cold Springs Harbor 1989). U.S. Pat. No. 4,237,224 to Cohen and Boyer, which is hereby incorporated by reference in its entirety, describes the production of expression systems in the form of recombinant plasmids using restriction enzyme cleavage and ligation with DNA ligase. These recombinant plasmids are then introduced by means of transformation and replicated in a suitable host cell.

A variety of genetic signals and processing events that control many levels of gene expression (e.g., DNA transcription and messenger RNA ("mRNA") translation) can be incorporated into the nucleic acid construct to maximize protein production. For the purposes of expressing a cloned nucleic acid sequence encoding a desired protein, it is advantageous to use strong promoters to obtain a high level of transcription. Depending upon the host system utilized, any one of a number of suitable promoters may be used. For instance, when cloning in E. coli, its bacteriophages, or plasmids, promoters such as the T7 phage promoter, lac promoter, trp promoter, recA promoter, ribosomal RNA promoter, the P.sub.R and P.sub.L promoters of coliphage lambda and others, including but not limited, to lacUV5, ompF, bla, lpp, and the like, may be used to direct high levels of transcription of adjacent DNA segments. Additionally, a hybrid trp-lacUV5 (tac) promoter or other E. coli promoters produced by recombinant DNA or other synthetic DNA techniques may be used to provide for transcription of the inserted gene. Common promoters suitable for directing expression in mammalian cells include, without limitation, SV40, MMTV, metallothionein-1, adenovirus Ela, CMV, immediate early, immunoglobulin heavy chain promoter and enhancer, and RSV-LTR.

There are other specific initiation signals required for efficient gene transcription and translation in prokaryotic cells that can be included in the nucleic acid construct to maximize protein production. Depending on the vector system and host utilized, any number of suitable transcription and/or translation elements, including constitutive, inducible, and repressible promoters, as well as minimal 5' promoter elements, enhancers or leader sequences may be used. For a review on maximizing gene expression see Roberts and Lauer, "Maximizing Gene Expression On a Plasmid Using Recombination In Vitro," Methods in Enzymology 68:473-82 (1979), which is hereby incorporated by reference in its entirety.

A nucleic acid molecule encoding an isolated protein of the present invention, a promoter molecule of choice, including, without limitation, enhancers, and leader sequences; a suitable 3' regulatory region to allow transcription in the host, and any additional desired components, such as reporter or marker genes, are cloned into the vector of choice using standard cloning procedures in the art, such as described in Joseph Sambrook et al., MOLECULAR CLONING: A LABORATORY MANUAL (Cold Springs Harbor 1989); Frederick M. Ausubel, SHORT PROTOCOLS IN MOLECULAR BIOLOGY (Wiley 1999); and U.S. Pat. No. 4,237,224 to Cohen and Boyer, which are hereby incorporated by reference in their entirety.

Once the nucleic acid molecule encoding the protein has been cloned into an expression vector, it is ready to be incorporated into a host. Recombinant molecules can be introduced into cells, without limitation, via transfection (if the host is a eukaryote), transduction, conjugation, mobilization, or electroporation, lipofection, protoplast fusion, mobilization, or particle bombardment, using standard cloning procedures known in the art, as described by JOSEPH SAMBROOK et al., MOLECULAR CLONING: A LABORATORY MANUAL (Cold Springs Harbor 1989), which is hereby incorporated by reference in its entirety.

A variety of suitable host-vector systems may be utilized to express the recombinant protein or polypeptide. Primarily, the vector system must be compatible with the host used. Host-vector systems include, without limitation, the following: bacteria transformed with bacteriophage DNA, plasmid DNA, or cosmid DNA; microorganisms such as yeast containing yeast vectors; mammalian cell systems infected with virus (e.g., vaccinia virus, adenovirus, etc.); insect cell systems infected with virus (e.g., baculovirus); and plant cells infected by bacteria.

Purified proteins may be obtained by several methods readily known in the art, including ion exchange chromatography, hydrophobic interaction chromatography, affinity chromatography, gel filtration, and reverse phase chromatography. The protein is preferably produced in purified form (preferably at least about 80% or 85% pure, more preferably at least about 90% or 95% pure) by conventional techniques. Depending on whether the recombinant host cell is made to secrete the protein into growth medium (see U.S. Pat. No. 6,596,509 to Bauer et al., which is hereby incorporated by reference in its entirety), the protein can be isolated and purified by centrifugation (to separate cellular components from supernatant containing the secreted protein) followed by sequential ammonium sulfate precipitation of the supernatant. The fraction containing the protein is subjected to gel filtration in an appropriately sized dextran or polyacrylamide column to separate the protein of interest from other proteins. If necessary, the protein fraction may be further purified by HPLC.

Another aspect of the present invention relates to a pharmaceutical composition that includes a chimeric protein according to the present invention and a pharmaceutically acceptable carrier.

"Carriers" as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers which are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. Often the physiologically acceptable carrier is an aqueous pH buffered solution. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEEN.TM., polyethylene glycol (PEG), and PLURONIC S.TM..

The term "pharmaceutically acceptable" means it is, within the scope of sound medical judgment, suitable for use in contact with the cells of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and is commensurate with a reasonable benefit/risk ratio.

In one embodiment, the pharmaceutical composition includes an organotropic targeting agent. In one embodiment, the targeting agent is covalently linked to the chimeric protein via a linker that is cleaved under physiological conditions.

Chimeric and/or modified proteins according to the present invention may also be modified using one or more additional or alternative strategies for prolonging the in vivo half-life of the protein. One such strategy involves the generation of D-peptide chimeric proteins, which consist of unnatural amino acids that are not cleaved by endogenous proteases. Alternatively, the chimeric and/or modified proteins may be fused to a protein partner that confers a longer half-life to the protein upon in vivo administration. Suitable fusion partners include, without limitation, immunoglobulins (e.g., the Fc portion of an IgG), human serum albumin (HAS) (linked directly or by addition of the albumin binding domain of streptococcal protein G), fetuin, or a fragment of any of these. The chimeric and/or modified proteins may also be fused to a macromolecule other than protein that confers a longer half-life to the protein upon in vivo administration. Suitable macromolecules include, without limitation, polyethylene glycols (PEGs). Methods of conjugating proteins or peptides to polymers to enhance stability for therapeutic administration are described in U.S. Pat. No. 5,681,811 to Ekwuribe, which is hereby incorporated by reference in its entirety. Nucleic acid conjugates are described in U.S. Pat. No. 6,528,631 to Cook et al., U.S. Pat. No. 6,335,434 to Guzaev et al., U.S. Pat. No. 6,235,886 to Manoharan et al., U.S. Pat. No. 6,153,737 to Manoharan et al., U.S. Pat. No. 5,214,136 to Lin et al., or U.S. Pat. No. 5,138,045 to Cook et al., which are hereby incorporated by reference in their entirety.

The pharmaceutical composition according to the present invention can be formulated for administration orally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by implantation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, transdermally, or by application to mucous membranes. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

Another aspect of the present invention relates to a method for treating a subject suffering from a disorder. This method involves selecting a subject suffering from the disorder and administering the pharmaceutical composition according to the present invention to the selected subject under conditions effective to treat the disorder. In one embodiment the disorder is diabetes, obesity, or metabolic syndrome.

Another aspect of the present invention relates to a method for treating a subject suffering from a disorder. This method involves selecting a subject suffering from the disorder and providing a chimeric FGF protein, where the chimeric FGF protein includes an N-terminus coupled to a C-terminus. The N-terminus includes a portion of a paracrine FGF and the C-terminus includes a C-terminal portion of FGF21. The portion of the paracrine FGF is modified to decrease binding affinity for heparin and/or heparan sulfate compared to the portion without the modification. This method also involves administering a therapeutically effective amount of the chimeric FGF protein to the selected subject under conditions effective to treat the disorder.

Suitable chimeric proteins for use in accordance with this aspect of the present invention are described above and throughout the present application.

In one embodiment, the selected subject is a mammal. In one embodiment, the selected subject is a human. In another embodiment, the selected subject is a rodent.

In one embodiment, the selected subject is in need of increased FGF21-.beta.Klotho-FGF receptor ("FGFR") complex formation.

In one embodiment, the disorder is a selected from diabetes, obesity, and metabolic syndrome. As used herein, diabetes includes type I diabetes, type II diabetes, gestational diabetes, and drug-induced diabetes. In yet another embodiment, the subject has obesity. In yet another embodiment, the subject has metabolic syndrome.

The chimeric protein of the present invention or pharmaceutical composition thereof can be used to treat a number of conditions. In one embodiment, the condition is one which the therapeutic outcome includes a decrease in blood glucose, a decrease in blood fructosamine, an increase in energy expenditure, an increase in fat utilization, a decrease in body weight, a decrease in body fat, a decrease in triglycerides, a decrease in free fatty acids, an increase in fat excretion, an improvement, or even a preservation, of pancreatic .beta.-cell function and mass, a decrease in total blood cholesterol, a decrease in blood low-density lipoprotein cholesterol, an increase in blood high-density lipoprotein cholesterol, an increase in blood adiponectin, an increase in insulin sensitivity, an increase in leptin sensitivity, a decrease in blood insulin, a decrease in blood leptin, a decrease in blood glucagon, an increase in glucose uptake by adipocytes, a decrease in fat accumulation in hepatocytes, and/or an increase in fat oxidation in hepatocytes. Each of these parameters can be measured by standard methods, for example, by measuring oxygen consumption to determine metabolic rate, using scales to determine weight, and measuring lean body mass composition or mass to determine fat. Moreover, the presence and amount of triglycerides, free fatty acids, glucose and leptin can be determined by standard methods (e.g., blood test).

Additional conditions that are treatable in accordance with the present invention include one or more of type 1 diabetes, type 2 diabetes, gestational diabetes, drug-induced diabetes, high blood glucose, metabolic syndrome, lipodystrophy syndrome, dyslipidemia, insulin resistance, leptin resistance, atherosclerosis, vascular disease, inflammatory disease, fibrotic disease, hypercholesterolemia, hypertriglyceridemia, non-alcoholic fatty liver disease, overweight, and obesity.

In one embodiment, the chimeric protein of the present invention or pharmaceutical composition thereof is administered with a pharmaceutically-acceptable carrier.

The chimeric protein according to the present invention or pharmaceutical composition thereof can be administered orally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation, by implantation, by intracavitary or intravesical instillation, intraocularly, intraarterially, intralesionally, transdermally, or by application to mucous membranes. The most suitable route may depend on the condition and disorder of the recipient. Formulations including chimeric proteins according to the present invention may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

Dosages and desired drug concentrations of pharmaceutical compositions of the present invention may vary depending on the particular use envisioned. The determination of the appropriate dosage or route of administration is well within the skill of an ordinary physician. Those skilled in the art can readily optimize pharmaceutically effective dosages and administration regimens for therapeutic compositions including the chimeric protein according to the present invention, as determined by good medical practice and the clinical condition of the individual patient.

When in vivo administration of a chimeric protein of the present invention or is employed, normal dosage amounts may vary from, for example, about 10 ng/kg to up to 100 mg/kg of mammal body weight or more per day. In one embodiment, the dosage may be from about 1 g/kg/day to 10 mg/kg/day, depending upon the route of administration. In one embodiment, the chimeric protein according to the present invention is administered at a dose of about 0.1 to 10 mg/kg once or twice daily. In one embodiment, the chimeric protein according to the present invention is administered at a dose of about 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2 mg/kg. In one embodiment, the dosage is the same as that of a native FGF21 therapeutic. In one embodiment, the dosage is less than that of a native FGF21 therapeutic, but has the same effect as a higher dosage of a native FGF21 therapeutic. Guidance as to particular dosages and methods of delivery of proteins is provided in the literature; see, for example, U.S. Pat. No. 4,657,760; 5,206,344; or 5,225,212, which are hereby incorporated by reference in their entirety. It is anticipated that different formulations will be effective for different treatment compounds and different disorders, that administration targeting one organ or tissue, for example, may necessitate delivery in a manner different from that to another organ or tissue.

Where sustained-release administration of a chimeric protein of the present invention is desired in a formulation with release characteristics suitable for the treatment of any disease or disorder requiring administration of the chimeric protein of the present invention, microencapsulation is contemplated. Microencapsulation of recombinant proteins for sustained release has been successfully performed with human growth hormone (rhGH), interferon-(rhIFN-), interleukin-2, and MN rgp120. Johnson et al., "Preparation and Characterization of Poly(D,L-lactide-co-glycolide) Microspheres for Controlled Release of Human Growth Hormone," Nat. Med. 2:795-799 (1996); Yasuda, "Sustained Release Formulation of Interferon," Biomed. Ther. 27:1221-1223 (1993); Hora et al., "Controlled Release of Interleukin-2 from Biodegradable Microspheres," Nat. Biotechnol. 8:755-758 (1990); Cleland, "Design and Production of Single Immunization Vaccines Using Polylactide Polyglycolide Microsphere Systems," in VACCINE DESIGN: THE SUBUNIT AND ADJUVANT APPROACH 439-462 (Powell and Newman, eds. 1995); WO 97/03692; WO 96/40072; WO 96/07399; and U.S. Pat. No. 5,654,010, which are hereby incorporated by reference in their entirety. The sustained-release formulations of these proteins were developed using poly-lactic-coglycolic acid (PLGA) polymer due to its biocompatibility and wide range of biodegradable properties. The degradation products of PLGA, lactic and glycolic acids, can be cleared quickly within the human body. Moreover, the degradability of this polymer can be adjusted from months to years depending on its molecular weight and composition. Lewis, "Controlled release of bioactive agents from lactide/glycolide polymer," in: BIODEGRADABLE POLYMERS AS DRUG DELIVERY SYSTEMS 1-41 (M. Chasin and R. Langer eds. 1990), which is hereby incorporated by reference in its entirety.

The chimeric protein of the present invention or pharmaceutical composition thereof may be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond rapidly to a higher or lower dose and may find much weaker maintenance doses adequate. For other patients, it may be necessary to have long-term treatments at the rate of 1 to 4 doses per day, in accordance with the physiological requirements of each particular patient. For other patients, it will be necessary to prescribe not more than one or two doses per day.

In some embodiments, the chimeric protein of the present invention or a pharmaceutical composition thereof is administered in a therapeutically effective amount in combination with a therapeutically effective amount of a second agent. In one embodiment, the chimeric protein of the present invention or pharmaceutical composition thereof is administered in conjunction with the second agent, i.e., the respective periods of administration are part of a single administrative regimen. In one embodiment, the chimeric protein of the present invention or pharmaceutical composition thereof and the second agent are administered concurrently, i.e., the respective periods of administration overlap each other. In one embodiment, the chimeric protein of the present invention or pharmaceutical composition thereof and the second agent are administered non-concurrently, i.e., the respective periods of administration do not overlap each other. In one embodiment, the chimeric protein of the present invention or pharmaceutical composition thereof and the second agent are administered sequentially, i.e., the chimeric protein of the present invention or pharmaceutical composition thereof is administered prior to and/or after the administration of the second agent. In one embodiment, the chimeric protein of the present invention or pharmaceutical composition thereof and the second agent are administered simultaneously as separate compositions. In one embodiment, the chimeric protein of the present invention or pharmaceutical composition thereof and the second agent are administered simultaneously as part of the same compositions.

In one embodiment, the second agent is an anti-inflammatory agent, an anti-fibrotic agent, an antihypertensive agent, an anti-diabetic agent, a triglyceride-lowering agent, and/or cholesterol-lowering drug such as a drug of the "statin" class. In one embodiment, the second agent is insulin. In one embodiment, the insulin is rapid acting, short acting, regular acting, intermediate acting, or long acting insulin. In one embodiment, the insulin is and/or comprises Humalog.RTM., Lispro, Novolog.RTM., Apidra.RTM., Humulin.RTM., Aspart, regular insulin, NPH, Lente, Ultralente, Lantus.RTM., Glargine, Levemir.RTM., or Detemir. In one embodiment, the second agent is a statin. In one embodiment, the statin is and/or comprises Atorvastatin (e.g., Lipitor.RTM. or Torvast.RTM.), Cerivastatin (e.g., Lipobay.RTM. or Baycol.RTM.), Fluvastatin (e.g., Lescol.RTM. or LescolXL.RTM.), Lovastatin (e.g., Mevacor.RTM., Altocor.RTM., or Altoprev.RTM.) Mevastatin, Pitavastatin (e.g., Livalo.RTM. or Pitava.RTM.), Pravastatin (e.g., Pravachol.RTM., Selektine, or Lipostat.RTM.) Rosuvastatin (e.g., Crestor.RTM.), Simvastatin (e.g., Zocor.RTM. or Lipex.RTM.), Vytorin.RTM., Advicor.RTM., Besylate Caduet.RTM. or Simcor.RTM..

In one embodiment of the present invention, the chimeric protein according to the present invention or the pharmaceutical composition thereof is administered with an anti-inflammatory agent, an antifibrotic agent, an antihypertensive agent, an antidiabetic agent, a triglyceride-lowering agent, and/or a cholesterol-lowering agent.

Another aspect of the present invention relates to a method of making a chimeric FGF protein possessing enhanced endocrine activity. This method involves introducing one or more modifications to an FGF protein, where the modification decreases the affinity of the FGF protein for heparin and/or heparan sulfate and coupling a Klotho co-receptor binding domain to the modified FGF protein's C-terminus, whereby a chimeric FGF protein possessing enhanced endocrine activity is made.

In one embodiment, the method includes selecting a Klotho co-receptor binding domain, where the Klotho co-receptor binding domain is selected to target an endocrine FGF target tissue. In one embodiment, the Klotho co-receptor binding domain is selected to home the chimeric FGF protein into a target tissue of endocrine FGF. In one embodiment, the Klotho co-receptor binding domain is selected to target white adipose tissue, brown adipose tissue, skeletal muscle, pancreas, and/or liver.

In one embodiment, the Klotho co-receptor binding domain includes a .beta.-Klotho co-receptor binding domain. In one embodiment, the .beta.-Klotho co-receptor binding domain includes a C-terminal portion from FGF21. In one embodiment, the C-terminal portion from the FGF21 includes amino acid residues 168-209 of SEQ ID NO: 233. In one embodiment, the C-terminal portion derived from FGF21 further includes one or more substitutions while retaining the ability to bind .beta.-Klotho. In one embodiment, the C-terminal portion derived from FGF21 further includes one or more substitutions to enhance its binding affinity for .beta.-Klotho. In one embodiment, the C-terminal portion from FGF21 is derived from a mammalian FGF21. In one embodiment, the C-terminal portion derived from FGF21 is from a vertebrate FGF21. Suitable FGF21 molecules, C-terminal portions thereof, and modifications thereto, are described above.

In one embodiment, the chimeric FGF protein has greater binding affinity for FGFR than native endocrine FGF ligand having the Klotho co-receptor binding domain. In one embodiment, the chimeric FGF protein possesses enhanced endocrine activity compared to the chimeric FGF protein in the absence of the modification or the Klotho co-receptor binding domain. In one embodiment, the native endocrine FGF ligand having the Klotho co-receptor binding domain is native FGF21. In one embodiment, the FGFR is FGFR1c, FGFR2c, or FGFR4.

In one embodiment, the chimeric FGF protein has greater stability than a native endocrine FGF ligand possessing the Klotho co-receptor binding domain. In one embodiment, increasing the stability includes an increase in thermal stability of the protein as compared to either wild type protein or native endocrine FGF ligand. In one embodiment, increasing the stability includes increasing the half-life of the protein in the blood circulation as compared to wild type protein or native endocrine FGF ligand.

In one embodiment, the method involves introducing one or more modifications to the FGF protein, where the modification alters the receptor-binding specificity of the FGF protein. In one embodiment, the method involves introducing one or more modifications to the FGF protein, where the modification alters the receptor-binding affinity of the FGF protein.

In one embodiment, the FGF is derived from a mammalian FGF. In one embodiment, the FGF is derived from a vertebrate FGF. In one embodiment, the FGF protein is a paracrine FGF molecule. In one embodiment the FGF molecule is FGF1 or FGF2. In one embodiment, the FGF protein is an FGF protein that possesses intrinsically greater binding affinity for FGF receptor than a native endocrine FGF ligand. In one embodiment, the FGF protein is an FGF protein that possesses intrinsically greater thermal stability than a native endocrine FGF ligand. In one embodiment, the method involves introducing one or more modifications to the FGF protein, where the modification alters receptor-binding specificity and/or receptor-binding affinity of the FGF protein. In one embodiment, the method involves introducing one or more modifications to the FGF protein, where the modification alters the stability of the FGF protein. For example, receptor-binding specificity of FGF1, which by nature binds to all the seven principal FGFRs, may be altered to, for example, reduce any risk for adverse effects (e.g., mitogenicity). Paracrine FGFs, portions of paracrine FGFs, and modifications thereto are described above.

In one embodiment, the chimeric FGF protein is effective to treat diabetes, obesity, and/or metabolic syndrome.

Suitable methods of generating chimeric proteins according to the present invention include standard methods of synthesis known in the art, as described above.

Yet another aspect of the present invention relates to a method of facilitating fibroblast growth factor receptor ("FGFR")-.beta.Klotho co-receptor complex formation. This method involves providing a cell that includes a .beta.Klotho co-receptor and an FGFR and providing a chimeric FGF protein. The chimeric FGF protein includes a C-terminal portion of FGF21 and a portion of a paracrine FGF, where the portion of the paracrine FGF is modified to decrease binding affinity for heparin and/or heparan sulfate compared to the portion without the modification. This method also involves contacting the cell and the chimeric FGF protein under conditions effective to cause FGFR-.beta.Klotho co-receptor complex formation.

The portion of the paracrine FGF may also be modified to alter receptor-binding specificity and/or receptor-binding affinity of the FGF, as noted above. Suitable portions of the paracrine FGFs for use in accordance with the present invention, as well as modifications to alter receptor-binding specificity and/or receptor-binding affinity of the FGF, are described above. Suitable modifications to the paracrine FGFs for use in accordance with the present invention are also described above. Suitable C-terminal portions from FGF21 are described above and throughout the present application.

In one embodiment according to the present invention, .beta.Klotho is mammalian .beta.Klotho. In one embodiment, .beta.Klotho is human or mouse .beta.Klotho. In one particular embodiment of the present invention, .beta.Klotho is human or mouse .beta.Klotho having the amino acid sequence of SEQ ID NO: 347 (i.e., GenBank Accession No. NP_783864, which is hereby incorporated by reference in its entirety) or SEQ ID NO: 348 (i.e., GenBank Accession No. NP_112457, which is hereby incorporated by reference in its entirety), respectively, as follows:

TABLE-US-00018 SEQ ID NO: 348: 1 MKPGCAAGSP GNEWIFFSTD EITTRYRNTM SNGGLQRSVI LSALILLRAV TGFSGDGRAI 61 WSKNPNFTPV NESQLFLYDT FPKNFFWGIG TGALQVEGSW KKDGKGPSIW DHFIHTHLKN 121 VSSTNGSSDS YIFLEKDLSA LDFIGVSFYQ FSISWPRLFP DGIVTVANAK GLQYYSTLLD 181 ALVLRNIEPI VTLYHWDLPL ALQEKYGGWK NDTIIDIFND YATYCFQMFG DRVKYWITIH 241 NPYLVAWHGY GTGMHAPGEK GNLAAVYTVG HNLIKAHSKV WHNYNTHFRP HQKGWLSITL 301 GSHWIEPNRS ENTMDIFKCQ QSMVSVLGWF ANPIHGDGDY PEGMRKKLFS VLPIFSEAEK 361 HEMRGTADFF AFSFGPNNFK PLNTMAKMGQ NVSLNLREAL NWIKLEYNNP RILIAENGWF 421 TDSRVKTEDT TAIYMMKNFL SQVLQAIRLD EIRVFGYTAW SLLDGFEWQD AYTIRRGLFY 481 VDFNSKQKER KPKSSAHYYK QIIRENGFSL KESTPDVQGQ FPCDFSWGVT ESVLKPESVA 541 SSPQFSDPHL YVWNATGNRL LHRVEGVRLK TRPAQCTDFV NIKKQLEMLA RMKVTHYRFA 601 LDWASVLPTG NLSAVNRQAL RYYRCVVSEG LKLGISAMVT LYYPTHAHLG LPEPLLHADG 661 WLNPSTAEAF QAYAGLCFQE LGDLVKLWIT INEPNRLSDI YNRSGNDTYG AAHNLLVAHA 721 LAWRLYDRQF RPSQRGAVSL SLHADWAEPA NPYADSHWRA AERFLQFEIA WFAEPLFKTG 781 DYPAAMREYI ASKHRRGLSS SALPRLTEAE RRLLKGTVDF CALNHFTTRF VMHEQLAGSR 841 YDSDRDIQFL QDITRLSSPT RLAVIPWGVR KLLRWVRRNY GDMDIYITAS GIDDQALEDD 901 RLRKYYLGKY LQEVLKAYLI DKVRIKGYYA FKLAEEKSKP RFGFFTSDFK AKSSIQFYNK 961 VISSRGFPFE NSSSRCSQTQ ENTECTVCLF LVQKKPLIFL GCCFFSTLVL LLSIAIFQRQ 1021 KRRKFWKAKN LQHIPLKKGK RVVS SEQ ID NO: 348: 1 MKTGCAAGSP GNEWIFFSSD ERNTRSRKTM SNRALQRSAV LSAFVLLRAV TGFSGDGKAI 61 WDKKQYVSPV NPSQLFLYDT FPKNFSWGVG TGAFQVEGSW KTDGRGPSIW DRYVYSHLRG 121 VNGTDRSTDS YIFLEKDLLA LDFLGVSFYQ FSISWPRLFP NGTVAAVNAQ GLRYYRALLD 181 SLVLRNIEPI VTLYHWDLPL TLQEEYGGWK NATMIDLFND YATYCFQTFG DRVKYWITIH 241 NPYLVAWHGF GTGMHAPGEK GNLTAVYTVG HNLIKAHSKV WHNYDKNFRP HQKGWLSITL 301 GSHWIEPNRT DNMEDVINCQ HSMSSVLGWF ANPIHGDGDY PEFMKTGAMI PEFSEAEKEE 361 VRGTADFFAF SFGPNNFRPS NTVVKMGQNV SLNLRQVLNW IKLEYDDPQI LISENGWFTD 421 SYIKTEDTTA IYMMKNFLNQ VLQAIKFDEI RVFGYTAWTL LDGFEWQDAY TTRRGLFYVD 481 FNSEQKERKP KSSAHYYKQI IQDNGFPLKE STPDMKGRFP CDFSWGVTES VLKPEFTVSS 541 PQFTDPHLYV WNVTGNRLLY RVEGVRLKTR PSQCTDYVSI KKRVEMLAKM KVTHYQFALD 601 WTSILPTGNL SKVNRQVLRY YRCVVSEGLK LGVFPMVTLY HPTHSHLGLP LPLLSSGGWL 661 NMNTAKAFQD YAELCFRELG DLVKLWITIN EPNRLSDMYN RTSNDTYRAA HNLMIAHAQV 721 WHLYDRQYRP VQHGAVSLSL HCDWAEPANP FVDSHWKAAE RFLQFEIAWF ADPLFKTGDY 781 PSVMKEYIAS KNQRGLSSSV LPRFTAKESR LVKGTVDFYA LNHFTTRFVI HKQLNTNRSV 841 ADRDVQFLQD ITRLSSPSRL AVTPWGVRKL LAWIRRNYRD RDIYITANGI DDLALEDDQI 901 RKYYLEKYVQ EALKAYLIDK VKIKGYYAFK LTEEKSKPRF GFFTSDFRAK SSVQFYSKLI 961 SSSGLPAENR SPACGQPAED TDCTICSFLV EKKPLIFFGC CFISTLAVLL SITVFHHQKR 1021 RKFQKARNLQ NIPLKKGHSR VFS

In one particular embodiment of the present invention, .beta.Klotho is human or mouse .beta.Klotho encoded by a nucleotide sequence having the nucleotide sequences of SEQ ID NO: 349 (GenBank Accession No. NM_175737, which is hereby incorporated by reference in its entirety) and SEQ ID NO: 350 (GenBank Accession No. NM_031180, which is hereby incorporated by reference in its entirety), as follows:

TABLE-US-00019 (Human .beta.Klotho gene coding sequence): SEQ ID NO: 349 98 ATG AAGCCAGGCT GTGCGGCAGG ATCTCCAGGG AATGAATGGA TTTTCTTCAG 151 CACTGATGAA ATAACCACAC GCTATAGGAA TACAATGTCC AACGGGGGAT TGCAAAGATC 211 TGTCATCCTG TCAGCACTTA TTCTGCTACG AGCTGTTACT GGATTCTCTG GAGATGGAAG 271 AGCTATATGG TCTAAAAATC CTAATTTTAC TCCGGTAAAT GAAAGTCAGC TGTTTCTCTA 331 TGACACTTTC CCTAAAAACT TTTTCTGGGG TATTGGGACT GGAGCATTGC AAGTGGAAGG 391 GAGTTGGAAG AAGGATGGAA AAGGACCTTC TATATGGGAT CATTTCATCC ACACACACCT 451 TAAAAATGTC AGCAGCACGA ATGGTTCCAG TGACAGTTAT ATTTTTCTGG AAAAAGACTT 511 ATCAGCCCTG GATTTTATAG GAGTTTCTTT TTATCAATTT TCAATTTCCT GGCCAAGGCT 571 TTTCCCCGAT GGAATAGTAA CAGTTGCCAA CGCAAAAGGT CTGCAGTACT ACAGTACTCT 631 TCTGGACGCT CTAGTGCTTA GAAACATTGA ACCTATAGTT ACTTTATACC ACTGGGATTT 691 GCCTTTGGCA CTACAAGAAA AATATGGGGG GTGGAAAAAT GATACCATAA TAGATATCTT 751 CAATGACTAT GCCACATACT GTTTCCAGAT GTTTGGGGAC CGTGTCAAAT ATTGGATTAC 811 AATTCACAAC CCATATCTAG TGGCTTGGCA TGGGTATGGG ACAGGTATGC ATGCCCCTGG 871 AGAGAAGGGA AATTTAGCAG CTGTCTACAC TGTGGGACAC AACTTGATCA AGGCTCACTC 931 GAAAGTTTGG CATAACTACA ACACACATTT CCGCCCACAT CAGAAGGGTT GGTTATCGAT 991 CACGTTGGGA TCTCATTGGA TCGAGCCAAA CCGGTCGGAA AACACGATGG ATATATTCAA 1051 ATGTCAACAA TCCATGGTTT CTGTGCTTGG ATGGTTTGCC AACCCTATCC ATGGGGATGG 1111 CGACTATCCA GAGGGGATGA GAAAGAAGTT GTTCTCCGTT CTACCCATTT TCTCTGAAGC 1171 AGAGAAGCAT GAGATGAGAG GCACAGCTGA TTTCTTTGCC TTTTCTTTTG GACCCAACAA 1231 CTTCAAGCCC CTAAACACCA TGGCTAAAAT GGGACAAAAT GTTTCACTTA ATTTAAGAGA 1291 AGCGCTGAAC TGGATTAAAC TGGAATACAA CAACCCTCGA ATCTTGATTG CTGAGAATGG 1351 CTGGTTCACA GACAGTCGTG TGAAAACAGA AGACACCACG GCCATCTACA TGATGAAGAA 1411 TTTCCTCAGC CAGGTGCTTC AAGCAATAAG GTTAGATGAA ATACGAGTGT TTGGTTATAC 1471 TGCCTGGTCT CTCCTGGATG GCTTTGAATG GCAGGATGCT TACACCATCC GCCGAGGATT 1531 ATTTTATGTG GATTTTAACA GTAAACAGAA AGAGCGGAAA CCTAAGTCTT CAGCACACTA 1591 CTACAAACAG ATCATACGAG AAAATGGTTT TTCTTTAAAA GAGTCCACGC CAGATGTGCA 1651 GGGCCAGTTT CCCTGTGACT TCTCCTGGGG TGTCACTGAA TCTGTTCTTA AGCCCGAGTC 1711 TGTGGCTTCG TCCCCACAGT TCAGCGATCC TCATCTGTAC GTGTGGAACG CCACTGGCAA 1771 CAGACTGTTG CACCGAGTGG AAGGGGTGAG GCTGAAAACA CGACCCGCTC AATGCACAGA 1831 TTTTGTAAAC ATCAAAAAAC AACTTGAGAT GTTGGCAAGA ATGAAAGTCA CCCACTACCG 1891 GTTTGCTCTG GATTGGGCCT CGGTCCTTCC CACTGGCAAC CTGTCCGCGG TGAACCGACA 1951 GGCCCTGAGG TACTACAGGT GCGTGGTCAG TGAGGGGCTG AAGCTTGGCA TCTCCGCGAT 2011 GGTCACCCTG TATTATCCGA CCCACGCCCA CCTAGGCCTC CCCGAGCCTC TGTTGCATGC 2071 CGACGGGTGG CTGAACCCAT CGACGGCCGA GGCCTTCCAG GCCTACGCTG GGCTGTGCTT 2131 CCAGGAGCTG GGGGACCTGG TGAAGCTCTG GATCACCATC AACGAGCCTA ACCGGCTAAG 2191 TGACATCTAC AACCGCTCTG GCAACGACAC CTACGGGGCG GCGCACAACC TGCTGGTGGC 2251 CCACGCCCTG GCCTGGCGCC TCTACGACCG GCAGTTCAGG CCCTCACAGC GCGGGGCCGT 2311 GTCGCTGTCG CTGCACGCGG ACTGGGCGGA ACCCGCCAAC CCCTATGCTG ACTCGCACTG 2371 GAGGGCGGCC GAGCGCTTCC TGCAGTTCGA GATCGCCTGG TTCGCCGAGC CGCTCTTCAA 2431 GACCGGGGAC TACCCCGCGG CCATGAGGGA ATACATTGCC TCCAAGCACC GACGGGGGCT 2491 TTCCAGCTCG GCCCTGCCGC GCCTCACCGA GGCCGAAAGG AGGCTGCTCA AGGGCACGGT 2551 CGACTTCTGC GCGCTCAACC ACTTCACCAC TAGGTTCGTG ATGCACGAGC AGCTGGCCGG 2611 CAGCCGCTAC GACTCGGACA GGGACATCCA GTTTCTGCAG GACATCACCC GCCTGAGCTC 2671 CCCCACGCGC CTGGCTGTGA TTCCCTGGGG GGTGCGCAAG CTGCTGCGGT GGGTCCGGAG 2731 GAACTACGGC GACATGGACA TTTACATCAC CGCCAGTGGC ATCGACGACC AGGCTCTGGA 2791 GGATGACCGG CTCCGGAAGT ACTACCTAGG GAAGTACCTT CAGGAGGTGC TGAAAGCATA 2851 CCTGATTGAT AAAGTCAGAA TCAAAGGCTA TTATGCATTC AAACTGGCTG AAGAGAAATC 2911 TAAACCCAGA TTTGGATTCT TCACATCTGA TTTTAAAGCT AAATCCTCAA TACAATTTTA 2971 CAACAAAGTG ATCAGCAGCA GGGGCTTCCC TTTTGAGAAC AGTAGTTCTA GATGCAGTCA 3031 GACCCAAGAA AATACAGAGT GCACTGTCTG CTTATTCCTT GTGCAGAAGA AACCACTGAT 3091 ATTCCTGGGT TGTTGCTTCT TCTCCACCCT GGTTCTACTC TTATCAATTG CCATTTTTCA 3151 AAGGCAGAAG AGAAGAAAGT TTTGGAAAGC AAAAAACTTA CAACACATAC CATTAAAGAA 3211 AGGCAAGAGA GTTGTTAGCT AA (House mouse .beta.Klotho gene coding sequence): SEQ ID NO: 350 2 ATGAAGACA GGCTGTGCAG CAGGGTCTCC GGGGAATGAA TGGATTTTCT TCAGCTCTGA 61 TGAAAGAAAC ACACGCTCTA GGAAAACAAT GTCCAACAGG GCACTGCAAA GATCTGCCGT 121 GCTGTCTGCG TTTGTTCTGC TGCGAGCTGT TACCGGCTTC TCCGGAGACG GGAAAGCAAT 181 ATGGGATAAA AAACAGTACG TGAGTCCGGT AAACCCAAGT CAGCTGTTCC TCTATGACAC 241 TTTCCCTAAA AACTTTTCCT GGGGCGTTGG GACCGGAGCA TTTCAAGTGG AAGGGAGTTG 301 GAAGACAGAT GGAAGAGGAC CCTCGATCTG GGATCGGTAC GTCTACTCAC ACCTGAGAGG 361 TGTCAACGGC ACAGACAGAT CCACTGACAG TTACATCTTT CTGGAAAAAG ACTTGTTGGC 421 TCTGGATTTT TTAGGAGTTT CTTTTTATCA GTTCTCAATC TCCTGGCCAC GGTTGTTTCC 481 CAATGGAACA GTAGCAGCAG TGAATGCGCA AGGTCTCCGG TACTACCGTG CACTTCTGGA 541 CTCGCTGGTA CTTAGGAATA TCGAGCCCAT TGTTACCTTG TACCATTGGG ATTTGCCTCT 601 GACGCTCCAG GAAGAATATG GGGGCTGGAA AAATGCAACT ATGATAGATC TCTTCAACGA 661 CTATGCCACA TACTGCTTCC AGACCTTTGG AGACCGTGTC AAATATTGGA TTACAATTCA 721 CAACCCTTAC CTTGTTGCTT GGCATGGGTT TGGCACAGGT ATGCATGCAC CAGGAGAGAA 781 GGGAAATTTA ACAGCTGTCT ACACTGTGGG ACACAACCTG ATCAAGGCAC ATTCGAAAGT 841 GTGGCATAAC TACGACAAAA ACTTCCGCCC TCATCAGAAG GGTTGGCTCT CCATCACCTT 901 GGGGTCCCAT TGGATAGAGC CAAACAGAAC AGACAACATG GAGGACGTGA TCAACTGCCA 961 GCACTCCATG TCCTCTGTGC TTGGATGGTT CGCCAACCCC ATCCACGGGG ACGGCGACTA 1021 CCCTGAGTTC ATGAAGACGG GCGCCATGAT CCCCGAGTTC TCTGAGGCAG AGAAGGAGGA 1081 GGTGAGGGGC ACGGCTGATT TCTTTGCCTT TTCCTTCGGG CCCAACAACT TCAGGCCCTC 1141 AAACACCGTG GTGAAAATGG GACAAAATGT ATCACTCAAC TTAAGGCAGG TGCTGAACTG 1201 GATTAAACTG GAATACGATG ACCCTCAAAT CTTGATTTCG GAGAACGGCT GGTTCACAGA 1261 TAGCTATATA AAGACAGAGG ACACCACGGC CATCTACATG ATGAAGAATT TCCTAAACCA 1321 GGTTCTTCAA GCAATAAAAT TTGATGAAAT CCGCGTGTTT GGTTATACGG CCTGGACTCT 1381 CCTGGATGGC TTTGAGTGGC AGGATGCCTA TACGACCCGA CGAGGGCTGT TTTATGTGGA 1441 CTTTAACAGT GAGCAGAAAG AGAGGAAACC CAAGTCCTCG GCTCATTACT ACAAGCAGAT 1501 CATACAAGAC AACGGCTTCC CTTTGAAAGA GTCCACGCCA GACATGAAGG GTCGGTTCCC 1561 CTGTGATTTC TCTTGGGGAG TCACTGAGTC TGTTCTTAAG CCCGAGTTTA CGGTCTCCTC 1621 CCCGCAGTTT ACCGATCCTC ACCTGTATGT GTGGAATGTC ACTGGCAACA GATTGCTCTA 1681 CCGAGTGGAA GGGGTAAGGC TGAAAACAAG ACCATCCCAG TGCACAGATT ATGTGAGCAT 1741 CAAAAAACGA GTTGAAATGT TGGCAAAAAT GAAAGTCACC CACTACCAGT TTGCTCTGGA 1801 CTGGACCTCT ATCCTTCCCA CTGGCAATCT GTCCAAAGTT AACAGACAAG TGTTAAGGTA 1861 CTATAGGTGT GTGGTGAGCG AAGGACTGAA GCTGGGCGTC TTCCCCATGG TGACGTTGTA 1921 CCACCCAACC CACTCCCATC TCGGCCTCCC CCTGCCACTT CTGAGCAGTG GGGGGTGGCT 1981 AAACATGAAC ACAGCCAAGG CCTTCCAGGA CTACGCTGAG CTGTGCTTCC GGGAGTTGGG 2041 GGACTTGGTG AAGCTCTGGA TCACCATCAA TGAGCCTAAC AGGCTGAGTG ACATGTACAA 2101 CCGCACGAGT AATGACACCT ACCGTGCAGC CCACAACCTG ATGATCGCCC ATGCCCAGGT 2161 CTGGCACCTC TATGATAGGC AGTATAGGCC GGTCCAGCAT GGGGCTGTGT CGCTGTCCTT 2221 ACATTGCGAC TGGGCAGAAC CTGCCAACCC CTTTGTGGAT TCACACTGGA AGGCAGCCGA 2281 GCGCTTCCTC CAGTTTGAGA TCGCCTGGTT TGCAGATCCG CTCTTCAAGA CTGGCGACTA 2341 TCCATCGGTT ATGAAGGAAT ACATCGCCTC CAAGAACCAG CGAGGGCTGT CTAGCTCAGT 2401 CCTGCCGCGC TTCACCGCGA AGGAGAGCAG GCTGGTGAAG GGTACCGTCG ACTTCTACGC 2461 ACTGAACCAC TTCACTACGA GGTTCGTGAT ACACAAGCAG CTGAACACCA ACCGCTCAGT 2521 TGCAGACAGG GACGTCCAGT TCCTGCAGGA CATCACCCGC CTAAGCTCGC CCAGCCGCCT 2581 GGCTGTAACA CCCTGGGGAG TGCGCAAGCT CCTTGCGTGG ATCCGGAGGA ACTACAGAGA 2641 CAGGGATATC TACATCACAG CCAATGGCAT CGATGACCTG GCTCTAGAGG ATGATCAGAT 2701 CCGAAAGTAC TACTTGGAGA AGTATGTCCA GGAGGCTCTG AAAGCATATC TCATTGACAA 2761 GGTCAAAATC AAAGGCTACT ATGCATTCAA ACTGACTGAA GAGAAATCTA AGCCTAGATT 2821 TGGATTTTTC ACCTCTGACT TCAGAGCTAA GTCCTCTGTC CAGTTTTACA GCAAGCTGAT 2881 CAGCAGCAGT GGCCTCCCCG CTGAGAACAG AAGTCCTGCG TGTGGTCAGC CTGCGGAAGA 2941 CACAGACTGC ACCATTTGCT CATTTCTCGT GGAGAAGAAA CCACTCATCT TCTTCGGTTG 3001 CTGCTTCATC TCCACTCTGG CTGTACTGCT ATCCATCACC GTTTTTCATC ATCAAAAGAG 3061 AAGAAAATTC CAGAAAGCAA GGAACTTACA AAATATACCA TTGAAGAAAG GCCACAGCAG 3121 AGTTTTCAGC TAA

In one embodiment, the FGFR is FGFR1c, FGFR2c, or FGFR4. In one embodiment of the present invention, the FGF receptor is FGFR1c receptor. In one particular embodiment, the FGFR1c receptor is the human FGFR1c receptor (GenBank Accession No. NP_075598, which is hereby incorporated by reference in its entirety). In another embodiment, the FGF receptor is FGFR2c receptor. In one particular embodiment, the FGFR2c receptor is the human FGFR2c receptor (GenBank Accession No. NP_000132, which is hereby incorporated by reference in its entirety). In another embodiment, the FGF receptor is FGFR4 receptor. In one particular embodiment, the FGFR4 receptor is the human FGFR4 receptor (GenBank Accession No. NP_002002, which is hereby incorporated by reference in its entirety).

In one embodiment, the method of facilitating FGFR-.beta.Klotho co-receptor complex formation is carried out in vitro. In one embodiment, the method is carried out in an adipocyte. In another embodiment, the method is carried out in a skeletal muscle cell, a pancreatic .beta. cell, or a hepatocyte.

In one embodiment, the method of facilitating FGFR-Klotho co-receptor complex formation is carried out in vivo. In one embodiment, the method is carried out in a mammal. In one particular embodiment, the mammal is a mouse.

Yet a further aspect of the present invention relates to a method of screening for agents capable of facilitating FGFR-.beta.Klotho complex formation in the treatment of a disorder. This method involves providing a chimeric FGF that includes an N-terminus coupled to a C-terminus, where the N-terminus includes a portion of a paracrine FGF and the C-terminus includes a C-terminal portion of FGF21. The portion of the paracrine FGF is modified to decrease binding affinity for heparin and/or heparan sulfate compared to the portion without the modification. This method also involves providing binary .beta.Klotho-FGFR complex and providing one or more candidate agents. This method further involves combining the chimeric FGF, the binary .beta.Klotho-FGFR complex, and the one or more candidate agents under conditions permitting the formation of a ternary complex between the chimeric FGF and the binary .beta.Klotho-FGFR complex in the absence of the one or more candidate agents. This method also involves identifying the one or more candidate agents that decrease ternary complex formation between the chimeric FGF and the binary .beta.Klotho-FGFR complex compared to the ternary complex formation in the absence of the one or more candidate agents as suitable for treating the disorder.

The portion of the paracrine FGF may also be modified to alter receptor-binding specificity and/or reduce receptor-binding affinity compared to the portion without the modification.

Suitable chimeric proteins for use in accordance with this aspect of the present invention are described above and throughout the present application. Suitable paracrine FGFs, as well as suitable modifications to decrease binding affinity for heparin and/or heparan sulfate, to alter receptor-binding specificity and/or to reduce receptor-binding affinity compared to the portion without the modification, are also described above.

In one embodiment, the modulation is a competitive interaction between the chimeric FGF molecule and the one or more candidate agents for binding to the binary .beta.Klotho-FGFR complex.

In one embodiment, the FGFR is FGFR1c, FGFR2c, or FGFR4.

In one embodiment, the disorder is a selected from diabetes, obesity, and metabolic syndrome. In one embodiment, the disorder is diabetes selected from type II diabetes, gestational diabetes, or drug-induced diabetes. In one embodiment, the disorder is type I diabetes. In one embodiment, the disorder is obesity. In one embodiment, the disorder is metabolic syndrome.

In one embodiment of the screening aspects of the present invention, a plurality of compounds or agents is tested. Candidate agents may include small molecule compounds or larger molecules (e.g., proteins or fragments thereof). In one embodiment, the candidate compounds are biomolecules. In one embodiment, the biomolecules are proteins. In one embodiment, the biomolecules are peptides. In one embodiment, the candidates are peptides or peptide mimetics having similar structural features to native FGF ligand. In one embodiment, the candidate agent is a second chimeric FGF molecule. In one particular embodiment, the peptides are synthetic peptides. In one embodiment, the compounds are small organic molecules.

In one embodiment of the screening aspects of the present invention, the method is carried out using a cell-based assay. In one embodiment, the identifying is carried out using a cell-based assay.

In one embodiment of the screening aspects of the present invention, the method is carried out using a binding assay. In one embodiment, the binding assay is a direct binding assay. In one embodiment, the binding assay is a competition-binding assay. In one embodiment, the modulation stabilizes the ternary complex between the chimeric FGF molecule and the binary .beta.Klotho-FGFR complex. In one embodiment, the stabilization is compared to the native ternary complex.

In one embodiment, the modulation is an allosteric or kinetic modulation. In one embodiment, the allosteric or kinetic modulation is compared to the native ternary complex. Such stabilization or allosteric or kinetic modulation can be measured using methods known in the art (e.g., by use of surface plasmon resonance (SPR) spectroscopy experiments as described in the Examples infra).

In one embodiment, the binding assay is carried out using surface plasmon resonance spectroscopy. In one embodiment, the identifying is carried out using a binding assay. In one embodiment, the identifying is carried out using surface plasmon resonance spectroscopy.

In one embodiment of the screening aspects of the present invention, the cell-based assay is carried out with adipocytes. In one embodiment, the cell-based assay is carried out with skeletal muscle cells. In one embodiment, the cell-based assay is carried out with pancreatic .beta. cells. In one embodiment, the cell-based assay is carried out with hepatocytes. In one embodiment, stimulation of glucose uptake is the assay readout. In one embodiment, induction of glucose transporter 1 gene expression is the assay readout. In one embodiment, a dose-response curve is generated for the stimulation of glucose uptake by a candidate compound to determine potency and efficacy of the candidate compound. In one embodiment, a dose-response curve is generated for the induction of glucose transporter 1 gene expression by a candidate compound to determine potency and efficacy of the candidate compound. For example, if the dose-response curve is shifted to the left compared to that obtained for the chimeric FGF protein, the candidate compound has greater potency than the chimeric FGF protein and/or native FGF21. In one embodiment, an IC.sub.50 value is derived from the dose-response curve of a candidate compound to determine potency of the candidate compound. An IC.sub.50 value smaller than that obtained for the chimeric FGF protein identifies a candidate compound as more potent than the chimeric FGF protein and/or native FGF21.

In one embodiment of the screening aspects of the present invention, the cell-based assay is carried out with mammalian cells ectopically expressing .beta.Klotho. In one particular embodiment, the cells are HEK293 cells. In one embodiment, activation of FGF receptor is the assay readout. In one embodiment, tyrosine phosphorylation of an FGF receptor substrate is used as readout for FGF receptor activation. In one particular embodiment, the FGF receptor substrate is FGF receptor substrate 2.alpha.. In one embodiment, activation of downstream mediators of FGF signaling is used as readout for (or an indicator of) FGF receptor activation. In one particular embodiment, the downstream mediator of FGF signaling is 44/42 mitogen-activated protein kinase. In one embodiment, the downstream mediator of FGF signaling is a transcription factor. In one particular embodiment, the transcription factor is early growth response 1. In one embodiment, a dose-response curve is generated for .beta.Klotho-dependent activation of FGF receptor by a candidate compound to determine potency and efficacy of the candidate compound. For example, if the dose-response curve is shifted to the left compared to that obtained for the chimeric FGF protein, the candidate compound is more potent than the chimeric FGF protein and/or native FGF21. In one embodiment, an IC.sub.50 value is derived from the dose-response curve of a candidate compound to determine potency of the candidate compound. An IC.sub.50 value smaller than that obtained for the chimeric FGF protein identifies a candidate compound as more potent than the chimeric FGF protein and/or native FGF21.

In one embodiment of the screening aspects of the present invention, the surface plasmon resonance spectroscopy-based assay is carried out using the chimeric FGF protein as ligand coupled to a biosensor chip. In one embodiment, mixtures of .beta.Klotho ectodomain with increasing concentrations of a candidate compound are passed over a biosensor chip containing chimeric FGF protein. In one embodiment, mixtures of the binary complex of FGFR ligand-binding domain and .beta.Klotho ectodomain with increasing concentrations of a candidate compound are passed over a biosensor chip containing chimeric FGF protein. In one particular embodiment, the FGFR ligand-binding domain is the FGFR1c ligand-binding domain. In one embodiment, an inhibition-binding curve is plotted for a candidate compound to determine potency of the candidate compound. For example, if the inhibition-binding curve is shifted to the left compared to that obtained for the chimeric FGF protein, the candidate compound has greater potency than the chimeric FGF protein and/or native FGF21. In one embodiment, an IC.sub.50 value is derived from the inhibition-binding curve of a candidate compound to determine potency of the candidate compound. An IC.sub.50 value smaller than that obtained for containing chimeric FGF protein identifies a candidate compound as more potent than the chimeric FGF protein and/or native FGF21. In one embodiment, the inhibition constant K.sub.i is determined for a candidate compound to determine potency of the candidate compound. A K.sub.i value smaller than that obtained for native FGF21 identifies a candidate compound as more potent than the chimeric FGF protein and/or native FGF21.

In one embodiment of the screening aspects of the present invention, the method is carried out in vivo. In one embodiment, the method is carried out in a mammal. In one particular embodiment, the mammal is a mouse. In one embodiment, the mammal has obesity, diabetes, or a related metabolic disorder. In one embodiment, the ability of a candidate compound to potentiate the hypoglycemic effect of insulin is used as readout for FGF21-like metabolic activity. This involves fasting the mammal for a period of time prior to insulin injection and measuring fasting blood glucose levels. The mammal is then injected with insulin alone or co-injected with insulin plus a candidate compound. Blood glucose levels are measured at several time points after the injection. If a candidate compound potentiates the hypoglycemic effect of insulin to a greater degree than the chimeric FGF protein and/or native FGF21 does, the candidate compound exhibits enhanced efficacy. Likewise, if a candidate compound potentiates the hypoglycemic effect of insulin to a similar degree than the chimeric FGF protein and/or native FGF21 does but at a lower dose compared to that of the chimeric FGF protein and/or native FGF21 and/or for a longer period of time compared to the chimeric FGF protein and/or native FGF21, the candidate compound has enhanced agonistic properties. In one embodiment, the ability of a candidate compound to elicit a hypoglycemic effect in a mammal with diabetes, obesity, or a related metabolic disorder is used as readout for FGF21-like metabolic activity. This involves injecting a mammal suffering from diabetes, obesity, or a related metabolic disorder with the candidate compound. Blood glucose levels are measured before the injection and at several time points thereafter. If a candidate compound has a greater hypoglycemic effect than the chimeric FGF protein and/or native FGF21 does, the candidate compound exhibits enhanced efficacy. Likewise, if a candidate compound shows a similar hypoglycemic effect than the chimeric FGF protein and/or native FGF21 does but at a lower dose compared to that of the chimeric FGF protein and/or native FGF21 and/or for a longer period of time compared to the chimeric FGF protein and/or native FGF21, the candidate compound has enhanced agonistic properties.

EXAMPLES

Example 1--Purification of FGF, FGFR, and Klotho Proteins

The N-terminally hexahistidine-tagged, mature form of human FGF19 (SEQ ID NO: 337) (R23 to K216), human FGF21 (SEQ ID NO:233) (H29 to 5209; FIG. 5A), and human FGF23 (SEQ ID NO: 351) (Y25 to 1251; FIG. 5A) was refolded in vitro from bacterial inclusion bodies, and purified by published protocols (Ibrahimi et al., Hum. Mol. Genet. 13:2313-2324 (2004); Plotnikov et al., Cell 101:413-424 (2000), which is hereby incorporated by reference in its entirety). The amino acid sequence of human FGF23 (SEQ ID NO:351) (GenBank accession no. AAG09917, which is hereby incorporated by reference in its entirety) is as follows:

TABLE-US-00020 1 MLGARLRLWV CALCSVCSMS VLRAYPNASP LLGSSWGGLI HLYTATARNS YHLQIHKNGH 61 VDGAPHQTIY SALMIRSEDA GFVVITGVMS RRYLCMDFRG NIFGSHYFDP ENCRFQHQTL 121 ENGYDVYHSP QYHFLVSLGR AKRAFLPGMN PPPYSQFLSR RNEIPLIHFN TPIPRRHTRS 181 AEDDSERDPL NVLKPRARMT PAPASCSQEL PSAEDNSPMA SDPLGVVRGG RVNTHAGGTG 241 PEGCRPFAKF I

HS-binding site mutants of FGF19 (K149A) and FGF23 (R140A/R143A) were purified from bacterial inclusion bodies by similar protocols as the wild-type proteins. In order to minimize proteolysis of FGF23 wild-type and mutant proteins, arginine residues 176 and 179 of the proteolytic cleavage site .sup.176RXXR.sup.179 were replaced with glutamine as it occurs in the phosphate wasting disorder "autosomal dominant hypophosphatemic rickets" (ADHR) (White et al., Nat. Genet. 26:345-348 (2000); White et al., Kidney Int. 60:2079-2086 (2001), which are hereby incorporated by reference in their entirety). Human FGF1 (SEQ ID NO:1) (M1 to D155; FIG. 6), N-terminally truncated human FGF1 (K25 to D155, termed FGF1.sup..DELTA.NT; FIG. 6), human FGF2 (SEQ ID NO: 121) (M1 to S155; FIG. 5A), and human FGF homologous factor 1B (FHF1B; M1 to T181) were purified by published protocols (Plotnikov et al., Cell 101:413-424 (2000); Olsen et al., J. Biol. Chem. 278:34226-34236 (2003), which are hereby incorporated by reference in their entirety).

Chimeras composed of the core domain of FGF2 (M1 to M151) and the C-terminal region of either FGF21 (P168 to S209) or FGF23 (R161 to I251) (termed FGF2.sup.WTcore-FGF21.sup.C-tail and FGF2.sup.WTcore-FGF23.sup.C-tail, respectively; FIG. 5A) were purified by the same protocol as that for native FGF2 (Plotnikov et al., Cell 101:413-424 (2000), which is hereby incorporated by reference in its entirety). Analogous chimeras containing three mutations in the HS-binding site of the FGF2 core (K128D/R129Q/K134V) (termed FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail and FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail, respectively, FIG. 5A) were purified from the soluble bacterial cell lysate fraction by ion-exchange and size-exclusion chromatographies. In order to minimize proteolysis of the chimeras containing the C-terminal sequence from R161 to I251 of FGF23, arginine residues 176 and 179 of the proteolytic cleavage site .sup.176RXXR.sup.179 located within this sequence were replaced with glutamine as it occurs in ADHR (White et al., Nat. Genet. 26:345-348 (2000); White et al., Kidney Int. 60:2079-2086 (2001), which are hereby incorporated by reference in their entirety). In addition, in order to prevent disulfide-mediated dimerization of FGF2 and chimeric FGF2 proteins, cysteine residues 78 and 96 were mutated to serine. An HS-binding site mutant of FGF1 (K127D/K128Q/K133V) (termed FGF1.sup..DELTA.HBScore; FIG. 6) and chimeras composed of the core domain of the HS-binding site mutant of FGF1 (M1 to L150, K127D/K128Q/K133V) and the C-terminal region of either FGF19 (L169 to K216) or FGF21 (P168 to S209) (termed FGF1.sup..DELTA.HBScore-FGF19.sup.C-tail and FGF1.sup..DELTA.HBScore-FGF21.sup.C-tail respectively; FIG. 6) were purified from the soluble bacterial cell lysate fraction by ion-exchange and size-exclusion chromatographies. The N-terminally hexahistidine-tagged C-terminal tail peptide of FGF23 (S180 to I251, termed FGF23.sup.C-tail) was purified by a published protocol (Goetz et al., Proc. Nat'l. Acad. Sci. U.S.A. 107:407-412 (2010), which is hereby incorporated by reference in its entirety). The ligand-binding domain of human FGFR1c (D142 to R365) was refolded in vitro from bacterial inclusion bodies, and purified by published protocols (Ibrahimi et al., Hum. Mol. Genet. 13:2313-2324 (2004); Plotnikov et al., Cell 101:413-424 (2000), which are hereby incorporated by reference in their entirety). The ectodomain of murine .alpha.Klotho (A35 to K982) and the ectodomain of murine .beta.Klotho (F53 to L995) were expressed in HEK293 cells as fusion proteins with a C-terminal FLAG tag (Kurosu et al., J. Biol. Chem. 281:6120-6123 (2006); Kurosu et al., Science 309:1829-1833 (2005), which are hereby incorporated by reference in their entirety). The binary complex of FGFR1c ligand-binding domain with .alpha.Klotho ectodomain (referred to as .alpha.Klotho-FGFR1c complex) was prepared by a published protocol (Goetz et al., Proc. Nat'l. Acad. Sci. U.S.A. 107:407-412 (2010), which is hereby incorporated by reference in its entirety). The binary complex of FGFR1c ligand-binding domain with .beta.Klotho ectodomain (referred to as .beta.Klotho-FGFR1c complex) was prepared in the same fashion as the .alpha.Klotho-FGFR1c complex.

Example 2--Analysis of FGF-Heparin and FGF-FGFR-.alpha./Klotho Interactions by Surface Plasmon Resonance Spectroscopy

Surface plasmon resonance (SPR) experiments were performed on a Biacore 2000 instrument (Biacore AB), and the interactions were studied at 25.degree. C. in HBS-EP buffer (10 mM HEPES-NaOH, pH 7.4, 150 mM NaCl, 3 mM EDTA, 0.005% (v/v) polysorbate 20). To study endocrine FGF-heparin interactions, a heparin chip was prepared by immobilizing biotinylated heparin (Sigma-Aldrich) on flow channels of a research-grade streptavidin chip (Biacore AB). The coupling density was .about.5 fmol mm.sup.-2 of flow channel. To measure binding of chimeric FGF2 proteins to heparin, biotinylated heparin was coupled to a streptavidin chip at an approximately 4-fold lower density as judged based on the binding responses obtained for FGF1. To study FGF-FGFR-.alpha./.beta.Klotho interactions, FGF chips were prepared by covalent coupling of FGF proteins through their free amino groups on flow channels of research grade CM5 chips (Biacore AB). Proteins were injected over a chip at a flow rate of 50 .mu.l min.sup.-1, and at the end of each protein injection (180 and 300 s, respectively), HBS-EP buffer (50 .mu.l min.sup.-1) was flowed over the chip to monitor dissociation for 180 or 240 s. The heparin chip surface was regenerated by injecting 50 .mu.l of 2.0 M NaCl in 10 mM sodium acetate, pH 4.5. For FGF chips, regeneration was achieved by injecting 2.0 M NaCl in 10 mM sodium/potassium phosphate, pH 6.5. To control for nonspecific binding in experiments where an FGF ligand was immobilized on the chip, FHF1B, which shares structural similarity with FGFs but does not exhibit any FGFR binding (Olsen et al., J. Biol. Chem. 278:34226-34236 (2003), which is hereby incorporated by reference in its entirety), was coupled to the control flow channel of the chip (.about.15-30 fmol mm.sup.-2). In experiments where heparin was immobilized on the chip, the control flow channel was left blank. The data were processed with BiaEvaluation software (Biacore AB). For each protein injection over the heparin chip, the nonspecific responses from the control flow channel were subtracted from the responses recorded for the heparin flow channel. Similarly, for each protein injection over a FGF chip, the nonspecific responses from the FHF1B control flow channel were subtracted from the responses recorded for the FGF flow channel. Where possible, equilibrium dissociation constants (K.sub.Ds) were calculated from fitted saturation binding curves. Fitted binding curves were judged to be accurate based on the distribution of the residuals (even and near zero) and .chi..sup.2 (<10% of R.sub.max).

To examine whether the K149A mutation abrogates residual heparin binding of FGF19, increasing concentrations of wild-type FGF19 were passed over a heparin chip. Thereafter, the FGF19.sup.K149A mutant was injected over the heparin chip at the highest concentration tested for the wild-type ligand. The effect of the R140A/R143A double mutation in the HS-binding site of FGF23 on residual heparin binding of FGF23 was examined in the same fashion as was the effect of the HS-binding site mutation in FGF19.

To verify that the K128D/R129Q/K134V triple mutation in the HS-binding site of the FGF2 core domain diminishes heparin-binding affinity of the FGF2 core, increasing concentrations of FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail and FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail were passed over a heparin chip. As a control, binding of FGF2.sup.WTcore-FGF21.sup.C-tail and FGF2.sup.WTcore-FGF23.sup.C-tail to heparin was studied.

To examine whether the FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail chimera can compete with FGF23 for binding to the .alpha.Klotho-FGFR1c complex, FGF23 was immobilized on a chip (.about.16 fmol mm.sup.-2 of flow channel). Increasing concentrations of FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail were mixed with a fixed concentration of .alpha.Klotho-FGFR1c complex in HBS-EP buffer, and the mixtures were injected over the FGF23 chip. As controls, the binding competition was carried out with FGF23 or FGF2 as the competitor in solution. As an additional specificity control, competition of the FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail chimera with FGF21 for binding to the .alpha.Klotho-FGFR1c complex was studied. .alpha.Klotho-FGFR1c complex was mixed with FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail or FGF23 at a molar ratio of 1:10, and the mixture was injected over a chip containing immobilized FGF21 (.about.12 fmol mm.sup.-2 of flow channel).

To test whether the FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail chimera can compete with FGF21 for binding to the .beta.Klotho-FGFR1c complex, increasing concentrations of FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail were mixed with a fixed concentration of .beta.Klotho-FGFR1c complex in HBS-EP buffer, and the mixtures were passed over a chip containing immobilized FGF21 (.about.19 fmol mm.sup.-2 of flow channel). As controls, the binding competition was carried out with FGF21 or FGF2 as the competitor in solution. As an additional specificity control, competition of the FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail chimera with FGF23 for binding to the .alpha.Klotho-FGFR1c complex was studied. .alpha.Klotho-FGFR1c complex was mixed with FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail or FGF21 at a molar ratio of 1:10, and the mixture was injected over a chip containing immobilized FGF23 (.about.12 fmol mm.sup.-2 of flow channel).

To measure binding of FGFR1c to each of the three endocrine FGFs, increasing concentrations of FGFR1c ligand-binding domain were injected over a chip containing immobilized FGF19, FGF21, and FGF23 (.about.30 fmol mm.sup.-2 of flow channel). As a control, binding of FGFR1c to FGF2 immobilized on a chip was studied. As additional controls, binding of the .alpha.Klotho-FGFR1c complex to FGF23 and binding of FGFR1c to the C-terminal tail peptide of FGF23 was measured.

Example 3--Analysis of Phosphorylation of FRS2.alpha. and 44/42 MAP Kinase in Hepatoma and Epithelial Cell Lines

To examine whether the FGF19.sup.K149A and FGF23.sup.R140A/R143A mutants can activate FGFR in a .alpha./.beta.Klotho-dependent fashion, induction of tyrosine phosphorylation of FGFR substrate 2.alpha. (FRS2.alpha.) and downstream activation of MAP kinase cascade was used as readout for FGFR activation. Subconfluent cells of the H4IIE rat hepatoma cell line, which endogenously expresses .beta.Klotho (Kurosu et al., J. Biol. Chem. 282:26687-26695 (2007), which is hereby incorporated by reference in its entirety), were serum starved for 16 h and then stimulated for 10 min with the FGF19.sup.K149A mutant or wild-type FGF19 (0.2 ng ml.sup.-1 to 2.0 .mu.g ml.sup.-1). Similarly, subconfluent cells of a HEK293 cell line ectopically expressing the transmembrane isoform of murine .alpha.Klotho (Kurosu et al., J. Biol. Chem. 281:6120-6123 (2006), which is hereby incorporated by reference in its entirety) were treated with the FGF23.sup.R140A/R143A mutant or wild-type FGF23 (0.1 to 100 ng ml.sup.-1). After stimulation, the cells were lysed (Kurosu et al., Science 309:1829-1833 (2005), which is hereby incorporated by reference in its entirety), and cellular proteins were resolved on SDS-polyacrylamide gels and transferred to nitrocellulose membranes. The protein blots were probed with antibodies to phosphorylated FRS2.alpha., phosphorylated 44/42 MAP kinase, total (phosphorylated and nonphosphorylated) 44/42 MAP kinase, and .alpha.Klotho. Except for the anti-.alpha.Klotho antibody (KM2119) (Kato et al., Biochem. Biophys. Res. Commun. 267:597-602 (2000), which is hereby incorporated by reference in its entirety), all antibodies were from Cell Signaling Technology.

Example 4--Analysis of Egr1 Protein Expression in an Epithelial Cell Line

To examine whether the FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail and FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail chimeras can activate FGFR in a HS-dependent fashion, induction of protein expression of the transcription factor early growth response 1 (Egr1), a known downstream mediator of FGF signaling, was used as readout for FGFR activation. HEK293 cells were serum starved overnight and then stimulated for 90 min with FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail or FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail (0.1 and 0.3 nM). Cell stimulation with FGF2.sup.WTcore-FGF21.sup.C-tail, FGF2.sup.WTcore-FGF23.sup.C-tail, FGF21, and FGF23 served as controls. To test whether the FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail chimera can activate FGFR in a .beta.Klotho-dependent fashion, HEK293 cells transfected with murine .beta.Klotho were serum starved overnight and then stimulated for 90 min with FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail or FGF21 (3 to 300 ng ml.sup.-1). After stimulation, the cells were lysed (Kurosu et al., Science 309:1829-1833 (2005), which is hereby incorporated by reference in its entirety), and cellular proteins were resolved on SDS-polyacrylamide gels and transferred to nitrocellulose membranes. The protein blots were probed with antibodies to Egr1 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The anti-Egr1 antibody was from Cell Signaling Technology and the anti-GAPDH antibody was from Abcam.

Example 5--Analysis of CYP7A1 and CYP8B1 mRNA Expression in Murine Liver Tissue

To examine the metabolic activity of the FGF19.sup.K149A mutant in vivo, 6- to 8-week old C57BL/6 mice were fasted overnight and then given intraperitoneally a single dose (1 mg kg body weight.sup.-1) of FGF19.sup.K149A or FGF19 as a control. 6 h after the injection, the mice were sacrificed, and liver tissue was excised and frozen. Total RNA was isolated from liver tissue, and mRNA levels of cholesterol 7.alpha.-hydroxylase (CYP7A1) and sterol 12.alpha.-hydroxylase (CYP8B1) were measured using quantitative real time RT-PCR as described previously (Inagaki et al., Cell Metab. 2:217-225 (2005); Kim et al., J. Lipid Res. 48:2664-2672 (2007), which are hereby incorporated by reference in their entirety). The Institutional Animal Care and Use Committee at the University of Texas Southwestern Medical Center at Dallas had approved the experiments.

Example 6--Measurement of Serum Phosphate in Mice

The metabolic activity of the FGF23.sup.R140A/R143A mutant was examined both in normal mice and in Fgf23 knockout mice. 4- to 5-week old C57BL/6 mice were given intraperitoneally a single dose (0.29 mg kg body weight.sup.-1) of FGF23.sup.R140A/R143A or FGF23 as a control. Before the injection and 8 h after the injection, blood was drawn from the cheek pouch and spun at 3,000.times.g for 10 min to obtain serum. Phosphate concentration in serum was measured using the Phosphorus Liqui-UV Test (Stanbio Laboratory). 6- to 8-week old Fgf23 knockout mice (Sitara et al., Matrix Biol. 23:421-432 (2004), which is hereby incorporated by reference in its entirety) (56) were given two injections of FGF23.sup.R140A/R143A or FGF23 at 8 h intervals (0.71 mg kg body weight.sup.-1 each), and blood samples were collected for phosphate analysis before the first injection and 8 h after the second injection.

To test whether the FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail chimera exhibits FGF23-like metabolic activity, 5- to 6-week old C57BL/6 mice were given a single injection of FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail (0.21 mg kg body weight.sup.-1). As controls, mice were injected with FGF2.sup.WTcore-FGF23.sup.C-tail or FGF23. Before the injection and 8 h after the injection, blood samples were collected for measurement of serum phosphate. To confirm that .alpha.Klotho is required for the metabolic activity of the FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail chimera, 7- to 8-week old .alpha.Klotho knockout mice (Lexicon Genetics) were injected once with FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail or FGF23 as a control (0.51 mg kg body weight.sup.-1). Before the injection and 8 h after the injection, blood samples were collected for phosphate analysis. The Harvard University Animal Care and Research committee board had approved all the experiments.

Example 7--Analysis of CYP27B1 mRNA Expression in Murine Renal Tissue

The ability of the FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail chimera to reduce renal expression of 25-hydroxyvitamin D.sub.3 1.alpha.-hydroxylase (CYP27B1) was used as another readout for FGF23-like metabolic activity. C57BL/6 mice injected with FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail, FGF2.sup.WTcore-FGF23.sup.C-tail, or FGF23 were sacrificed 8 h after the protein injection, and renal tissue was excised and frozen. CYP27B1 mRNA levels in total renal tissue RNA were measured using real time quantitative PCR as described previously (Nakatani et al., FASEB J. 23:3702-3711 (2009); Ohnishi et al., Kidney Int. 75:1166-1172 (2009), which are hereby incorporated by reference in their entirety). The Harvard University Animal Care and Research committee board had approved the experiments.

Example 8--Insulin Tolerance Test in Mice

The ability of the FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail chimera to potentiate the hypoglycemic effect of insulin was used as readout for FGF21-like metabolic activity (Ohnishi et al., FASEB J. 25:2031-2039 (2011), which is hereby incorporated by reference in its entirety). 8- to 12-week old C57BL/6 mice were kept on normal chow. On the day of the insulin tolerance test, mice were fasted for 4 h and then bled from the cheek pouch for measuring fasting blood glucose levels. Thereafter, mice were administered intraperitoneally insulin (0.5 units kg body weight.sup.-1) alone or insulin (0.5 units-kg body weight.sup.-1) plus FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail chimera (0.3 mg kg body weight.sup.-1). As a control, mice were co-injected with insulin plus FGF21. At the indicated time points after the injection (FIG. 7G), blood was drawn from the tail vein. Glucose concentrations in the blood samples were determined using Bayer Contour.RTM. blood glucose test strips (Bayer Corp.). The Harvard University Animal Care and Research committee board had approved the experiments.

Example 9--Analysis of Blood Glucose in ob/ob Mice

ob/ob mice were injected subcutaneously with FGF1.sup..DELTA.NT, FGF1.sup..DELTA.HBS, or FGF1.sup..DELTA.HBScore-FGF21.sup.C-tail chimera. Injection of native FGF1 or native FGF21 served as controls. A single bolus of 0.5 mg of protein per kg of body weight was injected. This dose was chosen on the basis that maximal efficacy of the hypoglycemic effect of native FGF1 is seen at this dose. Before the protein injection and at the indicated time points after the injection (FIGS. 9A-9C), blood glucose concentrations were measured using an OneTouch Ultra glucometer (Lifescan). The Institutional Animal Care and Use Committee at the Salk Institute for Biological Sciences at La Jolla had approved the experiments.

Example 10--Statistical Analysis

Data are expressed as mean.+-.SEM. A Student's t test or analysis of variance (ANOVA) was used as appropriate to make statistical comparisons. A value of P<0.05 was considered significant.

Example 11--HS is Dispensable for the Metabolic Activity of FGF19 and FGF23

In order to engineer endocrine FGFs devoid of HS binding, the FGF19 crystal structure (PDB ID: 2P23; (Goetz et al., Mol. Cell Biol. 27:3417-3428 (2007), which is hereby incorporated by reference in its entirety) was compared with that of FGF2 bound to a heparin hexasaccharide (PDB ID: 1FQ9; (Schlessinger et al., Mol. Cell 6:743-750 (2000), which is hereby incorporated by reference in its entirety)). This analysis shows that solvent-exposed residues K149, Q150, Q152, and R157 of FGF19 lie at the corresponding HS-binding site of this ligand, and hence could account for the residual HS binding of FGF19 (FIGS. 1A, 1B, and 2). Likewise, comparative analysis of the FGF23 crystal structure (PDB ID: 2P39; (Goetz et al., Mol. Cell Biol. 27:3417-3428 (2007), which is hereby incorporated by reference in its entirety) (29)) with that of heparin-bound FGF2 (PDB ID: 1FQ9; (Schlessinger et al., Mol. Cell 6:743-750 (2000), which is hereby incorporated by reference in its entirety)) points to R48, N49, R140, and R143 as candidates mediating the residual HS binding of this ligand (FIGS. 1A, 1C, and 2). In agreement with the structural predictions, replacement of K149 alone in FGF19 with alanine and combined substitution of R140 and R143 in FGF23 for alanine were sufficient to abolish residual HS binding of these ligands (FIGS. 3B-3G).

To test the impact of knocking out residual HS binding of FGF19 on the signaling by this ligand, H4IIE hepatoma cells were stimulated with the FGF19.sup.K149A mutant or wild-type FGF19. H4IIE cells endogenously express FGFR4 and .beta.Klotho (Kurosu et al., J. Biol. Chem. 282:26687-26695 (2007), which is hereby incorporated by reference in its entirety), the cognate receptor and co-receptor, respectively, for FGF19. The FGF19.sup.K149A mutant was as effective as wild-type FGF19 in inducing tyrosine phosphorylation of FRS2.alpha. and downstream activation of MAP kinase cascade (FIG. 4A). These data show that elimination of residual HS binding has no impact on the ability of FGF19 to signal in cultured cells. To test whether the same holds true for FGF23 signaling, HEK293 cells, which naturally express two of the three cognate receptors of FGF23, namely FGFR1c and FGFR3c (Kurosu et al., J. Biol. Chem. 281:6120-6123 (2006), which is hereby incorporated by reference in its entirety) were transfected with the transmembrane isoform of .alpha.Klotho, the co-receptor of FGF23. These cells were treated with the FGF23.sup.R140A/R143A double mutant or wild-type FGF23. The FGF23.sup.R140A/R143A mutant had the same capacity as wild-type FGF23 in inducing phosphorylation of FRS2.alpha. and downstream activation of MAP kinase cascade (FIG. 4B). These data show that similar to FGF19, FGF23 does not need to bind HS in order to activate FGFR in cultured cells.

To substantiate the findings in cells, the metabolic activity of wild-type and mutated ligands in vivo were compared. Mice were injected with the FGF19.sup.K149A mutant or wild-type FGF19 and liver gene expression of CYP7A1 and CYP8B1, which are key enzymes in the major bile acid biosynthetic pathway (Russell, D. W., Annu. Rev. Biochem. 72:137-174 (2003), which is hereby incorporated by reference in its entirety), was analyzed. Like wild-type FGF19, the FGF19.sup.K149A mutant markedly decreased CYP7A1 and CYP8B1 mRNA levels (FIG. 4C), demonstrating that knockout of residual HS binding does not affect the metabolic activity of FGF19. To examine whether residual HS binding is also dispensable for the metabolic activity of FGF23, mice were injected with the FGF23.sup.R140A/R143A mutant or wild-type FGF23 and serum phosphate concentrations were measured. The FGF23.sup.R140A/R143A mutant reduced serum phosphate as effectively as wild-type FGF23 (FIG. 4D). Moreover, when injected into Fgf23 knockout mice, the FGF23.sup.R140A/R143A mutant exhibited as much of phosphate-lowering activity as wild-type FGF23 (FIG. 4D). These data show that, as in the case of FGF19, abolishment of residual HS binding does not impact the metabolic activity of FGF23 leading to the conclusion that HS is not a component of the endocrine FGF signal transduction unit (FIG. 1D).

Example 12--Conversion of a Paracrine FGF into an Endocrine Ligand Confirms that HS is Dispensable for the Metabolic Activity of Endocrine FGFs

If HS is dispensable for the metabolic activity of endocrine FGFs, then it should be feasible to convert a paracrine FGF into an endocrine FGF by eliminating HS-binding affinity of the paracrine FGF and substituting its C-terminal tail for that of an endocrine FGF containing the Klotho co-receptor binding site. Reducing HS-binding affinity will allow the ligand to freely diffuse and enter the blood circulation while attaching the C-terminal tail of an endocrine FGF will home the ligand into its target tissues. FGF2, a prototypical paracrine FGF, was chosen for conversion into FGF23-like and FGF21-like ligands, respectively. FGF2 was selected as paracrine ligand for this protein engineering exercise because it preferentially binds to the "c" isoform of FGFR1, the principal receptor mediating the metabolic activity of FGF23 (Gattineni et al., Am. J. Physiol. Renal Physiol. 297:F282-291 (2009); Liu et al., J. Am. Soc. Nephrol. 19:2342-2350 (2008), which are hereby incorporated by reference in their entirety) and FGF21 (Kurosu et al., J. Biol. Chem. 282:26687-26695 (2007), which is hereby incorporated by reference in its entirety), respectively. In the crystal structure of heparin-bound FGF2 (PDB ID: 1FQ9; (Schlessinger et al., Mol. Cell 6:743-750 (2000), which is hereby incorporated by reference in its entirety)), K128, R129, and K134 mediate the majority of hydrogen bonds with heparin and hence mutation of these residues was predicted to cause a major reduction in HS-binding affinity of FGF2 (FIGS. 1A, 2, and 5A). Accordingly, these three residues were mutated and then the short C-terminal tail of the mutated FGF2 was replaced with the C-terminal tail of FGF23 (R161 to I251) or the C-terminal tail of FGF21 (P168 to S209) (FIG. 5A). The resulting chimeras were termed FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail and FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail (FIG. 5A). To demonstrate that reduction in HS-binding affinity is required for converting FGF2 into an endocrine ligand, two control chimeras were made in which the HS-binding site of the FGF2 core was left intact (FGF2.sup.WTcore-FGF23.sup.C-tail and FGF2.sup.WTcore-FGF21.sup.C-tail; FIG. 5A).

Consistent with the structural prediction, FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail and FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail exhibited poor binding affinity for HS compared to the corresponding control chimeras with intact HS-binding site (FIGS. 5B-5E). Since HS is an obligatory cofactor in paracrine FGF signaling, the FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail and FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail chimeras were predicted to lose the ability to activate FGFR1c in an HS-dependent fashion. To test this, HEK293 cells, which endogenously express FGFR1c, were stimulated with FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail or FGF2.sup.WTcore-FGF23.sup.C-tail. Induction of protein expression of the transcription factor Egr1, a known downstream mediator of FGF signaling, was used as readout for FGFR activation. As shown in FIG. 5G, the FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail chimera, like native FGF23, was ineffective in inducing Egr1 expression at concentrations at which the FGF2.sup.WTcore-FGF23.sup.C-tail chimera elicited a near maximal effect. The same observations were made for the FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail chimera (FIG. 5F). These data show that, similar to native FGF23 and FGF21, the FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail and FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail chimeras lost the ability to activate FGFR in an HS-dependent, paracrine fashion.

To determine whether the FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail and FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail chimeras gained the ability to signal in a Klotho co-receptor-dependent, endocrine fashion, it was first analyzed whether these chimeras can form ternary complexes with FGFR1c and Klotho co-receptor. To this end, a SPR-based binding competition assay was employed. FGF23 was immobilized onto a SPR biosensor chip, and mixtures of a fixed concentration of binary .alpha.Klotho-FGFR1c complex with increasing concentrations of FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail chimera were passed over the chip. FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail competed, in a dose-dependent fashion, with immobilized FGF23 for binding to the .alpha.Klotho-FGFR1c complex (FIG. 7A), demonstrating that the chimera, like native FGF23 (FIG. 7B), is able to form a ternary complex with FGFR1c and .alpha.Klotho. To test whether the FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail chimera can likewise form a ternary complex with FGFR1c and .beta.Klotho, FGF21 was coupled to a SPR biosensor chip, and mixtures of the binary .beta.Klotho-FGFR1c complex with FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail were passed over the chip. FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail effectively competed with immobilized FGF21 for binding to the .beta.Klotho-FGFR1c complex (FIG. 8A), demonstrating that the chimera, like native FGF21 (FIG. 8B), is capable of binding to the binary complex of FGFR1c and .beta.Klotho. Notably, native FGF2 failed to compete with FGF23 for binding to the .alpha.Klotho-FGFR1c complex (FIG. 7C), and with FGF21 for binding to the .beta.Klotho-FGFR1c complex (FIG. 8C) since it lacks the Klotho co-receptor binding domain. To further confirm the binding specificity of the FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail chimera for the .alpha.Klotho-FGFR1c complex, FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail and .beta.Klotho-FGFR1c complex were mixed at a molar ratio of 10:1, and the mixture was injected over a chip containing immobilized FGF21. FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail, like native FGF23, failed to compete with FGF21 for binding to the .beta.Klotho-FGFR1c complex (FIGS. 7D and 7E). Similarly, the FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail chimera, like native FGF21, failed to compete with FGF23 for binding to the .alpha.Klotho-FGFR1c complex (FIGS. 8D and 8E). For the FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail chimera, we investigated whether it is able to activate FGFR1c in a .beta.Klotho-dependent fashion in cells. HEK293 cells were transfected with .beta.Klotho and then stimulated with FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail or FGF21. Similar to native FGF21, the FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail chimera induced Egr1 protein expression in HEK293-.beta.Klotho cells (FIG. 8F), indicating that the chimera is capable of activating FGFR1c in the presence of .beta.Klotho.

To provide definite proof for the ligand conversion, the metabolic activity of the chimeras in vivo was tested. Specifically, the ability of the FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail chimera to lower serum phosphate and to reduce renal gene expression of CYP27B1, which catalyzes the conversion of vitamin D into its bioactive form, was examined. Mice were injected with FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail or as controls, FGF23 or FGF2.sup.WTcore-FGF23.sup.C-tail, and serum phosphate concentrations and renal CYP27B1 mRNA levels were measured. Similar to native FGF23, the FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail chimera caused a decrease in serum phosphate in wild-type mice (FIG. 7F). The chimera also induced a marked decrease in CYP27B1 mRNA levels, just like the native FGF23 ligand (FIG. 7G). These data show that the FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail chimera acts as an FGF23-like hormone. Importantly, the FGF2.sup.WTcore-FGF23.sup.C-tail chimera failed to decrease serum phosphate or CYP27B1 mRNA levels (FIGS. 7F and 7G). This is expected because, owing to its high affinity for HS, this chimera should be trapped in the vicinity of the injection site and hence not be able to enter the blood circulation. Moreover, these data show that adding the Klotho co-receptor binding site is not sufficient to convert a paracrine FGF into an endocrine ligand. To confirm that the metabolic activity of the FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail chimera is dependent on .alpha.Klotho, .alpha.Klotho knockout mice were injected with FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail or FGF23 as a control, and serum concentrations of phosphate were measured. As shown in FIG. 7F, FGF2.sup..DELTA.HBScore-FGF23.sup.C-tail failed to lower serum phosphate, demonstrating that the chimera, like native FGF23 (FIG. 7F), requires .alpha.Klotho for metabolic activity.

To determine whether the FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail chimera exhibits FGF21-like metabolic activity, its ability to potentiate the hypoglycemic effect of insulin was examined (Ohnishi et al., FASEB J. 25:2031-2039 (2011), which is hereby incorporated by reference in its entirety). Mice were injected with insulin plus FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail, insulin plus FGF21, or insulin alone, and blood glucose concentrations were monitored for up to one hour after the injection. Similar to FGF21, the FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail chimera enhanced the hypoglycemic effect of insulin (FIG. 8G), demonstrating that the chimera acts as an FGF21-like hormone.

To substantiate further the concept of FGF ligand conversion, another FGF21-like ligand was engineered using FGF1 as paracrine FGF, and the metabolic activity of the engineered protein was tested in vivo in a mouse model of diabetes and obesity. Besides serving as an additional proof-of-concept, the use of FGF1 for this particular ligand conversion was appealing because FGF1 on its own plays an essential role in glucose metabolism (Jonker et al., "A PPAR.gamma.-FGF1 Axis is Required for Adaptive Adipose Remodelling and Metabolic Homeostasis," Nature 485:391-394 (2012), which is hereby incorporated by reference in its entirety). Notably, similar to FGF21, FGF1 is induced postprandially in gonadal white adipose tissue by the nuclear hormone receptor PPAR.gamma. (peroxisome proliferator activated receptor-.gamma.) (Jonker et al., "A PPAR.gamma.-FGF1 Axis is Required for Adaptive Adipose Remodelling and Metabolic Homeostasis," Nature 485:391-394 (2012); Dutchak et al., "Fibroblast Growth Factor-21 Regulates PPAR.gamma. Activity and the Antidiabetic Actions of Thiazolidinediones," Cell 148:556-567 (2012), which are hereby incorporated by reference in their entirety). FGF1 is required for the remodeling of adipose tissue to adjust to fluctuations in nutrient availability (Jonker et al., "A PPAR.gamma.-FGF1 Axis is Required for Adaptive Adipose Remodelling and Metabolic Homeostasis," Nature 485:391-394 (2012), which is hereby incorporated by reference in its entirety), and this process is influenced by FGF21 (Hotta et al., "Fibroblast Growth Factor 21 Regulates Lipolysis in White Adipose Tissue But is Not Required for Ketogenesis and Triglyceride Clearance in Liver," Endocrinology 150:4625-4633 (2009); Dutchak et al., "Fibroblast Growth Factor-21 Regulates PPAR.gamma. Activity and the Antidiabetic Actions of Thiazolidinediones," Cell 148:556-567 (2012), which are hereby incorporated by reference in their entirety). As part of a positive feedback loop, FGF21 stimulates PPAR.gamma. activity in adipocytes (Dutchak et al., "Fibroblast Growth Factor-21 Regulates PPAR.gamma. Activity and the Antidiabetic Actions of Thiazolidinediones," Cell 148:556-567 (2012), which is hereby incorporated by reference in its entirety), raising the intriguing possibility that FGF21 regulates FGF1 signaling in adipose tissue through PPAR.gamma.. An FGF1.sup..DELTA.HBScore-FGF21.sup.C-tail chimera was generated in the same manner as the FGF2.sup..DELTA.HBScore-FGF21.sup.C-tail chimera (FIGS. 5 and 6). Specifically, K127, K128, and K133 of FGF1, which correspond to the key HS-binding residues identified in the crystal structure of heparin-bound FGF2 (PDB ID: 1FQ9; (Schlessinger et al., Mol. Cell 6:743-750 (2000), which is hereby incorporated by reference in its entirety)), were mutated and then the short C-terminal tail of the mutated FGF1 was replaced with the C-terminal tail of FGF21 (P168 to S209) (FIG. 6). A full-length FGF1 protein harboring the HS-binding site mutations was used as a control (FIG. 6). Consistent with the structural prediction, this protein exhibited poor binding affinity for HS compared to wild-type FGF1 as evidenced by the fact that, unlike the wild-type ligand, the mutant protein did not bind to a Heparin sepharose column. A subcutaneous bolus injection of the FGF1.sup..DELTA.HBScore-FGF21.sup.C-tail chimera elicited a hypoglycemic effect in ob/ob mice (FIG. 9C), demonstrating that the chimera has metabolic activity. The effect was of similar magnitude as that observed for native FGF1 (FIG. 9C), which itself has a much greater hypoglycemic effect in ob/ob mice than native FGF21 (FIG. 9A). The HS-binding site mutant of FGF1, which was included as a control in these experiments, showed a similar hypoglycemic effect as the wild-type ligand (FIG. 9B), indicating that the loss in HS-binding affinity had no impact on the metabolic activity of FGF1. To alter the receptor-binding specificity of FGF1 such that FGF1 selectively binds to the "c" splice isoform of FGFR1, the principal receptor mediating the metabolic activity of FGF21, an N-terminally truncated FGF1 protein was made (FIG. 6). The truncated FGF1 ligand lacked twenty four residues from the N-terminus including the nine residues that are critical for the promiscuous binding of FGF1 to both splice isoforms of FGFR1-3 (Beenken et al., "Plasticity in Interactions of Fibroblast Growth Factor 1 (FGF1) N Terminus with FGF Receptors Underlies Promiscuity of FGF1," J Biol Chem 287(5):3067-3078 (2012), which is hereby incorporated by reference in its entirety). Based on the crystal structures of FGF1-FGFR complexes, the truncation was also predicted to reduce the receptor-binding affinity of FGF1, and hence the ligand's mitogenicity. The truncated FGF1 protein induced a similar hypoglycemic effect in ob/ob mice as native FGF1 did, indicating that the metabolic activity of FGF1 is mediated through the "c" splice isoform of FGFR. Together, these findings provide a starting point for engineering FGF1 ligands that have no mitogenicity but the same or enhanced metabolic activity compared to native FGF1.

The demonstrated ability to convert a paracrine FGF into an endocrine ligand by means of reducing HS-binding affinity of the paracrine FGF and adding the Klotho co-receptor binding site substantiates that HS does not participate in the formation of the endocrine FGF signal transduction unit. The dispensability of HS for the metabolic activity of endocrine FGFs has an intriguing implication as to how these FGFs have evolved to become hormones. It appears that these ligands have lost the requirement to bind HS in order to signal, while acquiring the ability to bind Klotho co-receptors, which is necessary to direct these ligands to their target organs.

In the target tissue, Klotho co-receptors constitutively associate with cognate receptors of endocrine FGFs to offset the inherently low receptor-binding affinity of endocrine FGFs (FIGS. 10B-10D; Kurosu et al., J. Biol. Chem. 282:26687-26695 (2007); Kurosu et al., J. Biol. Chem. 281:6120-6123 (2006); Ogawa et al., Proc. Nat'l. Acad. Sci. U.S.A. 104:7432-7437 (2007); Urakawa et al., Nature 444:770-774 (2006), which are hereby incorporated by reference in their entirety). This low binding affinity is due to the fact that key receptor-binding residues in the .beta.-trefoil core of endocrine FGFs are replaced by residues that are suboptimal for receptor binding (Goetz et al., Mol. Cell Biol. 27:3417-3428 (2007), which is hereby incorporated by reference in its entirety). To measure the degree to which Klotho co-receptors enhance the receptor-binding affinity of endocrine FGFs, SPR experiments were conducted using FGF23 and FGFR1c and .alpha.Klotho co-receptor as an example (see FIGS. 10A-10F). The SPR data show that .alpha.Klotho enhances the affinity of FGF23 for FGFR1c by over 20-fold (FIGS. 10D and 10E). The affinity of FGF23 for FGFR1c in the presence of .alpha.Klotho is comparable to that of FGF2 for FGFR1c in the absence of its HS cofactor (FIGS. 10A and 10E). It should be noted, however, that HS further increases the binding affinity of FGF2 for FGFR1c by at least an order of magnitude (Pantoliano et al., Biochemistry 33:10229-10248 (1994); Roghani et al., J. Biol. Chem. 269:3976-3984 (1994), which are hereby incorporated by reference in their entirety). Hence, the receptor-binding affinity of FGF23 in the presence of .alpha.Klotho co-receptor still is lower than that of FGF2 in the presence of HS cofactor. These observations imply that the signaling capacity of the endocrine FGF signal transduction unit should be weaker than that of the paracrine FGF signaling unit. Indeed, cell-based studies show that even in the presence of their Klotho co-receptor, endocrine FGFs are inferior to paracrine FGFs at activating FGFR-induced intracellular signaling pathways (Kurosu et al., J. Biol. Chem. 282:26687-26695 (2007); Urakawa et al., Nature 444:770-774 (2006), which are hereby incorporated by reference in their entirety).

The finding that endocrine FGFs do not need to rely on HS for signaling has another important implication in regard to the role of Klotho co-receptors. Since FGFR dimerization is a prerequisite for FGF signaling in general, it is proposed that Klotho co-receptors not only enhance the binding affinity of endocrine ligand for receptor but also promote receptor dimerization upon ligand binding. In other words, Klotho co-receptors must fulfill the same dual role that HS plays in signaling by paracrine FGFs (FIG. 1D). The ligand conversion also provides the framework for the rational design of endocrine FGF-like molecules for the treatment of metabolic disorders. An FGF23-like molecule, for example, will be useful for the treatment of inherited or acquired hyperphosphatemia, and an FGF21-like molecule, for example, for the treatment of type 2 diabetes, obesity, and related metabolic disorders.

Although preferred embodiments have been depicted and described in detail herein, it will be apparent to those skilled in the relevant art that various modifications, additions, substitutions, and the like can be made without departing from the spirit of the invention and these are therefore considered to be within the scope of the invention as defined in the claims which follow.

SEQUENCE LISTINGS

1

4181155PRTHomo sapiens 1Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Ile Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 2155PRTPapio anubis 2Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Pro Ala Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Ile Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 3155PRTPongo abelii 3Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Ile Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 4155PRTCallithrix jacchus 4Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asp Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Ile Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 5155PRTEquus caballus 5Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Thr Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 6155PRTPan troglodytes 6Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Ser Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Ile Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 7155PRTLoxodonta Africana 7Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Gly Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Thr Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 8155PRTCanis lupus familiaris 8Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Pro Gly Asn Tyr Met Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Thr Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 9155PRTAiluropoda melanoleuca 9Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Ala Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Thr Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 10155PRTSaimiri boliviensis boliviensis 10Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asp Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Leu His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Ile Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 11155PRTSus scrofa 11Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Ser Gly Leu Leu Tyr Gly Ser Gln Thr Pro Ser Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Thr Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 12155PRTOtolemur garnettii 12Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Leu Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Gln Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Gln Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Ser Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Val Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 13155PRTRhinolophus ferrumequinum 13Met Ala Glu Gly Glu Val Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Thr Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Lys Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Ser Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Ser Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Thr Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 14155PRTSorex araneus 14Met Ala Glu Gly Glu Ile Thr Thr Phe Gly Ala Leu Met Glu Lys Phe 1 5 10 15 Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly His Tyr Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Thr Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 15155PRTOryctolagus cuniculus 15Met Ala Glu Gly Glu Val Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Ala Gly Asn Tyr Lys Leu Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu

Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Ser Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Thr Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 16155PRTCricetulus griseus 16Met Ala Glu Gly Glu Ile Thr Thr Phe Ser Ala Leu Thr Glu Arg Phe 1 5 10 15 Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Ala Gly Glu Val Tyr Ile Lys Gly Thr Glu Thr Gly Gln Tyr Arg 65 70 75 80 Asn Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Thr Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 17155PRTSarcophilus harrisii 17Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Arg Phe 1 5 10 15 Asn Leu Pro Leu Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Lys Val Asp Gly 35 40 45 Thr Arg Asp Arg Asn Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Ser Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Thr Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Ile Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Glu 145 150 155 18155PRTMus musculus 18Met Ala Glu Gly Glu Ile Thr Thr Phe Ala Ala Leu Thr Glu Arg Phe 1 5 10 15 Asn Leu Pro Leu Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Ala Gly Glu Val Tyr Ile Lys Gly Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Glu Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Thr Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 19154PRTCavia porcellus 19Met Ala Glu Gly Glu Ile Thr Thr Phe Ala Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Gly Val Gly Glu Val Tyr Ile Gln Ser Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Ser Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Thr Ser Lys Lys His Val Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Asp 145 150 20155PRTMonodelphis domestica 20Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Arg Phe 1 5 10 15 Asn Leu Pro Leu Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Lys Val Asp Gly 35 40 45 Thr Arg Asp Arg Asn Asp Gln His Ile Gln Leu Gln Leu Ser Thr Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Ser Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Ser Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Thr Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Lys Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Glu 145 150 155 21155PRTDesmodus rotundus 21Met Ala Glu Gly Glu Val Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Leu Glu Ser Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Lys Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Gly Ser Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Ser Ala Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Thr Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Asn Ser Asp 145 150 155 22155PRTBos taurus 22Met Ala Glu Gly Glu Thr Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Leu Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly Tyr Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Lys Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Cys Ala Glu 50 55 60 Ser Ile Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Phe Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Ile Ser Lys Lys His Ala Glu Lys His Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Arg Ser Lys Leu Gly Pro Arg Thr His Phe Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 23155PRTOrnithorhynchus anatinus 23Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Met Glu Lys Phe 1 5 10 15 Asp Leu Pro Leu Gly Asn Tyr Lys Lys Pro Arg Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly Tyr Phe Leu Arg Ile Gln Pro Asp Gly Lys Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Ser Gly His Tyr Leu 65 70 75 80 Ala Met Asp Thr Glu Gly Leu Leu Tyr Gly Ser Gln Ala Pro Ser Glu 85 90 95 Asp Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Val Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ala Ser Asp 145 150 155 24155PRTTaeniopygia guttata 24Met Ala Glu Gly Glu Ile Thr Thr Phe Ser Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Val Val His Ile Gln Ser Thr Gln Ser Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asn Gly Leu Leu Tyr Gly Ser Gln Leu Pro Pro Gly 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Val Ser Lys Met His Ala Asp Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Thr Ser Lys Leu Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ala Ala Asp 145 150 155 25155PRTDasypus novemcinctus 25Met Ala Glu Gly Glu Ile Thr Thr Phe Met Ala Leu Met Glu Lys Phe 1 5 10 15 Asn Leu Pro Leu Glu Asn Tyr Lys His Pro Arg Leu Leu Tyr Cys Arg 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Ala Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Glu Thr Pro Ser Glu 85 90 95 Glu Cys Leu Phe Met Glu Lys Leu Glu Glu Asn Asn Tyr Asn Thr Tyr 100 105 110 Ile Ser Lys Lys His Ala Glu Lys Lys Trp Phe Val Gly Leu Lys Lys 115 120 125 Asp Gly Ser Ser Lys Arg Gly Pro Gln Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 26155PRTXenopus Silurana tropicalis 26Met Ala Glu Gly Asp Ile Thr Thr Phe Asn Pro Ile Ala Glu Ser Phe 1 5 10 15 Ser Leu Pro Ile Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Asn 20 25 30 Asn Gly Gly Tyr Phe Leu Arg Ile Leu Pro Asp Gly Val Val Asp Gly 35 40 45 Thr Arg Asp Arg Asp Asp Leu Tyr Ile Thr Leu Lys Leu Ser Ala Gln 50 55 60 Ser Gln Gly Glu Val His Ile Lys Ser Thr Glu Thr Gly Ser Tyr Leu 65 70 75 80 Ala Met Asp Ser Ser Gly Gln Leu Tyr Gly Thr Leu Thr Pro Asn Glu 85 90 95 Glu Ser Leu Phe Leu Glu Thr Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Lys Ser Lys Lys Tyr Ala Glu Asn Asn Trp Phe Val Gly Ile Lys Lys 115 120 125 Asn Gly Ala Ser Lys Lys Gly Ser Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Ala Ser Pro Asp 145 150 155 27155PRTHeterocephalus glaber 27Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Lys Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Gly Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Ala Ser Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Ile Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 28155PRTPteropus alecto 28Met Ala Glu Gly Glu Val Thr Thr Phe Thr Ala Leu Thr Glu Arg Phe 1 5 10 15 Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Lys Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Ser Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Ser Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asp Glu 85 90 95 Asp Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Thr Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 29155PRTTupaia chinensis 29Met Ala Glu Gly Glu Ile Thr Thr Phe Ala Ala Leu Thr Glu Lys Phe 1 5 10 15 Asp Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Thr Ala Glu 50 55 60 Asn Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Ala Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Ile Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Ala Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Leu Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140

Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 30155PRTColumba livia 30Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Lys Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Gln Ser Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Pro Thr Gly Leu Leu Tyr Gly Ser Gln Leu Leu Gly Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Ile Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Val Ser Lys Lys His Ala Asp Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Asn Ser Lys Leu Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ala Asp 145 150 155 31155PRTOvis aries 31Met Ala Glu Gly Glu Thr Thr Thr Phe Arg Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Leu Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly Tyr Phe Leu Arg Ile Leu Pro Asp Gly Arg Val Asp Gly 35 40 45 Thr Lys Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Tyr Ala Glu 50 55 60 Ser Ile Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Phe Leu 65 70 75 80 Ala Met Asp Thr Asn Gly Leu Leu Tyr Gly Ser Gln Thr Pro Ser Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Ile Ser Lys Lys His Ala Glu Lys Asn Trp Phe Ile Gly Leu Lys Lys 115 120 125 Asn Gly Ser Ser Lys Leu Gly Pro Arg Thr His Phe Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 32155PRTGallus gallus 32Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Arg Phe 1 5 10 15 Gly Leu Pro Leu Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Lys Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Asp Val Gly Glu Val Tyr Ile Lys Ser Thr Ala Ser Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asn Gly Leu Leu Tyr Gly Ser Gln Leu Pro Gly Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Ile Ser Lys Lys His Ala Asp Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Asn Ser Lys Leu Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ala Asp 145 150 155 3398PRTVicugna pacos 33Gln Leu Gln Leu Ser Ala Glu Ser Val Gly Glu Val Tyr Ile Lys Ser 1 5 10 15 Thr Glu Thr Gly Gln Tyr Leu Ala Met Asp Thr Asp Gly Leu Leu His 20 25 30 Gly Ser Gln Thr Pro Asn Glu Glu Cys Leu Phe Leu Glu Arg Leu Glu 35 40 45 Glu Asn His Tyr Asn Thr Tyr Thr Ser Lys Lys His Ala Glu Lys Asn 50 55 60 Trp Phe Val Gly Leu Lys Lys Asn Gly Ser Cys Lys Arg Gly Pro Arg 65 70 75 80 Thr His Tyr Gly Gln Lys Ala Ile Leu Phe Leu Pro Leu Pro Val Ser 85 90 95 Ser Asp 34155PRTAnolis carolinensis 34Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Arg Phe 1 5 10 15 Ala Leu Pro Met Glu Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Lys Val Asp Gly 35 40 45 Thr Met Asp Arg Asn Asp Ser Tyr Ile Gln Leu Leu Leu Thr Ala Glu 50 55 60 Asp Val Gly Val Val Tyr Ile Lys Gly Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Ala Asn Gly His Leu Tyr Gly Ser Gln Leu Pro Thr Glu 85 90 95 Glu Cys Leu Phe Val Glu Thr Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Thr Ser Lys Met His Gly Asp Lys Lys Trp Tyr Val Gly Leu Lys Lys 115 120 125 Asn Gly Lys Gly Lys Leu Gly Pro Arg Thr His Arg Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Pro Asp 145 150 155 35155PRTOtolemur garnettii 35Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Leu Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Gln Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Gln Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Ser Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Val Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 36155PRTFelis catus 36Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Thr Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 37155PRTPelodiscus sinensis 37Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Leu Gly Asn Tyr Lys Asn Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly Tyr Phe Leu Arg Ile His Pro Asp Gly Lys Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Ser Gly Gln Phe Leu 65 70 75 80 Ala Met Asp Ala Asn Gly Leu Leu Tyr Gly Ser Leu Ser Pro Ser Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Met Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Ile Ser Lys Lys His Ala Asp Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Leu Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Val Leu Phe Leu Pro Leu Pro Val Ser Ala Asp 145 150 155 38155PRTLatimeria chalumnae 38Met Ala Glu Asp Lys Ile Thr Thr Leu Lys Ala Leu Ala Glu Lys Phe 1 5 10 15 Asn Leu Pro Met Gly Asn Tyr Lys Lys Ala Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly Tyr Phe Leu Arg Ile Pro Pro Asp Gly Lys Val Glu Gly 35 40 45 Ile Arg Glu Arg Ser Asp Lys Tyr Ile Gln Leu Gln Met Asn Ala Glu 50 55 60 Ser Leu Gly Met Val Ser Ile Lys Gly Val Glu Ala Gly Gln Tyr Leu 65 70 75 80 Ala Met Asn Thr Asn Gly Leu Leu Tyr Gly Ser Gln Ser Leu Thr Glu 85 90 95 Glu Cys Leu Phe Met Glu Lys Met Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Arg Ser Lys Thr His Ala Asp Lys Asn Trp Tyr Val Gly Ile Arg Lys 115 120 125 Asn Gly Ser Ile Lys Pro Gly Pro Arg Thr His Ile Gly Gln Lys Ala 130 135 140 Val Leu Phe Leu Pro Leu Pro Ala Ser Ser Asp 145 150 155 39155PRTTursiops truncatus 39Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Ala Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 40155PRTMustela putorius furo 40Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Met Glu Lys Phe 1 5 10 15 Asn Leu Pro Ala Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Thr Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 41155PRTNomascus leucogenys 41Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Ile Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 42155PRTGorilla gorilla 42Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Ile Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 43155PRTErinaceus europaeus 43Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Leu Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Thr Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 4491PRTProcavia capensis 44Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Leu Glu Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Gly Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser 85 90 45114PRTDipodomys ordii 45Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Arg Phe 1 5 10 15 Gln Leu Gln Leu Ser Ala Glu Ser Val Gly Glu Val Tyr Ile Lys Ser 20

25 30 Thr Glu Thr Gly Gln Tyr Leu Ala Met Asp Ala Asp Gly Leu Leu Tyr 35 40 45 Gly Ser Gln Thr Pro Asp Glu Glu Cys Leu Phe Leu Glu Arg Leu Glu 50 55 60 Glu Asn His Tyr Asn Thr Tyr Ile Ala Lys Lys His Ala Glu Lys Asn 65 70 75 80 Trp Phe Val Gly Leu Lys Lys Asn Gly Ser Cys Lys Arg Gly Pro Arg 85 90 95 Thr His Tyr Gly Gln Lys Ala Ile Leu Phe Leu Pro Leu Pro Val Ser 100 105 110 Ser Asp 4692PRTPetromyzon marinus 46Met Glu Val Gly His Ile Gly Thr Leu Pro Val Val Pro Ala Gly Pro 1 5 10 15 Val Phe Pro Gly Ser Phe Lys Glu Pro Arg Arg Leu Tyr Cys Arg Ser 20 25 30 Ala Gly His His Leu Gln Ile Leu Gly Asp Gly Thr Val Ser Gly Thr 35 40 45 Gln Asp Glu Asn Glu Pro His Ala Val Leu Gln Leu Gln Ala Val Arg 50 55 60 Arg Gly Val Val Thr Ile Arg Gly Leu Cys Ala Glu Arg Phe Leu Ala 65 70 75 80 Met Ser Thr Glu Gly His Leu Tyr Gly Ala Val Arg 85 90 4798PRTEchinops telfairi 47Gln Leu Lys Leu Val Ala Glu Ser Val Gly Val Val Tyr Ile Lys Ser 1 5 10 15 Ile Lys Thr Gly Gln Tyr Leu Ala Met Asn Pro Asp Gly Leu Leu Tyr 20 25 30 Gly Ser Glu Thr Pro Glu Glu Glu Cys Leu Phe Leu Glu Thr Leu Glu 35 40 45 Glu Asn His Tyr Thr Thr Phe Lys Ser Lys Lys His Val Glu Lys Asn 50 55 60 Trp Phe Val Gly Leu Arg Lys Asn Gly Arg Val Lys Ile Gly Pro Arg 65 70 75 80 Thr His Gln Gly Gln Lys Ala Ile Leu Phe Leu Pro Leu Pro Val Ser 85 90 95 Ser Asp 48155PRTMacaca mulatta 48Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Thr Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 49155PRTPteropus vampyrus 49Met Ala Glu Gly Glu Val Thr Thr Phe Thr Ala Leu Thr Glu Arg Phe 1 5 10 15 Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Lys Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Ser Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Ser Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asp Glu 85 90 95 Asp Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Thr Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 50155PRTMyotis lucifugus 50Met Ala Glu Gly Glu Val Thr Thr Phe Thr Ala Leu Thr Glu Arg Phe 1 5 10 15 Asn Leu Pro Leu Glu Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Ser Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Ser Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Thr Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 51155PRTMicrocebus murinus 51Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Ala Gly Glu Val Tyr Ile Lys Ser Thr Gln Thr Gly Arg Tyr Leu 65 70 75 80 Ala Met Asp Ala Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Val Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 52144PRTOchotona princeps 52Met Ala Glu Gly Glu Val Thr Thr Phe Ser Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Gly Gly Asn Tyr Lys Leu Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Leu His Glu Val Phe Ile Lys Ser Thr Glu 50 55 60 Thr Gly Gln Tyr Leu Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser 65 70 75 80 Gln Thr Pro Ser Glu Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn 85 90 95 His Tyr Asn Thr Tyr Thr Ser Lys Lys His Ala Glu Lys Asn Trp Phe 100 105 110 Val Gly Ile Lys Lys Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His 115 120 125 Tyr Gly Gln Lys Ala Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 130 135 140 53155PRTRattus norvegicus 53Met Ala Glu Gly Glu Ile Thr Thr Phe Ala Ala Leu Thr Glu Arg Phe 1 5 10 15 Asn Leu Pro Leu Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Ala Gly Glu Val Tyr Ile Lys Gly Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Glu Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Thr Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 54155PRTCholoepus hoffmanni 54Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Met Glu Lys Phe 1 5 10 15 Asn Leu Pro Pro Gly Asn Tyr Met Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Leu His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Ala Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Gly Gly Leu Leu Tyr Gly Ser Gln Thr Pro Ser Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Val Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Ser Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 55155PRTIctidomys tridecemlineatus 55Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Thr Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 56155PRTTarsius syrichta 56Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Val Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 57155PRTTupaia belangeri 57Met Ala Glu Gly Glu Ile Thr Thr Phe Ala Ala Leu Thr Glu Lys Phe 1 5 10 15 Asp Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Thr Ala Glu 50 55 60 Asn Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Ala Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Ile Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Ala Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Leu Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp 145 150 155 5856PRTMeleagris gallopavo 58Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Arg Phe 1 5 10 15 Gly Leu Pro Leu Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Lys Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His 50 55 59155PRTMacropus eugenii 59Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Arg Phe 1 5 10 15 Asn Leu Pro Leu Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Lys Val Asp Gly 35 40 45 Thr Arg Asp Arg Asn Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Ser Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asn Gly Leu Leu Tyr Gly Ser Gln Thr Pro Ser Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Ile Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys 115 120 125 Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Glu 145 150 155 60147PRTDanio rerio 60Met Thr Glu Ala Asp Ile Ala Val Lys Ser Ser Pro Arg Asp Tyr Lys 1 5 10 15 Lys Leu Thr Arg Leu Tyr Cys Met Asn Gly Gly Phe His Leu Gln Ile 20 25 30 Leu Ala Asp Gly Thr Val Ala Gly Ala Ala Asp Glu Asn Thr Tyr Ser 35 40 45 Ile Leu Arg Ile Lys Ala Thr Ser Pro Gly Val Val Val Ile Glu Gly 50 55 60 Ser Glu Thr Gly Leu Tyr Leu Ser Met Asn Glu His Gly Lys Leu Tyr 65 70 75 80 Ala Ser Ser Leu Val Thr Asp Glu Ser Tyr Phe Leu Glu Lys Met Glu 85 90 95 Glu Asn His Tyr Asn Thr Tyr Gln Ser Gln Lys His Gly Glu Asn Trp 100 105 110 Tyr Val Gly Ile Lys Lys Asn Gly Lys Met Lys Arg Gly Pro Arg Thr 115 120 125 His Ile Gly Gln Lys Ala Ile Phe Phe Leu Pro Arg Gln Val Glu Gln 130 135 140 Glu Glu Asp 145 61468DNAHomo sapiens 61atggctgaag gggaaatcac caccttcaca gccctgaccg agaagtttaa tctgcctcca 60gggaattaca agaagcccaa actcctctac tgtagcaacg ggggccactt cctgaggatc 120cttccggatg gcacagtgga tgggacaagg gacaggagcg accagcacat tcagctgcag 180ctcagtgcgg aaagcgtggg ggaggtgtat ataaagagta ccgagactgg ccagtacttg 240gccatggaca ccgacgggct tttatacggc tcacagacac caaatgagga atgtttgttc 300ctggaaaggc tggaggagaa ccattacaac acctatatat ccaagaagca tgcagagaag 360aattggtttg ttggcctcaa gaagaatggg agctgcaaac gcggtcctcg gactcactat

420ggccagaaag caatcttgtt tctccccctg ccagtctctt ctgattaa 46862468DNAOlive Baboon 62atggctgaag gggaaatcac cacgttcaca gccctgaccg agaagtttaa tctgcctcca 60gcgaattaca agaagcccaa actgctctac tgtagcaacg ggggacactt cttgaggatc 120cttccggatg gcacagtgga tgggacaagg gacaggagcg accagcacat tcagctgcag 180ctcagtgcgg aaagcgtggg ggaggtgtat ataaagagta ccgagactgg ccagtacttg 240gccatggaca ccgacgggct tttatacggc tcacagacac caaatgagga atgtttgttc 300ctggaaaggc tggaggagaa ccattacaac acctacatat ccaagaagca cgcagagaag 360aattggtttg ttggcctcaa gaagaatgga agctgcaaac gtggtcctcg gactcactat 420ggccagaaag caatcttgtt tcttcccctg ccagtctctt ctgattaa 46863468DNASumatran orangutan 63atggctgaag gggaaatcac caccttcaca gccctgaccg agaagtttaa tctgcctcca 60gggaattaca agaagcccaa actcctctac tgtagcaacg ggggccactt cttgaggatc 120cttccggatg gcacagtgga tgggacaagg gacaggagcg accagcacat tcagctgcag 180ctcagtgcgg aaagcgtggg ggaggtgtat ataaagagta ccgagactgg ccagtacttg 240gccatggaca ccgacgggct tttatacggc tcacagacac caaatgagga atgtttgttc 300ctggaaaggc tggaggagaa ccattacaac acctatatat ccaagaagca tgcagagaag 360aattggtttg ttggcctcaa gaagaatgga agctgcaaac gcggtcctcg gactcactat 420ggccagaaag caatcttgtt tctccccctg ccagtctctt ccgattaa 46864468DNAWhite-tufted-ear marmoset 64atggctgaag gggaaatcac caccttcaca gccctgaccg agaagtttga tctgcctcca 60gggaattaca agaagcccaa actcctctac tgtagcaatg ggggccactt cttgaggatc 120cttccggatg gcacagtgga tgggacaagg gacaggagcg accagcacat tcagctgcag 180ctcagtgcgg aaagcgtggg ggaggtgtat ataaagagta ccgagactgg ccagtacttg 240gccatggaca ccgacgggct tttatacggc tcacagacac caaatgagga atgtttgttc 300ctggagaggc tggaggagaa ccattacaac acctatatat ccaagaaaca tgcagagaag 360aattggtttg tcggcctcaa gaagaatgga agctgtaaac gtggtcctcg gactcactat 420ggtcagaaag cgatcttgtt tctccccctg ccagtttctt ctgattaa 46865468DNAHorse 65atggctgaag gagaaatcac aaccttcacg gccctgaccg agaagtttaa tctgcctcca 60gggaattaca agaagcccaa actcctctac tgtagcaatg ggggccactt cctgaggatc 120cttccagatg gcacagtgga tgggacaagg gacaggagcg accagcacat tcagctgcag 180ctcagtgcgg aaagcgtggg ggaggtgtat ataaagagta ccgagactgg ccagtacttg 240gccatggaca ccgacgggct gttgtacggc tcacagacac caaacgagga atgtttgttc 300ctggaaaggc tggaggaaaa ccattacaac acctacacat ccaagaagca tgcagagaag 360aactggttcg ttggtctcaa gaagaatggg agctgcaaac gcggtcctcg gactcactat 420gggcagaaag caatcttgtt tcttcccctg cccgtctcct ctgactaa 46866468DNAChimpanzee 66atggctgaag gggaaatcac caccttcaca gccctgaccg agaagtttaa tctgccttca 60gggaattaca agaagcccaa actcctctac tgtagcaacg ggggccactt cctgaggatc 120cttccggatg gcacagtgga tgggacaagg gacaggagcg accagcacat tcagctgcag 180ctcagtgcgg aaagcgtggg ggaggtgtat ataaagagta ccgagactgg ccagtacttg 240gccatggaca ccgacgggct tttatacggc tcacagacac caaatgagga atgtttgttc 300ctggaacggc tggaggagaa ccattacaac acctatatat ccaagaagca tgcagagaag 360aattggtttg ttggcctcaa gaagaatgga agctgcaaac gcggtcctcg gactcactat 420ggccagaaag caatcttgtt tctccccctg ccagtctctt ccgattaa 46867468DNAElephant 67atggccgaag gggaaatcac aactttcaca gccctgacag agaagttcaa cctgcctcca 60gggaattaca agaagcccaa actcctctac tgtagcaatg gaggtcactt cttaaggatc 120cttccagatg gcacagtgga tggcaccagg gacaggagtg accagcacat tcagctgcag 180ctcagtgcgg aaagcgtggg ggaggtgtat ataaagggca ccgagactgg ccagtacttg 240gccatggaca ccgacgggct tttatacggc tcacagacac caaatgagga atgtttgttc 300ctggaaaggc tggaggaaaa ccattacaac acctacacat ccaagaagca cgcagagaag 360aattggttcg ttggtctcaa gaagaatgga agctgcaaac gcggtcctcg gactcactat 420ggccagaaag caatcttgtt tctccccctg ccagtctcct ctgattaa 46868468DNADog 68atggctgaag gggaaatcac aaccttcact gccctgacgg agaagtttaa tctgcctccg 60gggaattaca tgaagcccaa actcctctac tgtagcaacg ggggccactt cctgaggatc 120cttccagatg gcacagtgga tgggacaagg gacaggagcg accagcacat tcagctgcag 180ctcagcgcgg aaagcgtggg ggaggtgtat ataaagagca ccgagactgg ccagtacttg 240gccatggaca ccgatgggct tctgtacggc tcacagacac cgaatgagga atgtttgttc 300ctggaaaggc tggaggaaaa ccattacaac acctacacat ccaagaagca tgcagaaaaa 360aattggtttg ttggtctcaa gaagaatgga agctgcaaac gcggtcctcg gactcactat 420ggtcaaaaag caattttgtt tctccccctg ccagtgtcct ctgattaa 46869468DNAGiant panda 69atggctgaag gggagatcac aaccttcacc gccctgacgg agaagtttaa tctgcctgcg 60gggaattaca agaagcccaa actcctctac tgtagcaacg ggggccactt cctgaggatc 120cttccagatg gcacagtgga cgggacgagg gacaggagcg accagcacat tcaactgcag 180ctcagcgcgg aaagcgtagg ggaggtgtac ataaagagca ccgagaccgg ccagtacttg 240gccatggaca ccgatgggct tctgtacggc tcacagacac caaatgagga atgtttgttc 300ctggaaaggc tggaggaaaa ccattacaac acctacacat ccaagaagca cgcggagaag 360aattggtttg ttggtctcaa gaagaatgga agctgcaaac gtggtcctcg gactcactat 420ggccagaaag caattctgtt tctccccctg ccagtctcct ctgattaa 46870468DNABolivian squirrel monkey 70atggctgaag gggaaatcac cacctttaca gccctgaccg agaagtttga tctgcctcca 60gggaattaca agaagcccaa actcctctac tgtagcaacg ggggccactt cttgaggatc 120cttccggatg gcacagtgga tgggaccagg gacaggagcg atcttcacat tcagctgcag 180ctcagtgcgg aaagcgtggg ggaggtgtat ataaagagta ccgagactgg ccagtacttg 240gccatggaca ccgacgggct tttatacggc tcacagacac caaatgagga atgtttgttc 300ctggaaaggc tggaggagaa ccattacaac acctatatat ccaagaaaca cgcagagaag 360aattggtttg ttggcctcaa gaagaatgga agctgcaagc gcggtcctcg gactcactat 420ggccagaaag caatcttgtt tctccccctg ccagtctctt ctgattaa 46871468DNAPig 71atggctgaag gcgaaatcac aaccttcacg gccctgaccg agaagtttaa tctgcctcca 60ggaaattaca agaagcccaa gctcctctac tgcagcaacg ggggccattt cctcaggatc 120cttccagatg gcacagtgga tgggaccagg gacaggagcg accagcacat tcagctgcag 180ctcagtgcgg aaagcgtggg ggaggtgtat ataaagagta cggagactgg ccagtacttg 240gccatggaca ccagcgggct tttgtacggc tcacagacac ccagtgagga gtgtttgttc 300ctggagaggc tggaggaaaa ccattacaat acctacacat ccaagaagca cgcagagaag 360aactggttcg ttggcctcaa gaagaatgga agctgcaaac gcggtcctcg gactcactat 420ggccagaaag ccatcctgtt tctccccctg ccagtatcct cggattaa 46872468DNASmall-eared galago 72atggctgaag gggaaatcac aaccttcaca gccctcacag agaagtttaa tctgcctcta 60ggaaattaca agaagcccaa gctcctctac tgtagcaacg ggggtcactt tctgaggatc 120ctgccggatg gcaccgtgga tgggacacaa gacaggagcg accagcacat tcagctgcag 180ctcagtgcgg aaagcgtggg ggaggtgtat ataaagagta cccagactgg ccagtacttg 240gccatggact ccgacgggct tttatacggc tcacaaacac caaatgagga atgcctgttc 300ctggaacggc tggaggaaaa ccattacaac acctatgtgt ccaagaagca cgccgagaag 360aattggtttg tcggtctcaa gaagaacgga agttgcaaac gtggtcctcg gactcactac 420ggccagaaag caatcttgtt tctccccctg ccagtctcct ctgattaa 46873468DNAGreater horseshoe bat 73ttaatcagag gagactggca gggggagaaa caggattgct ttctggccat agtgagtccg 60aggaccgcgc ttgcagcttc cattcttctt gagcccaacg aaccaattct tttctgcgtg 120cttcttggac gtgtaggtgt tgtaatggtt ttcctccagc ctttccagga acagacattc 180ctcatttggt gtctgtgagc cgtacaaaag cccgtcggag tccatggcca agtactggcc 240actctcggtg ctctttatat acacctcccc cacgctttcc gcactgagct gcagctgaat 300gtgctggtca ctcttgtccc ttgtcccatc cactgtgcca tctggaagga tcctcaggaa 360gtggcccccg ttgctgcagt agagaagttt gggtttcttg taattccctg taggcagatt 420aaacttctca gtaagggctg tgaacgtggt gacttcccct tcggccat 46874468DNAEuropean shrew 74ctagtcggag gagacgggca gggggagaaa caagatcgct ttctggccgt agtgagtccg 60gggaccacgc ttgcagcttc cgttcttctt cagaccaaca aaccaattct tctcggcatg 120cttcttggag gtataggtgt tgtaatggtt ttcctccagc ctttccagaa acagacattc 180ctcattcggt gtttgtgagc cgtataaaag cccgtcggtg tccatggcca agtaatggcc 240agtctccgtg ctctttatat acacctcccc cacgctttcc gcactgagct gcagctgaat 300gtgctggtcg ctgcggtccc tggtcccatc cactgtgccg tccgggagga tgcgcaggaa 360gtggcccccg ttgctgcagt acaggagttt gggcttcttg tagttccctg gtggcaggtt 420aaacttctcc atgagggccc caaaggtggt gatctccccc tcggccat 46875468DNARabbit 75atggctgagg gggaggtcac caccttcaca gccctgaccg agaagttcaa cctgcctgca 60gggaactaca agttgcccaa actcctctac tgcagcaacg ggggccactt cctgaggatc 120ctgccggacg gcactgtgga cggcacaagg gacaggagcg accagcacat tcagctgcag 180ctgagtgcgg aaagcgtggg ggaggtgtat ataaagagta cggagaccgg ccagtacttg 240gccatggaca ccgacggcct tttatacggc tcgcaaacgc ccagtgagga gtgtttgttc 300ctggaacggc tggaggagaa ccactacaac acctacacgt ccaagaagca cgccgagaag 360aactggttcg tggggctgaa gaaaaacggg agctgcaagc gcggtcctcg gactcactac 420ggccagaaag ccatcttgtt cctccccctg ccggtctcct ccgactaa 46876468DNAChinese hamster 76atggctgaag gagaaatcac caccttctca gccctgacag agagatttaa tctgcctcca 60ggaaactaca agaagcccaa actgctctac tgcagcaacg ggggccactt cttgaggatc 120cttccagatg gcacagtgga tgggacaagg gacaggagtg accagcacat tcagctgcag 180ctgagtgcgg aaagcgcggg cgaagtgtat ataaagggta cagagacagg ccagtacagg 240aacatggaca cggatggcct tttatacggc tcacagacac caaatgaaga atgcctgttc 300ctggaaaggc tggaagaaaa ccattacaac acttatacat ccaagaagca cgcagagaag 360aactggtttg tgggcctcaa gaaaaacggg agctgcaagc gtggtcctcg gactcactat 420ggccagaaag caatcttgtt tctccccctg cctgtatctt ctgactag 46877468DNATasmanian devil 77atggccgaag gggagatcac aaccttcaca gccctgaccg aaagatttaa tctgccactg 60gggaattaca agaagcccaa gcttctctac tgtagcaatg ggggccactt tttgaggatt 120cttcctgatg gtaaagtgga tgggacaagg gacagaaatg atcaacacat tcaactgcaa 180ctaagcgcgg aaagcgtggg tgaggtgtat ataaagagca ctgagtctgg ccagtatttg 240gctatggaca ccgatggact tttatacggc tcacagacac ccactgaaga atgcttgttc 300ctggagagat tggaggagaa tcattacaac acctacatat caaagaagca tgcggagaaa 360aattggtttg tgggcctcaa gaaaaatgga agctgcaaaa gaggtcccag gactcactat 420ggccagaaag ccatcctctt ccttcccctc cctgtgtcct ctgagtaa 46878468DNAHouse mouse 78atggctgaag gggagatcac aaccttcgca gccctgaccg agaggttcaa cctgcctcta 60ggaaactaca aaaagcccaa actgctctac tgcagcaacg ggggccactt cttgaggatc 120cttcctgatg gcaccgtgga tgggacaagg gacaggagcg accagcacat tcagctgcag 180ctcagtgcgg aaagtgcggg cgaagtgtat ataaagggta cggagaccgg ccagtacttg 240gccatggaca ccgaagggct tttatacggc tcgcagacac caaatgagga atgtctgttc 300ctggaaaggc tggaagaaaa ccattataac acttacacct ccaagaagca tgcggagaag 360aactggtttg tgggcctcaa gaagaacggg agctgtaagc gcggtcctcg gactcactat 420ggccagaaag ccatcttgtt tctgcccctc ccggtgtctt ctgactag 46879465DNADomestic guinea pig 79atggctgaag gagaaatcac aacttttgca gccctgactg agaagtttaa tctgcctcca 60gggaattata agaagcccaa actgctctac tgcagcaatg ggggccactt cctgaggatc 120cttccagacg gcacagtgga cggcacaaga gacaggagcg accagcacat tcagctgcag 180ctcagtgcgg aaggcgtggg ggaggtgtat atacagagca ccgagaccgg ccagtacttg 240gccatggaca ccgacgggct tttatacggc tcacagacac caagtgagga atgcttgttc 300ctggaaaggc tggaggaaaa ccattacaac acctacacat ccaagaagca tgtggagaag 360aattggtttg ttggcctcaa gaagaacgga agctgcaagc gtggtcctcg gactcactat 420ggccagaaag caatcttgtt cctccccttg ccagtctctg attag 46580468DNAGray short-tailed opossum 80atggccgaag gggagatcac aaccttcaca gccctgactg aaagatttaa cctgccactg 60gggaattaca agaaacccaa gcttctctac tgtagcaatg ggggccattt cttgaggatc 120cttcctgatg gcaaagtgga tgggacacgg gacagaaatg atcaacacat tcaactgcag 180ctgagcacgg aaagtgtggg tgaggtgtat ataaagagca ctgagtctgg ccagtatttg 240gctatggaca ccgatggact tttatatggc tcacagacac ccagtgaaga atgcttgttt 300ctggagaggt tggaggagaa tcattacaac acctacacat cgaagaagca tgcagagaaa 360aattggtttg ttggtctcaa gaagaatgga agctgcaaaa agggtcccag gactcactac 420ggccagaaag ccatcctgtt ccttcccctc cctgtgtcct ctgagtaa 46881468DNACommon vampire bat 81atggctgaag gggaagtcac cacgttcaca gctctgactg agaagtttaa tctgcctctg 60gagagttaca agaagcccaa acttctctac tgcagcaacg gtggccactt cctgaggatc 120cttccagatg gtacagtgga tgggacaagg gacaagagcg accagcacat tcagctgcag 180ctcagtgcgg aaagcgtggg ggaggtgtac ataaagagca ccgggagtgg ccagtacttg 240gccatggact ccgccgggct tttgtatggc tcacagacac caaatgagga atgtttgttc 300ctggaaaggc tggaggaaaa ccattacaac acctacacat ccaagaagca tgcagaaaag 360aattggttcg tggggctcaa gaagaatgga agctgcaagc gtggcccccg gactcattat 420ggccagaaag caatcttgtt tctccccctg ccagtcaact ctgattaa 46882468DNACattle 82atggctgaag gagaaaccac gaccttcacg gccctgactg agaagtttaa cctgcctcta 60ggcaattaca agaagcccaa gctcctctac tgcagcaacg ggggctactt cctgagaatc 120ctcccagatg gcacagtgga tgggacgaag gacaggagcg accagcacat tcagctgcag 180ctctgtgcgg aaagcatagg ggaggtgtat attaagagta cggagactgg ccagttcttg 240gccatggaca ccgacgggct tttgtacggc tcacagacac ccaatgagga atgtttgttc 300ctggaaaggt tggaggaaaa ccattacaac acctacatat ccaagaagca tgcagagaag 360cattggttcg ttggtctcaa gaagaacgga aggtctaaac tcggtcctcg gactcacttc 420ggccagaaag ccatcttgtt tctccccctg ccagtctcct ctgattaa 46883468DNAPlatypus 83atggcggagg gtgaaatcac cacgttcaca gccctgatgg agaagttcga cctacccctg 60ggcaactaca aaaagcctag gctgctctac tgcagcaatg gcggctactt cctgcgcatc 120cagccagacg gtaaagtgga cgggaccagg gatcggagcg atcagcacat tcaactgcag 180ctaagcgcgg aaagcgtggg cgaggtgtat ataaagagca ccgagtctgg ccactatttg 240gctatggaca ccgaaggact tttatatggc tcacaggcac ccagtgaaga ctgcttgttc 300ctggagcggc tggaggagaa ccactataac acgtacgtgt ccaagaagca cgctgagaag 360aattggtttg tcggtctcaa gaagaacggg agctgcaaac gaggtccccg gactcactac 420ggccagaaag ccatcctctt cctcccgctc cccgtggcat ccgactag 46884468DNAZebra finch 84atggccgagg gggagatcac caccttcagc gccctgacgg agaagttcaa cctgcccccg 60gggaactaca agaagcccaa actgctgtac tgcagcaacg gggggcattt cctgcgcatc 120ctcccggacg gcaccgtgga tggcaccagg gaccgcagcg accagcacat tcagctccag 180ctgagtgcag agagcgtggg ggtggtgcac atccagagca cccagtcggg gcagtacctg 240gccatggaca ccaacgggct gctctacggc tcgcagctgc cacccggtga gtgtctgttc 300ctggaaaggc tggaggagaa ccattacaac acctacgtct ccaaaatgca cgcggacaag 360aactggtttg tggggctgaa gaagaacggg acaagcaagc tgggcccgcg gactcactac 420ggccagaagg cgatcctgtt cctgccgctg cccgtggcgg ccgactga 46885468DNANine-banded armadillo 85ttaatcagag gagactggca ggggaagaaa caagatagct ttctggccat agtgagtctg 60aggaccacgt ttgctgcttc cgtccttctt gagaccaaca aaccatttct tctctgcatg 120cttcttggat atgtaggtgt tgtaattgtt ttcttccagc ttttccatga acaagcattc 180ctcacttggt gtctctgagc catataaaag cccgtcggtg tccatggcta agtactggcc 240ggtctctgca ctctttatat acacctcccc cacgctttcc gcactgagct gcagctgaat 300gtgttggtcg ctcctgtccc ttgtcccatc caccgtgcca tctggaagga tcctcaagaa 360gtggcccccg tttctgcagt agaggagtct ggggtgcttg taattttcta ggggcaggtt 420gaacttctcc atcagggcca tgaaggttgt gatctcccct tcagccat 46886468DNAXenopus Silurana tropicalis 86atggcagagg gagacatcac aacattcaac cccattgcag agtccttcag tcttccaatt 60ggcaactaca agaaaccaaa acttctgtac tgtaataatg gagggtattt tttgcgcatc 120ctcccagatg gggttgtgga tggaacaaga gacagagatg acctttacat tacactgaag 180ttaagcgcac aaagccaagg ggaggtgcat atcaaaagca cagagacagg gagttactta 240gccatggact ccagtggaca gttgtatgga actctcacac caaatgaaga aagcctgttt 300ctggagacat tagaagagaa tcactataac acatacaagt caaagaagta tgcagaaaat 360aactggtttg tggggataaa gaagaacggg gcaagcaaaa agggatcaag gactcactat 420ggacaaaaag ccatcctttt tctgccgctg ccagcatcac ctgactag 46887465DNAHeterocephalus glaber 87atggcggaag gcgaaattac cacctttacc gcgctgaccg aaaaatttaa cctgccgccg 60ggcaactata aaaaaccgaa actgctgtat tgcagcaacg gcggccattt tctgcgcatt 120ctgccggatg gcaaagtgga tggcacccgc gatcgcagcg atcagcatat tcagctgcag 180ctgagcgcgg aaggcgtggg cgaagtgtat attaaaagca ccgaaaccgg ccagtatctg 240gcgatggata ccgatggcct gctgtatggc agccagaccg cgagcgaaga atgcctgttt 300ctggaacgcc tggaagaaaa ccattataac acctatatta gcaaaaaaca tgcggaaaaa 360aactggtttg tgggcctgaa aaaaaacggc agctgcaaac gcggcccgcg cacccattat 420ggccagaaag cgattctgtt tctgccgctg ccggtgagca gcgat 46588465DNABlack flying fox 88atggcggaag gcgaagtgac cacctttacc gcgctgaccg aacgctttaa cctgccgccg 60ggcaactata aaaaaccgaa actgctgtat tgcagcaacg gcggccattt tctgcgcatt 120ctgccggatg gcaccgtgga tggcacccgc gataaaagcg atcagcatat tcagctgcag 180ctgagcgcgg aaagcgtggg cgaagtgtat attaaaagca ccgaaagcgg ccagtatctg 240gcgatggata gcgatggcct gctgtatggc agccagaccc cggatgaaga ttgcctgttt 300ctggaacgcc tggaagaaaa ccattataac acctatacca gcaaaaaaca tgcggaaaaa 360aactggtttg tgggcctgaa aaaaaacggc agctgcaaac gcggcccgcg cacccattat 420ggccagaaag cgattctgtt tctgccgctg ccggtgagca gcgat 46589465DNAChinese tree shrew 89atggcggaag gcgaaattac cacctttgcg gcgctgaccg aaaaatttga tctgccgccg 60ggcaactata aaaaaccgaa actgctgtat tgcagcaacg gcggccattt tctgcgcatt 120ctgccggatg gcaccgtgga tggcacccgc gatcgcagcg atcagcatat tcagctgcag 180ctgaccgcgg aaaacgtggg cgaagtgtat attaaaagca ccgaaaccgg ccagtatctg 240gcgatggatg cggatggcct gctgtatggc agccagaccc cgaacgaaga atgcctgttt 300ctggaacgcc tggaagaaaa ccattataac acctatatta gcaaaaaaca tgcggaaaaa 360aactggtttg tggcgctgaa aaaaaacggc agctgcaaac tgggcccgcg cacccattat 420ggccagaaag cgattctgtt tctgccgctg ccggtgagca gcgat 46590465DNARock pigeon 90atggcggaag gcgaaattac cacctttacc gcgctgaccg aaaaatttaa cctgccgccg 60ggcaactata aaaaaccgaa actgctgtat tgcagcaacg gcggccattt tctgcgcatt 120ctgccggatg gcaaagtgga tggcacccgc gatcgcagcg atcagcatat tcagctgcag 180ctgagcgcgg aaagcgtggg cgaagtgtat attaaaagca cccagagcgg ccagtatctg 240gcgatggatc cgaccggcct gctgtatggc agccagctgc tgggcgaaga atgcctgttt 300ctggaacgca ttgaagaaaa ccattataac acctatgtga gcaaaaaaca tgcggataaa 360aactggtttg tgggcctgaa aaaaaacggc aacagcaaac tgggcccgcg cacccattat 420ggccagaaag cgattctgtt tctgccgctg ccggtgagcg cggat 46591468DNASheep 91atggctgaag gagaaaccac aaccttcagg gccctgactg agaagtttaa cctgcctcta 60ggcaattaca agaagcccaa gctcctctat tgcagcaacg ggggctactt cctgagaatc 120ctcccagatg gcagagtgga tgggacgaag gacaggagcg accagcacat tcagctgcag 180ctctatgcgg aaagcatagg ggaggtgtat attaagagta cggagactgg ccagttcttg 240gccatggaca ccaacgggct tttgtacggc tcacaaacac ccagtgagga atgtttgttc 300ctggaaaggc tggaggaaaa ccattataac acctacatat ccaagaagca

tgcagagaag 360aattggttca ttggtctcaa gaagaacgga agctccaaac tcggtcctcg gactcacttc 420ggccagaaag ccatcttgtt tctccccctg ccagtttcct ctgattaa 46892468DNAChicken 92atggccgagg gggagataac caccttcacc gccctgaccg agcgcttcgg cctgccgctg 60ggcaactaca agaagcccaa actcctgtac tgcagcaacg ggggccactt cctacggatc 120ctgccggacg gcaaggtgga cgggacgcgg gaccggagtg accagcacat tcagctgcag 180ctcagcgcgg aagatgtggg cgaggtctat ataaagagca cagcgtcggg gcagtacctg 240gcaatggaca ccaacgggct cctgtatggc tcgcagctac caggcgagga gtgcttgttc 300cttgagaggc tcgaggagaa ccattacaac acatacatct ccaaaaagca cgcagacaag 360aactggttcg tcgggctgaa gaaaaacggg aacagcaagc tggggccgcg gactcactat 420gggcaaaagg cgatcctctt cctcccattg ccggtgtcgg ctgactga 46893297DNAAlpaca 93cagctgcagc tcagtgcgga aagcgtgggg gaggtgtata taaagagtac cgagactggc 60cagtacttgg ccatggacac cgacgggctt ttgcacggct cacagacacc aaatgaggaa 120tgtttgttcc tggaaaggct ggaggagaac cattacaaca cctacacgtc caagaagcac 180gccgaaaaga attggtttgt tggtctcaag aagaatggaa gctgcaaacg cggtcctcgg 240actcactacg gccagaaggc gatcttgttt ctccccttgc cagtctcctc tgattaa 29794468DNAAnole lizard 94atggctgaag gtgaaataac aacattcaca gccttgaccg agaggtttgc tctcccaatg 60gagaattaca agaagcccaa actcctgtat tgcagcaatg gaggccactt cctgaggatc 120cttccagatg gaaaagtgga tggcaccatg gaccggaatg acagctatat tcagttgctg 180ttaacagcag aagatgtggg tgtggtatat ataaaaggca ctgagaccgg gcagtacttg 240gccatggatg ccaatggaca tttatatggc tcgcagttgc caacagaaga gtgtttattt 300gtggaaacgc tggaagaaaa ccattacaat acatatacct caaagatgca tggcgataag 360aagtggtatg ttggcttgaa aaagaatggg aaaggcaaac tggggccacg gactcatcgc 420ggccaaaagg caatactttt ccttccactg ccagtatcac ctgattag 46895468DNABushbaby 95atggctgaag gggaaatcac aaccttcaca gccctcacag agaagtttaa tctgcctcta 60ggaaattaca agaagcccaa gctcctctac tgtagcaacg ggggtcactt tctgaggatc 120ctgccggatg gcaccgtgga tgggacacaa gacaggagcg accagcacat tcagctgcag 180ctcagtgcgg aaagcgtggg ggaggtgtat ataaagagta cccagactgg ccagtacttg 240gccatggact ccgacgggct tttatacggc tcacaaacac caaatgagga atgcctgttc 300ctggaacggc tggaggaaaa ccattacaac acctatgtgt ccaagaagca cgccgagaag 360aattggtttg tcggtctcaa gaagaacgga agttgcaaac gtggtcctcg gactcactac 420ggccagaaag caatcttgtt tctccccctg ccagtctcct ctgattaa 46896468DNACat 96atggctgaag gggaaatcac aaccttcacg gccctgacgg agaagttcaa tctgcctcca 60gggaattaca agaaacccaa actcctctac tgtagcaacg ggggccactt cctgaggatc 120cttccagatg gcacagtgga tgggacgagg gacaggagcg accagcacat tcagctgcag 180ctcagtgcgg aaagcgtggg ggaggtgtat ataaagagta ccgagactgg ccagtacttg 240gccatggaca ccgacgggct tttgtacggc tcacagacac caaatgagga atgcttgttc 300ctggaaaggc tggaagaaaa ccattacaac acctacacat ccaagaagca cgcagaaaag 360aattggtttg tgggtctcaa gaagaatgga agctgcaaac gcggtccccg gactcactat 420ggccagaagg caattttgtt tctccccctg ccagtctcct ctgattaa 46897468DNAChinese softshell turtle 97atggctgaag gggaaataac aacgttcacc gccctgaccg aaaaattcaa ccttcccctg 60gggaattaca agaatcccaa actcttatat tgcagcaatg gaggctactt cttgaggata 120catccagatg gcaaagtaga tgggacaagg gaccgaagtg accaacacat tcagctgcag 180ctaagtgcgg aaagcgtggg tgaggtatat ataaagagca ctgagtctgg acagtttttg 240gctatggacg ccaatggact tttatatgga tcactgtcac cgagtgagga atgcttattc 300ttggaaagaa tggaagaaaa tcattataac acctacatct ccaagaagca tgcagacaag 360aactggttcg ttggcttaaa gaagaatgga agctgcaaac tgggaccgcg gacgcactac 420ggccaaaagg ccgtcctttt ccttccactg ccagtgtcag ctgattaa 46898468DNACoelacanth 98atggctgaag acaaaataac aacactgaag gccttggctg aaaaatttaa ccttcctatg 60ggaaattaca agaaagcaaa actcctctac tgcagcaacg gagggtattt cctgcgaata 120cccccagacg ggaaagtgga aggaattaga gaacgaagcg acaagtacat tcagctgcaa 180atgaatgcag aaagtttagg catggtgtct ataaagggtg tggaggcagg gcaataccta 240gctatgaata caaatggact cctgtatgga tctcagtctc taactgaaga atgccttttc 300atggaaaaga tggaagaaaa ccactacaac acatacaggt ctaagacaca tgcagataaa 360aactggtatg ttggcattag aaagaacggt agcatcaaac caggaccaag gactcacatt 420ggccaaaagg ctgttctttt tctccctctg cctgcctcga gtgattag 46899468DNADolphin 99atggctgaag gggaaatcac aaccttcaca gccctgaccg agaagtttaa tctgcctcca 60gggaattaca agaagcccaa actcctctac tgtagcaacg ggggccactt cctgaggatc 120cttccagatg gcacagtgga tgggacaagg gacaggagtg accagcacat tcagctgcag 180ctcagtgcgg aaagcgtggg ggaggtgtat ataaagagta cggagactgg ccagtacttg 240gccatggaca ccgacgggct tttgtacggc tcacagacac ccaatgagga atgtttgttc 300ctggaaaggt tggaggaaaa ccattacaac acctacgcat ccaagaagca tgcagaaaag 360aattggttcg ttggtctcaa gaagaacgga agctgcaaac gcggtcctcg gactcactac 420ggccagaaag caatcttgtt tctccccctg ccagtctcct ccgattaa 468100468DNAFerret 100atggctgaag gggaaatcac aaccttcaca gccctgatgg agaagtttaa tctgcctgcg 60gggaattaca agaagcccaa actcctctac tgtagcaatg ggggccactt cctgaggatc 120cttccagatg gcacagtgga cggcacaagg gacaggagcg accagcacat tcagctgcag 180ctcagtgcgg aaagcgtggg ggaggtgtac ataaagagta ccgagactgg ccagtacttg 240gccatggaca ccgatgggct tttgtacggc tcacaaacac caaatgagga atgtctgttc 300ctggaaaggc tggaggaaaa ccattacaac acctacacat ccaagaagca cgctgagaag 360aattggtttg taggtctcaa gaagaacgga agctgcaaac gcggtcctcg gactcactat 420ggccagaaag caattctgtt tctccccctg ccagtctcct ctgattaa 468101468DNAGibbon 101atggccgaag gggaaatcac caccttcaca gccctgaccg agaagtttaa tctgcctcca 60gggaattaca agaagcccaa actcctctac tgtagcaacg ggggccactt cttgaggatc 120cttccggatg gcacagtgga tgggacaagg gacaggagcg accagcacat tcagctgcag 180ctcagtgcgg aaagcgtggg ggaggtgtat ataaagagta ccgagactgg ccagtacttg 240gccatggaca ccgacgggct tttatacggc tcacagacac caaatgagga atgtttgttc 300ctggaaaggc tggaggagaa ccattacaac acctatatat ccaagaagca tgcagagaag 360aattggtttg ttggcctcaa gaagaatgga agctgcaaac gcggtcctcg gactcactat 420ggccagaaag caatcttgtt tctccccctg ccagtctctt ctgattaa 468102468DNAGorilla 102atggctgaag gggaaatcac caccttcaca gccctgaccg agaagtttaa tctgcctcca 60gggaattaca agaagcccaa actcctctac tgtagcaatg ggggccactt cttgaggatc 120cttccggatg gcacagtgga tgggacaagg gacaggagcg accagcacat tcagctgcag 180ctcagtgcgg aaagcgtggg ggaggtgtat ataaagagta ccgagactgg ccagtacttg 240gccatggaca ccgacgggct tttatacggc tcacagacac caaatgagga atgtttgttc 300ctggaaaggc tggaggagaa ccattacaac acctatatat ccaagaagca tgcagagaag 360aattggtttg ttggcctcaa gaagaatgga agctgcaaac gcggtcctcg gactcactat 420ggccagaaag caatcttgtt tctccccctg ccagtctctt ccgattaa 468103468DNAHedgehog 103atggctgaag gagaaatcac caccttcacg gccctgactg agaagtttaa tctgccacta 60gggaattaca agaagcccaa gctcctctac tgtagcaacg ggggccactt cctgaggatc 120cttccagatg gcaccgtgga tgggacaagg gacaggagcg accagcatat tcagctgcag 180ctcagtgcgg aaagcgtggg ggaggtgtat ataaagagta cggagactgg ccagtacttg 240gccatggaca ccgacgggct tttatacggc tcacaaacac caaatgagga atgtctgttc 300cttgaaaggc tggaagagaa ccattacaat acctacacat ccaagaagca tgccgagaag 360aactggtttg ttggcctcaa gaagaatgga agctgcaagc gtggtcctcg gactcattat 420ggccagaaag ctattttgtt tctccccctg ccagtttcct ctgattaa 468104273DNAHyrax 104atggctgaag gcgaaatcac aaccttcaca gccctgactg agaagtttaa cctgccacta 60gagaattaca agaagcccaa actcctctac tgtagcaacg gaggccactt cctgaggatc 120cttccggacg gcacagtgga tggcaccagg gacaggagtg accagcacat tcagctgcag 180ctcagtgcgg aaagcgtggg ggaggtgtat ataaagggca ccgagactgg ccagtacttg 240gccatggaca ccgacgggct tttatatggc tca 273105349DNAKangaroo rat 105atggctgaag gggaaatcac aaccttcaca gccctgacgg aaaggtttaa ttcagctgca 60actgagtgcg gaaagcgtgg gggaggtcta tataaagagc accgagactg gccaatactt 120ggccatggat gccgacgggc ttttatacgg ctcacagaca cctgatgaag aatgcttgtt 180cctggagagg ctggaagaaa atcattataa cacctacata gccaagaaac atgctgaaaa 240gaattggttt gtcggcctca aaaagaatgg aagctgcaag cgtggtcctc ggactcacta 300tggccagaaa gcaatcctgt tcctcccctt gcctgtctcc tctgattag 349106276DNALamprey 106atggaggtgg gccacatcgg cacgctgccc gtggtccccg cggggcccgt gttccccggc 60agtttcaagg agccacggcg cctctactgc cgcagcgcgg gccaccacct ccagatcctg 120ggggacggca ccgtgagtgg cacccaggac gagaacgagc cccacgccgt tctgcagctg 180caggcggtgc gccgcggggt ggtgacgatc cgtgggctct gcgccgagag gttcctcgcc 240atgagcacgg agggacacct gtacggggcg gtgagg 276107297DNALesser hedgehog tenrec 107cagctgaagc tcgttgccga aagcgtgggg gtggtgtata taaagagcat caagaccggc 60cagtacttgg ccatgaaccc cgacgggctt ttatacggct ccgagacccc agaggaagaa 120tgcttgttcc tggaaacgct ggaggaaaac cactacacca ccttcaaatc taagaagcac 180gtagagaaga attggttcgt tggtctccgg aagaatggaa gggtcaagat cgggcctcgg 240actcaccaag gccagaaagc aatcttgttc ctgcccctcc cggtgtcctc tgattaa 297108468DNARhesus monkey 108atggctgaag gggaaatcac cacgttcaca gccctgaccg agaagtttaa tctgcctcca 60gggaattaca agaagcccaa actgctctac tgtagcaatg ggggccactt cttgaggatc 120cttccggatg gcacagtgga tgggacaagg gacaggagcg accagcacat tcagctgcag 180ctcagtgcgg aaagcgtggg ggaggtgtat ataaagagta ccgagactgg ccagtacttg 240gccatggaca ccgacgggct tttatacggc tcacagacac caaatgagga atgtttgttc 300ctggaaaggc tggaggagaa ccattacaac acctatacat ccaagaagca cgcagagaag 360aattggtttg ttggcctcaa gaagaatgga agctgcaaac gtggtcctcg gactcactat 420ggccagaaag caatcttgtt tcttcccctg ccagtctctt ctgattaa 468109468DNAMegabat 109atggccgagg gggaagtcac gacgttcacg gccctgaccg agaggtttaa cctgcctcca 60gggaattaca agaagcccaa acttctctac tgcagcaacg ggggccactt cctgaggatc 120ctcccagatg gcacagtgga tgggacaagg gacaagagcg accagcacat tcagctgcag 180ctcagtgcgg aaagtgtggg ggaggtgtat ataaagagca ccgagagtgg ccagtacttg 240gccatggact ccgacgggct tttgtacggc tcacagacac cagatgagga ctgtttgttc 300ctggaaaggc tggaggaaaa ccattacaac acctacacat ccaagaagca cgcagagaag 360aattggtttg ttgggctcaa gaagaatgga agctgcaagc gcggtccccg gactcactac 420ggccagaaag cgatcctgtt tctccccctg ccagtctcct ctgattag 468110468DNAMicrobat 110atggctgagg gggaagtcac cacattcacg gccctgaccg agaggttcaa tctgcctctg 60gagaactaca agaagcccaa gcttctctac tgcagcaacg ggggccactt cctgcggatc 120ctcccagacg gcaccgtgga cgggacgagg gacaggagcg accagcacat tcagctgcag 180ctcagtgcgg aaagcgtggg ggaggtgtat ataaagagca ccgagagtgg ccagtacttg 240gccatggact ccgacgggct tttgtacggc tcacaaacac ccaatgagga atgtttgttc 300ctggaaaggc tggaggagaa ccactacaac acctacacgt ccaagaagca cgcagaaaag 360aattggttcg ttgggctcaa gaagaacgga agctgcaagc gtggtcctcg gacgcattat 420ggccagaaag caatcttgtt tctccccctg ccagtctcct ccgattaa 468111468DNAMouse lemur 111atggccgaag gggagatcac aaccttcacg gccctcaccg agaagtttaa cctgcctccg 60gggaactaca agaagcccaa gctcctctac tgcagcaacg gcggccactt cctgcgcatc 120cttcccgacg gcaccgtgga tggcacgaga gacaggagcg accagcacat tcagctgcag 180ctcagtgcgg aaagcgcggg ggaggtgtat ataaagagca cccagactgg ccggtacttg 240gccatggacg ccgacgggct tttatacggc tcacaaacac caaatgagga atgtttgttc 300ctggaaaggc tggaggaaaa ccattacaac acctacgtat ccaagaagca cgcagagaag 360aattggtttg ttggcctcaa gaagaatgga agttgcaaac gcggcccccg gactcactat 420ggccagaaag caatcttgtt tctgcccctg ccagtctcct ctgattaa 468112436DNAPika 112atggccgagg gagaagtcac caccttctca gccctgacgg agaagttcaa tctgcctgga 60ggaaactaca agttgcccaa gctcctttac tgtagcaacg gaggccactt cctgaggatc 120cttccagatg gcacagtgga tgggaccagg gacaggagcg acctgcacag aggtgtttat 180aaagagtacg gagactggcc agtacttggc tatggacacc gatggccttt tatatggctc 240gcagacaccc agtgaggagt gtttgttcct ggagcggctg gaggagaacc actacaacac 300ctacacatcc aagaagcatg ccgagaagaa ctggtttgtg ggcatcaaga agaatggaag 360ctgcaagcgt ggtcctcgga ctcactacgg ccagaaagcc atcttgtttc tccctctgcc 420agtctcttct gactaa 436113468DNARat 113atggccgaag gggagatcac aacctttgca gccctgaccg agaggttcaa tctgcctcta 60gggaactaca aaaaacccaa actgctctac tgcagcaacg ggggccactt cttgaggatt 120cttcccgatg gcaccgtgga tgggaccagg gacaggagcg accagcacat tcagctgcag 180ctcagtgcgg aaagcgcggg cgaagtgtat ataaagggta cagagactgg ccagtacttg 240gccatggaca ccgaagggct tttatacggc tcgcagacac caaatgaaga atgcctattc 300ctggaaaggc tagaagaaaa ccattataac acttacacat ccaagaagca cgcggagaag 360aactggtttg tgggcctcaa gaagaacggg agttgtaagc gcggtcctcg gactcactac 420ggccagaaag ccatcttgtt tctccccctc ccggtatctt ctgactaa 468114468DNASloth 114atggctgaag gggaaatcac aaccttcaca gctctgatgg agaagtttaa cctgccacca 60gggaattaca tgaagcccaa actcctctac tgtagcaacg ggggccactt cttgaggatc 120cttccagacg gcacagtgga tgggacaagg gacaggagcg acctgcacat tcagctgcag 180ctcagtgcgg aaagcgtggg ggaggtgtat ataaagagtg cggagaccgg ccagtactta 240gccatggaca ccggcgggct tttatacggc tcacagacac caagtgagga atgcctgttc 300ctagaaaggc tggaggaaaa ccattacaac acctacgtat ccaagaagca tgcggagaag 360aactggttcg ttggcctaaa gaagaatgga agcagcaaac gcggcccccg gactcactat 420ggccagaaag ccatcttgtt tcttcccctg ccagtctcct ctgattaa 468115468DNASquirrel 115atggctgaag gggaaatcac aaccttcaca gccctgaccg agaagttcaa tctgcctcca 60gggaactaca agaagcccaa actgctctac tgtagcaacg gaggccactt cttgaggatc 120cttcctgatg gcacagtgga tgggacaaga gacaggagcg accaacacat tcagctgcag 180ctcagtgcgg aaagcgtggg ggaggtgtat ataaagagta ccgagaccgg ccagtacttg 240gccatggaca ccgacgggct tttatatggc tcacagaccc caaatgagga atgcttattc 300ctggaaaggc tggaggaaaa ccattacaac acgtacacat ccaagaagca tgcagagaag 360aattggtttg ttggcctcaa gaagaacgga agctgcaagc gcggtccccg gactcactat 420ggccagaaag cgatcttgtt tctcccactg cctgtctcct ctgattag 468116468DNATarsier 116atggccgaag gggaaatcac aaccttcaca gccctgaccg agaagttcaa cctgcccccg 60gggaattaca agaagcccaa actcctctac tgcagcaacg ggggccactt cttgaggatc 120cttccggatg gcactgtgga tggaacgagg gacaggagcg accagcacat tcagctgcag 180ctcagcgcgg aaagcgtggg ggaggtgtat ataaagagta ccgagaccgg ccagtacttg 240gccatggaca ccgacgggct tttgtacggc tcacagacac caaatgagga gtgtctgttc 300ctggaaaggc tggaagagaa tcattacaat acctacgtgt ccaagaagca tgcggagaag 360aattggtttg tcggcctcaa gaagaatgga agctgcaaac gcggtcctcg gactcactat 420ggccagaaag caatcttgtt tctccccctg ccagtttcct ctgattaa 468117468DNATree shrew 117atggctgaag gggaaatcac gaccttcgca gccctgaccg agaagtttga tctgcctcca 60gggaattaca agaagcccaa acttctctac tgtagcaacg ggggccattt cttgaggatt 120cttccagatg gcaccgtgga tgggacaaga gacaggagcg accagcacat tcagctgcag 180ctcactgcgg aaaacgtggg ggaggtgtac ataaagagta cggagactgg ccagtacttg 240gccatggacg ccgacgggct tttatatggc tcacagacac caaacgagga atgtttgttc 300ctggaaaggc tggaggagaa ccattacaac acctacatat ccaagaagca cgcagagaag 360aattggtttg ttgccctcaa gaagaacgga agctgcaaac tcggtcctcg gactcactat 420ggccagaaag caatcttgtt tctccccctg ccagtctcct ctgattaa 468118168DNATurkey 118atggccgagg gggagataac caccttcaca gccctgaccg agcgcttcgg cctgccgctg 60ggcaactaca agaagcccaa actcctgtac tgcagcaacg ggggccactt cctacggatc 120ctgccggacg gcaaggtgga cgggacgcgg gaccggagcg accagcac 168119468DNAWallaby 119atggccgaag gggagatcac aaccttcaca gccctgaccg aaagatttaa cctgccactg 60gggaattaca agaagcccaa gcttctctac tgtagcaatg ggggccactt tttgaggatc 120cttcctgatg gcaaagtgga tgggacaagg gacagaaatg atcaacacat tcaactgcaa 180ctaagcgcgg aaagcgtggg tgaggtgtat ataaagagca ctgagtctgg gcagtatttg 240gccatggaca ccaatggact tttatatggc tcacagaccc ccagcgaaga atgcttattc 300ctggagaggt tggaggagaa tcattacaac acctacatat caaagaagca tgcggagaaa 360aattggtttg ttggcctcaa gaagaacgga agttgcaaaa gaggtcccag gactcactat 420ggccagaaag ccatcctatt ccttcccctc cctgtgtcct ctgagtaa 468120444DNAZebrafish 120atgaccgagg ccgatattgc ggtaaagtcc agcccgcgcg actataaaaa actgacgcgg 60ctgtactgta tgaatggagg atttcacctt cagatcctgg cggacgggac agtggctgga 120gcagcagacg aaaacacata cagcatactg cgcataaaag caacaagtcc aggagtggtg 180gtgatcgaag gatcagaaac aggtctttac ctctcgatga atgaacatgg caagctgtac 240gcttcatcat tagtgacgga tgaaagttat ttcctggaga agatggagga aaaccactac 300aacacatatc agtctcaaaa gcacggtgaa aactggtacg tcggaataaa aaagaacggg 360aaaatgaaac ggggcccaag aactcacatc ggacaaaagg ccattttctt tcttccacga 420caggtggagc aggaagagga ctga 444121155PRTHomo sapiens 121Met Ala Ala Gly Ser Ile Thr Thr Leu Pro Ala Leu Pro Glu Asp Gly 1 5 10 15 Gly Ser Gly Ala Phe Pro Pro Gly His Phe Lys Asp Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile His Pro Asp Gly Arg 35 40 45 Val Asp Gly Val Arg Glu Lys Ser Asp Pro His Ile Lys Leu Gln Leu 50 55 60 Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Cys Ala Asn 65 70 75 80 Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu Leu Ala Ser Lys Cys 85 90 95 Val Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn Asn Tyr 100 105 110 Asn Thr Tyr Arg Ser Arg Lys Tyr Thr Ser Trp Tyr Val Ala Leu Lys 115 120 125 Arg Thr Gly Gln Tyr Lys Leu Gly Ser Lys Thr Gly Pro Gly Gln Lys 130 135 140 Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 145 150 155 122155PRTGorilla gorilla 122Met Ala Ala Gly Ser Ile Thr Thr Leu Pro Ala Leu Pro Glu Asp Gly 1 5 10 15 Gly Ser Gly Ala Phe Pro Pro Gly His Phe Lys Asp Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile His Pro Asp Gly Arg 35 40 45 Val Asp Gly Val Arg Glu Lys Ser Asp Pro His Ile Lys Leu Gln Leu 50 55 60 Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly

Val Cys Ala Asn 65 70 75 80 Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu Leu Ala Ser Lys Cys 85 90 95 Val Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn Asn Tyr 100 105 110 Asn Thr Tyr Arg Ser Arg Lys Tyr Thr Ser Trp Tyr Val Ala Leu Lys 115 120 125 Arg Thr Gly Gln Tyr Lys Leu Gly Ser Lys Thr Gly Pro Gly Gln Lys 130 135 140 Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 145 150 155 123155PRTPongo abelii 123Met Ala Ala Gly Ser Ile Thr Thr Leu Pro Ala Leu Pro Glu Asp Gly 1 5 10 15 Gly Ser Gly Ala Phe Pro Pro Gly His Phe Lys Asp Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile His Pro Asp Gly Arg 35 40 45 Val Asp Gly Val Arg Glu Lys Ser Asp Pro His Ile Lys Leu Gln Leu 50 55 60 Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Cys Ala Asn 65 70 75 80 Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu Leu Ala Ser Lys Cys 85 90 95 Val Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn Asn Tyr 100 105 110 Asn Thr Tyr Arg Ser Arg Lys Tyr Thr Ser Trp Tyr Val Ala Leu Lys 115 120 125 Arg Thr Gly Gln Tyr Lys Leu Gly Ser Lys Thr Gly Pro Gly Gln Lys 130 135 140 Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 145 150 155 124155PRTMacaca mulatta 124Met Ala Ala Gly Ser Ile Thr Thr Leu Pro Ala Leu Pro Glu Asp Gly 1 5 10 15 Gly Ser Gly Ala Phe Pro Pro Gly His Phe Lys Asp Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile His Pro Asp Gly Arg 35 40 45 Val Asp Gly Val Arg Glu Lys Ser Asp Pro His Ile Lys Leu Gln Leu 50 55 60 Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Cys Ala Asn 65 70 75 80 Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu Leu Ala Ser Lys Cys 85 90 95 Val Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn Asn Tyr 100 105 110 Asn Thr Tyr Arg Ser Arg Lys Tyr Thr Ser Trp Tyr Val Ala Leu Lys 115 120 125 Arg Thr Gly Gln Tyr Lys Leu Gly Ser Lys Thr Gly Pro Gly Gln Lys 130 135 140 Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 145 150 155 125155PRTPan troglodytes 125Met Ala Ala Gly Ser Ile Thr Thr Leu Pro Ala Leu Pro Glu Asp Gly 1 5 10 15 Gly Ser Gly Ala Phe Pro Pro Gly His Phe Lys Asp Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile His Pro Asp Gly Arg 35 40 45 Val Asp Gly Val Arg Glu Lys Ser Asp Pro His Ile Lys Leu Gln Leu 50 55 60 Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Cys Ala Asn 65 70 75 80 Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu Leu Ala Ser Lys Cys 85 90 95 Val Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn Asn Tyr 100 105 110 Asn Thr Tyr Arg Ser Arg Lys Tyr Thr Ser Trp Tyr Val Ala Leu Lys 115 120 125 Arg Thr Gly Gln Tyr Lys Leu Gly Ser Lys Thr Gly Pro Gly Gln Lys 130 135 140 Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 145 150 155 126155PRTPan paniscus 126Met Ala Ala Gly Ser Ile Thr Thr Leu Pro Ala Leu Pro Glu Asp Gly 1 5 10 15 Gly Ser Gly Ala Phe Pro Pro Gly His Phe Lys Asp Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile His Pro Asp Gly Arg 35 40 45 Val Asp Gly Val Arg Glu Lys Ser Asp Pro His Ile Lys Leu Gln Leu 50 55 60 Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Cys Ala Asn 65 70 75 80 Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu Leu Ala Ser Lys Cys 85 90 95 Val Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn Asn Tyr 100 105 110 Asn Thr Tyr Arg Ser Arg Lys Tyr Thr Ser Trp Tyr Val Ala Leu Lys 115 120 125 Arg Thr Gly Gln Tyr Lys Leu Gly Ser Lys Thr Gly Pro Gly Gln Lys 130 135 140 Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 145 150 155 127155PRTSaimiri boliviensis boliviensis 127Met Ala Ala Gly Ser Ile Thr Thr Leu Pro Ala Leu Pro Glu Asp Gly 1 5 10 15 Gly Ser Gly Ala Phe Pro Pro Gly His Phe Lys Asp Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile His Pro Asp Gly Arg 35 40 45 Val Asp Gly Val Arg Glu Lys Ser Asp Pro His Ile Lys Leu Gln Leu 50 55 60 Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Cys Ala Asn 65 70 75 80 Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu Leu Ala Ser Lys Cys 85 90 95 Val Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn Asn Tyr 100 105 110 Asn Thr Tyr Arg Ser Arg Lys Tyr Thr Ser Trp Tyr Val Ala Leu Lys 115 120 125 Arg Thr Gly Gln Tyr Lys Leu Gly Ser Lys Thr Gly Pro Gly Gln Lys 130 135 140 Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 145 150 155 128155PRTNomascus leucogenys 128Met Ala Ala Gly Ser Ile Thr Thr Leu Pro Ala Leu Pro Glu Asp Gly 1 5 10 15 Gly Ser Gly Ala Phe Pro Pro Gly His Phe Lys Asp Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile His Pro Asp Gly Arg 35 40 45 Val Asp Gly Val Arg Glu Lys Ser Asp Pro His Ile Lys Leu Gln Leu 50 55 60 Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Cys Ala Asn 65 70 75 80 Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu Leu Ala Ser Lys Cys 85 90 95 Val Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn Asn Tyr 100 105 110 Asn Thr Tyr Arg Ser Arg Lys Tyr Thr Ser Trp Tyr Val Ala Leu Lys 115 120 125 Arg Thr Gly Gln Tyr Lys Leu Gly Ser Lys Thr Gly Pro Gly Gln Lys 130 135 140 Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 145 150 155 129155PRTEquus caballus 129Met Ala Ala Gly Ser Ile Thr Thr Leu Pro Ala Leu Pro Glu Asp Gly 1 5 10 15 Gly Ser Gly Ala Phe Pro Pro Gly His Phe Lys Asp Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile His Pro Asp Gly Arg 35 40 45 Val Asp Gly Val Arg Glu Lys Ser Asp Pro His Ile Lys Leu Gln Leu 50 55 60 Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Cys Ala Asn 65 70 75 80 Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu Leu Ala Ser Lys Cys 85 90 95 Val Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn Asn Tyr 100 105 110 Asn Thr Tyr Arg Ser Arg Lys Tyr Ser Ser Trp Tyr Val Ala Leu Lys 115 120 125 Arg Thr Gly Gln Tyr Lys Leu Gly Pro Lys Thr Gly Pro Gly Gln Lys 130 135 140 Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 145 150 155 130155PRTBos Taurus 130Met Ala Ala Gly Ser Ile Thr Thr Leu Pro Ala Leu Pro Glu Asp Gly 1 5 10 15 Gly Ser Gly Ala Phe Pro Pro Gly His Phe Lys Asp Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile His Pro Asp Gly Arg 35 40 45 Val Asp Gly Val Arg Glu Lys Ser Asp Pro His Ile Lys Leu Gln Leu 50 55 60 Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Cys Ala Asn 65 70 75 80 Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu Leu Ala Ser Lys Cys 85 90 95 Val Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn Asn Tyr 100 105 110 Asn Thr Tyr Arg Ser Arg Lys Tyr Ser Ser Trp Tyr Val Ala Leu Lys 115 120 125 Arg Thr Gly Gln Tyr Lys Leu Gly Pro Lys Thr Gly Pro Gly Gln Lys 130 135 140 Ala Ile Leu Phe Leu Pro Met Ala Ser Lys Ser 145 150 155 131155PRTPapio Anubis 131Met Ala Ala Gly Ser Ile Thr Thr Leu Pro Ala Leu Pro Glu Asp Gly 1 5 10 15 Gly Ser Gly Ala Phe Pro Pro Gly His Phe Lys Asp Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile His Pro Asp Gly Arg 35 40 45 Val Asp Gly Val Arg Glu Lys Ser Asp Pro His Ile Lys Leu Gln Leu 50 55 60 Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Cys Ala Asn 65 70 75 80 Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu Leu Ala Ser Lys Cys 85 90 95 Val Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn Asn Tyr 100 105 110 Asn Thr Tyr Arg Ser Arg Lys Tyr Thr Ser Trp Tyr Val Ala Leu Lys 115 120 125 Arg Thr Gly Gln Tyr Lys Leu Gly Ser Lys Thr Gly Pro Gly Gln Lys 130 135 140 Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 145 150 155 132155PRTVicugna pacos 132Met Ala Ala Gly Ser Ile Thr Thr Leu Pro Ala Leu Pro Glu Asp Gly 1 5 10 15 Gly Ser Gly Ala Phe Pro Pro Gly His Phe Lys Asp Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile His Pro Asp Gly Arg 35 40 45 Val Asp Gly Val Arg Glu Lys Ser Asp Pro His Ile Lys Leu Gln Leu 50 55 60 Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Cys Ala Asn 65 70 75 80 Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu Leu Ala Ser Lys Cys 85 90 95 Val Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn Asn Tyr 100 105 110 Asn Thr Tyr Arg Ser Arg Lys Tyr Ser Ser Trp Tyr Val Ala Leu Lys 115 120 125 Arg Thr Gly Gln Tyr Lys Leu Gly Pro Lys Thr Gly Pro Gly Gln Lys 130 135 140 Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 145 150 155 133155PRTOvis aries 133Met Ala Ala Gly Ser Ile Thr Thr Leu Pro Ala Leu Pro Glu Asp Gly 1 5 10 15 Gly Ser Ser Ala Phe Pro Pro Gly His Phe Lys Asp Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile His Pro Asp Gly Arg 35 40 45 Val Asp Gly Val Arg Glu Lys Ser Asp Pro His Ile Lys Leu Gln Leu 50 55 60 Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Cys Ala Asn 65 70 75 80 Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu Leu Ala Ser Lys Cys 85 90 95 Val Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn Asn Tyr 100 105 110 Asn Thr Tyr Arg Ser Arg Lys Tyr Ser Ser Trp Tyr Val Ala Leu Lys 115 120 125 Arg Thr Gly Gln Tyr Lys Leu Gly Pro Lys Thr Gly Pro Gly Gln Lys 130 135 140 Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 145 150 155 134108PRTCapreolus capreolus 134Arg Ile His Pro Asp Gly Arg Val Asp Gly Val Arg Glu Lys Ser Asp 1 5 10 15 Pro His Ile Lys Leu Gln Leu Gln Ala Glu Glu Arg Gly Val Val Ser 20 25 30 Ile Lys Gly Val Cys Ala Asn Arg Tyr Leu Ala Met Lys Glu Asp Gly 35 40 45 Arg Leu Leu Ala Ser Lys Cys Val Thr Asp Glu Cys Phe Phe Phe Glu 50 55 60 Arg Leu Glu Ser Asn Asn Tyr Asn Thr Tyr Arg Ser Arg Lys Tyr Ser 65 70 75 80 Ser Trp Tyr Val Ala Leu Lys Arg Thr Gly Gln Tyr Lys Leu Gly Pro 85 90 95 Lys Thr Gly Pro Gly Gln Lys Ala Ile Leu Phe Leu 100 105 13596PRTLoxodonta Africana 135Val Lys Leu Gln Leu Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys 1 5 10 15 Gly Val Cys Ala Asn Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu 20 25 30 Leu Ala Ser Arg Cys Val Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu 35 40 45 Glu Ser Asn Asn Tyr Asn Thr Tyr Arg Ser Arg Lys Tyr Thr Ser Trp 50 55 60 Tyr Val Ala Leu Lys Arg Thr Gly Gln Tyr Lys Leu Gly Ser Lys Thr 65 70 75 80 Gly Pro Gly Gln Lys Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 85 90 95 136120PRTSus scrofa 136Asn Gly Gly Phe Phe Leu Arg Ile His Pro Asp Gly Arg Val Asp Gly 1 5 10 15 Val Arg Glu Lys Ser Asp Pro His Ile Lys Leu Gln Leu Gln Ala Glu 20 25 30 Glu Arg Gly Val Val Ser Ile Lys Gly Val Cys Ala Asn Arg Tyr Leu 35 40 45 Ala Met Lys Glu Asp Gly Arg Leu Leu Ala Ser Lys Cys Val Thr Asp 50 55 60 Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn Asn Tyr Asn Thr Tyr 65 70 75 80 Arg Ser Arg Lys Tyr Ser Ser Trp Tyr Val Ala Leu Lys Arg Thr Gly 85 90 95 Gln Tyr Lys Leu Gly Pro Lys Thr Gly Pro Gly Gln Lys Ala Ile Leu 100 105 110 Phe Leu Pro Met Ser Ala Lys Ser 115 120 13796PRTAiluropoda melanoleuca 137Val Lys Leu Gln Leu Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys 1 5 10 15 Gly Val Cys Ala Asn Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu 20 25 30 Leu Ala Ser Lys Cys Val Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu 35 40 45 Glu Ser Asn Asn Tyr Asn Thr Tyr Arg Ser Arg Lys Tyr Ser Ser Trp 50 55 60 Tyr Val Ala Leu Lys Arg Thr Gly Gln Tyr Lys Leu Gly Pro Lys Thr 65 70 75 80 Gly Pro Gly Gln Lys Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 85 90 95 138155PRTCholoepus hoffmanni 138Met Ala Ala Gly Ser Ile Thr Thr Leu Pro Ala Leu Pro Glu Asp Gly 1 5 10 15 Gly Ser Gly Ala Leu Pro Pro Gly His Phe Lys Asp Pro Lys Arg Leu 20 25

30 Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile His Pro Asp Gly Arg 35 40 45 Val Asp Gly Val Arg Glu Lys Ser Asp Pro His Ile Lys Leu Gln Leu 50 55 60 Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Cys Ala Asn 65 70 75 80 Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu Gln Ala Ser Lys Cys 85 90 95 Val Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn Asn Tyr 100 105 110 Asn Thr Tyr Arg Ser Arg Lys Tyr Ser Ser Trp Tyr Val Ala Leu Lys 115 120 125 Arg Thr Gly Gln Tyr Lys Leu Gly Pro Lys Thr Gly Pro Gly Gln Lys 130 135 140 Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 145 150 155 139155PRTBubalus bubalis 139Met Ala Ala Gly Ser Ile Thr Thr Leu Pro Pro Leu Pro Glu Asp Gly 1 5 10 15 Gly Ser Gly Ala Phe Pro Pro Gly His Phe Lys Asp Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile His Pro Asp Gly Arg 35 40 45 Val Asp Gly Val Arg Glu Lys Ser Asp Pro His Ile Lys Leu Gln Leu 50 55 60 Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Cys Ala Asn 65 70 75 80 Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu Leu Ala Ser Lys Cys 85 90 95 Val Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Ser Asn Tyr 100 105 110 Asn Thr Tyr Arg Ser Arg Lys Tyr Ser Ser Trp Tyr Val Ala Leu Lys 115 120 125 Arg Thr Gly Gln Tyr Lys Leu Gly Pro Lys Thr Gly Pro Gly Gln Lys 130 135 140 Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 145 150 155 140155PRTCanis lupus familiaris 140Met Ala Ala Gly Ser Ile Thr Thr Leu Pro Ala Leu Pro Glu Asp Gly 1 5 10 15 Gly Ser Gly Ala Phe Pro Pro Gly His Phe Lys Asp Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Lys Gly Gly Phe Phe Leu Arg Ile His Pro Asp Gly Arg 35 40 45 Val Asp Gly Val Arg Glu Lys Ser Asp Pro His Val Lys Leu Gln Leu 50 55 60 Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Cys Ala Asn 65 70 75 80 Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu Leu Ala Ser Lys Cys 85 90 95 Val Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn Asn Tyr 100 105 110 Asn Thr Tyr Arg Ser Arg Lys Tyr Ser Ser Trp Tyr Val Ala Leu Lys 115 120 125 Arg Thr Gly Gln Tyr Lys Leu Gly Pro Lys Thr Gly Pro Gly Gln Lys 130 135 140 Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 145 150 155 141154PRTRattus norvegicus 141Met Ala Ala Gly Ser Ile Thr Ser Leu Pro Ala Leu Pro Glu Asp Gly 1 5 10 15 Gly Gly Ala Phe Pro Pro Gly His Phe Lys Asp Pro Lys Arg Leu Tyr 20 25 30 Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile His Pro Asp Gly Arg Val 35 40 45 Asp Gly Val Arg Glu Lys Ser Asp Pro His Val Lys Leu Gln Leu Gln 50 55 60 Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Cys Ala Asn Arg 65 70 75 80 Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu Leu Ala Ser Lys Cys Val 85 90 95 Thr Glu Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn Asn Tyr Asn 100 105 110 Thr Tyr Arg Ser Arg Lys Tyr Ser Ser Trp Tyr Val Ala Leu Lys Arg 115 120 125 Thr Gly Gln Tyr Lys Leu Gly Ser Lys Thr Gly Pro Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 145 150 142134PRTHeterocephalus glaber 142Pro Pro Gly His Phe Lys Asp Pro Lys Arg Leu Tyr Cys Lys Asn Gly 1 5 10 15 Gly Phe Phe Leu Arg Ile His Pro Asp Gly Arg Val Asp Gly Val Arg 20 25 30 Glu Lys Ser Asp Pro His Val Lys Leu Gln Leu Gln Ala Glu Glu Arg 35 40 45 Gly Val Val Ser Ile Lys Gly Val Cys Ala Asn Arg Tyr Leu Ala Met 50 55 60 Lys Glu Asp Gly Arg Leu Leu Ala Ser Lys Cys Val Thr Asp Glu Cys 65 70 75 80 Phe Phe Phe Glu Arg Leu Glu Ser Asn Asn Tyr Asn Thr Tyr Arg Ser 85 90 95 Arg Lys Tyr Ser Ser Trp Tyr Val Ala Leu Lys Arg Thr Gly Gln Tyr 100 105 110 Lys Leu Gly Ser Lys Thr Gly Pro Gly Gln Lys Ala Ile Leu Phe Leu 115 120 125 Pro Met Ser Ala Lys Ser 130 143155PRTOtolemur garnettii 143Met Ala Ala Gly Ser Ile Thr Thr Leu Pro Ser Leu Pro Glu Asp Gly 1 5 10 15 Gly Ser Asp Ala Phe Pro Pro Gly His Phe Lys Asp Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile His Pro Asp Gly Arg 35 40 45 Val Asp Gly Val Arg Glu Lys Ser Asp Pro Tyr Ile Lys Leu Gln Leu 50 55 60 Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Cys Ala Asn 65 70 75 80 Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu Leu Ala Ser Lys Leu 85 90 95 Ile Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn Asn Tyr 100 105 110 Asn Thr Tyr Arg Ser Arg Lys Tyr Ser Ser Trp Tyr Val Ala Leu Lys 115 120 125 Arg Thr Gly Gln Tyr Lys Leu Gly Ser Lys Thr Gly Pro Gly Gln Lys 130 135 140 Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 145 150 155 144154PRTMus musculus 144Met Ala Ala Ser Gly Ile Thr Ser Leu Pro Ala Leu Pro Glu Asp Gly 1 5 10 15 Gly Ala Ala Phe Pro Pro Gly His Phe Lys Asp Pro Lys Arg Leu Tyr 20 25 30 Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile His Pro Asp Gly Arg Val 35 40 45 Asp Gly Val Arg Glu Lys Ser Asp Pro His Val Lys Leu Gln Leu Gln 50 55 60 Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Cys Ala Asn Arg 65 70 75 80 Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu Leu Ala Ser Lys Cys Val 85 90 95 Thr Glu Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn Asn Tyr Asn 100 105 110 Thr Tyr Arg Ser Arg Lys Tyr Ser Ser Trp Tyr Val Ala Leu Lys Arg 115 120 125 Thr Gly Gln Tyr Lys Leu Gly Ser Lys Thr Gly Pro Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 145 150 145144PRTIctidomys tridecemlineatus 145Leu Pro Glu Asp Gly Gly Gly Gly Ala Phe Pro Pro Gly His Phe Lys 1 5 10 15 Asp Pro Lys Arg Leu Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile 20 25 30 His Pro Asp Gly Arg Val Asp Gly Val Arg Glu Lys Ser Asp Pro His 35 40 45 Ile Lys Leu Gln Leu Gln Ala Glu Asp Arg Gly Val Val Ser Ile Lys 50 55 60 Gly Val Cys Ala Asn Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu 65 70 75 80 Leu Ala Ser Lys Cys Val Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu 85 90 95 Glu Ser Asn Asn Tyr Asn Thr Tyr Arg Ser Arg Lys Tyr Ser Ser Trp 100 105 110 Tyr Val Ala Leu Lys Arg Thr Gly Gln Tyr Lys Leu Gly Ser Lys Thr 115 120 125 Gly Pro Gly Gln Lys Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 130 135 140 146106PRTFelis catus 146His Phe Lys Asp Pro Lys Arg Leu Tyr Cys Lys Asn Gly Gly Phe Phe 1 5 10 15 Leu Arg Ile His Pro Asp Gly Arg Val Asp Gly Val Arg Glu Lys Ser 20 25 30 Asp Pro His Ile Lys Leu Gln Leu Gln Ala Glu Glu Arg Gly Val Val 35 40 45 Ser Ile Lys Gly Val Cys Ala Asn Arg Tyr Leu Ala Met Lys Glu Asp 50 55 60 Gly Arg Leu Leu Ala Ser Lys Cys Val Thr Asp Glu Cys Phe Phe Phe 65 70 75 80 Glu Arg Leu Glu Ser Asn Asn Tyr Asn Thr Tyr Arg Ser Arg Lys Tyr 85 90 95 Ser Ser Trp Tyr Val Ala Leu Lys Arg Thr 100 105 14796PRTCavia porcellus 147Val Lys Leu Gln Leu Gln Ala Glu Asp Arg Gly Val Val Ser Ile Lys 1 5 10 15 Gly Val Cys Ala Asn Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu 20 25 30 Leu Ala Ser Lys Cys Val Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu 35 40 45 Glu Ser Asn Asn Tyr Asn Thr Tyr Arg Ser Arg Lys Tyr Ser Ser Trp 50 55 60 Tyr Val Ala Leu Lys Arg Thr Gly Gln Tyr Lys Leu Gly Ser Lys Thr 65 70 75 80 Gly Pro Gly Gln Lys Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 85 90 95 148156PRTSarcophilus harrisii 148Met Ala Ala Gly Ser Ile Thr Thr Leu Pro Ala Leu Ala Gly Asp Gly 1 5 10 15 Ala Ser Gly Gly Ala Phe Pro Pro Gly His Phe Gln Asp Pro Lys Arg 20 25 30 Leu Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile His Pro Asp Gly 35 40 45 His Val Asp Gly Ile Arg Glu Lys Ser Asp Pro His Ile Lys Leu Gln 50 55 60 Leu Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Cys Ala 65 70 75 80 Asn Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu Leu Ala Leu Lys 85 90 95 Cys Val Thr Glu Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn Asn 100 105 110 Tyr Asn Thr Tyr Arg Ser Arg Lys Tyr Ser Asn Trp Tyr Val Ala Leu 115 120 125 Lys Arg Thr Gly Gln Tyr Lys Leu Gly Ser Lys Thr Gly Pro Gly Gln 130 135 140 Lys Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 145 150 155 149156PRTMonodelphis domestica 149Met Ala Ala Gly Ser Ile Thr Thr Leu Pro Ala Leu Ser Gly Asp Gly 1 5 10 15 Gly Gly Gly Gly Ala Phe Pro Pro Gly His Phe Lys Asp Pro Lys Arg 20 25 30 Leu Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile His Pro Asp Gly 35 40 45 Arg Val Asp Gly Ile Arg Glu Lys Ser Asp Pro Asn Ile Lys Leu Gln 50 55 60 Leu Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Cys Ala 65 70 75 80 Asn Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu Leu Ala Leu Lys 85 90 95 Tyr Val Thr Glu Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn Asn 100 105 110 Tyr Asn Thr Tyr Arg Ser Arg Lys Tyr Ser Asn Trp Tyr Val Ala Leu 115 120 125 Lys Arg Thr Gly Gln Tyr Lys Leu Gly Ser Lys Thr Gly Pro Gly Gln 130 135 140 Lys Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 145 150 155 150155PRTOryctolagus cuniculus 150Met Ala Ala Glu Ser Ile Thr Thr Leu Pro Ala Leu Pro Glu Asp Gly 1 5 10 15 Gly Ser Gly Ala Phe Pro Pro Gly His Phe Lys Asp Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile His Pro Asp Gly Arg 35 40 45 Val Asp Gly Val Arg Glu Lys Ser Asp Pro His Ile Lys Leu Gln Leu 50 55 60 Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Cys Ala Asn 65 70 75 80 Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu Leu Ala Ser Lys Cys 85 90 95 Val Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn Asn Tyr 100 105 110 Asn Thr Tyr Arg Ser Arg Lys Tyr Ser Ser Trp Tyr Val Ala Leu Lys 115 120 125 Arg Thr Gly Gln Tyr Lys Leu Gly Ser Lys Thr Gly Pro Gly Gln Lys 130 135 140 Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 145 150 155 151125PRTMeleagris gallopavo 151Arg Leu Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile Asn Pro Asp 1 5 10 15 Gly Arg Val Asp Gly Val Arg Glu Lys Ser Asp Pro His Ile Lys Leu 20 25 30 Gln Leu Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Ser 35 40 45 Ala Asn Arg Phe Leu Ala Met Lys Glu Asp Gly Arg Leu Leu Ala Leu 50 55 60 Lys Cys Ala Thr Glu Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn 65 70 75 80 Asn Tyr Asn Thr Tyr Arg Ser Arg Lys Tyr Ser Asp Trp Tyr Val Ala 85 90 95 Leu Lys Arg Thr Gly Gln Tyr Lys Pro Gly Pro Lys Thr Gly Pro Gly 100 105 110 Gln Lys Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 115 120 125 152158PRTGallus gallus 152Met Ala Ala Gly Ala Ala Gly Ser Ile Thr Thr Leu Pro Ala Leu Pro 1 5 10 15 Asp Asp Gly Gly Gly Gly Ala Phe Pro Pro Gly His Phe Lys Asp Pro 20 25 30 Lys Arg Leu Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile Asn Pro 35 40 45 Asp Gly Arg Val Asp Gly Val Arg Glu Lys Ser Asp Pro His Ile Lys 50 55 60 Leu Gln Leu Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val 65 70 75 80 Ser Ala Asn Arg Phe Leu Ala Met Lys Glu Asp Gly Arg Leu Leu Ala 85 90 95 Leu Lys Cys Ala Thr Glu Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser 100 105 110 Asn Asn Tyr Asn Thr Tyr Arg Ser Arg Lys Tyr Ser Asp Trp Tyr Val 115 120 125 Ala Leu Lys Arg Thr Gly Gln Tyr Lys Pro Gly Pro Lys Thr Gly Pro 130 135 140 Gly Gln Lys Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 145 150 155 153153PRTTaeniopygia guttata 153Met Ala Ala Ala Gly Gly Ile Ala Thr Leu Pro Asp Asp Gly Gly Ser 1 5 10 15 Gly Ala Phe Pro Pro Gly His Phe Lys Asp Pro Lys Arg Leu Tyr Cys 20 25 30 Lys Asn Gly Gly Phe Phe Leu Arg Ile Asn Pro Asp Gly Lys Val Asp 35 40 45 Gly Val Arg Glu Lys Ser Asp Pro His Ile Lys Leu Gln Leu Gln Ala 50 55 60 Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Ser Ala Asn Arg Phe 65 70 75 80 Leu Ala Met Lys Glu Asp Gly Arg Leu Leu Ala Leu Lys Tyr Ala Thr 85 90 95 Glu Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn Asn Tyr Asn Thr 100 105

110 Tyr Arg Ser Arg Lys Tyr Ser Asp Trp Tyr Val Ala Leu Lys Arg Thr 115 120 125 Gly Gln Tyr Lys Pro Gly Pro Lys Thr Gly Pro Gly Gln Lys Ala Ile 130 135 140 Leu Phe Leu Pro Met Ser Ala Lys Ser 145 150 154155PRTCynops pyrrhogaster 154Met Ala Ala Gly Ser Ile Thr Ser Leu Pro Ala Leu Pro Glu Asp Gly 1 5 10 15 Asn Gly Gly Thr Phe Thr Pro Gly Gly Phe Lys Glu Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile Asn Ser Asp Gly Lys 35 40 45 Val Asp Gly Ala Arg Glu Lys Ser Asp Ser Tyr Ile Lys Leu Gln Leu 50 55 60 Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Cys Ala Asn 65 70 75 80 Arg Tyr Leu Ala Met Lys Asp Asp Gly Arg Leu Met Ala Leu Lys Trp 85 90 95 Ile Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn Asn Tyr 100 105 110 Asn Thr Tyr Arg Ser Arg Lys Tyr Ser Asp Trp Tyr Val Ala Leu Lys 115 120 125 Arg Thr Gly Gln Tyr Lys Asn Gly Ser Lys Thr Gly Ala Gly Gln Lys 130 135 140 Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 145 150 155 155155PRTXenopus laevis 155Met Ala Ala Gly Ser Ile Thr Thr Leu Pro Thr Glu Ser Glu Asp Gly 1 5 10 15 Gly Asn Thr Pro Phe Ser Pro Gly Ser Phe Lys Asp Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile Asn Ser Asp Gly Arg 35 40 45 Val Asp Gly Ser Arg Asp Lys Ser Asp Ser His Ile Lys Leu Gln Leu 50 55 60 Gln Ala Val Glu Arg Gly Val Val Ser Ile Lys Gly Ile Thr Ala Asn 65 70 75 80 Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu Thr Ser Leu Arg Cys 85 90 95 Ile Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu Glu Ala Asn Asn Tyr 100 105 110 Asn Thr Tyr Arg Ser Arg Lys Tyr Ser Ser Trp Tyr Val Ala Leu Lys 115 120 125 Arg Thr Gly Gln Tyr Lys Asn Gly Ser Ser Thr Gly Pro Gly Gln Lys 130 135 140 Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 145 150 155 156156PRTDidelphis albiventris 156Met Ala Ala Gly Ser Ile Thr Thr Leu Pro Ala Leu Ser Gly Asp Gly 1 5 10 15 Gly Gly Gly Gly Ala Phe Pro Pro Gly His Phe Lys Asp Pro Lys Arg 20 25 30 Leu Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile His Pro Asp Gly 35 40 45 Arg Val Asp Gly Ile Arg Glu Lys Ser Asp Pro Asn Ile Lys Leu Gln 50 55 60 Leu Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Cys Ala 65 70 75 80 Asn Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu Leu Ala Leu Lys 85 90 95 Tyr Val Thr Glu Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn Asn 100 105 110 Tyr Asn Thr Tyr Arg Ser Arg Lys Tyr Ser Asn Trp Tyr Val Ala Leu 115 120 125 Lys Arg Thr Gly Gln Tyr Lys Leu Gly Ser Lys Thr Gly Pro Gly Gln 130 135 140 Lys Ala Ile Leu Phe Ser Pro Cys Leu Leu Arg Cys 145 150 155 15796PRTMyotis lucifugus 157Val Lys Leu Gln Leu Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys 1 5 10 15 Gly Val Cys Ala Asn Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu 20 25 30 Gln Ala Ser Lys Cys Val Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu 35 40 45 Glu Ser Asn Asn Tyr Asn Thr Tyr Arg Ser Arg Lys Tyr Ser Ser Trp 50 55 60 Tyr Val Ala Leu Lys Arg Asn Gly Gln Tyr Lys Leu Gly Pro Lys Thr 65 70 75 80 Gly Pro Gly Gln Lys Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 85 90 95 158140PRTAnolis carolinensis 158Ala Ala Ala Ala Ser Phe Pro Pro Gly Pro Phe Lys Asp Pro Lys Arg 1 5 10 15 Leu Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile Asn Pro Asp Gly 20 25 30 Gly Val Asp Gly Val Arg Glu Lys Ser Asp Pro Asn Ile Lys Leu Leu 35 40 45 Leu Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Cys Ala 50 55 60 Asn Arg Phe Leu Ala Met Asn Glu Asp Gly Arg Leu Leu Ala Leu Lys 65 70 75 80 Tyr Val Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn Asn 85 90 95 Tyr Asn Thr Tyr Arg Ser Arg Lys Tyr Arg Asp Trp Tyr Ile Ala Leu 100 105 110 Lys Arg Thr Gly Gln Tyr Lys Leu Gly Pro Lys Thr Gly Arg Gly Gln 115 120 125 Lys Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 130 135 140 15994PRTDasypus novemcinctus 159Met Ala Ala Gly Ser Ile Thr Thr Leu Pro Ala Leu Pro Glu Asp Gly 1 5 10 15 Gly Ser Gly Ala Phe Pro Pro Gly His Phe Lys Asp Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile His Pro Asp Gly Arg 35 40 45 Val Asp Gly Val Arg Glu Lys Ser Asp Pro Asn Ile Lys Leu Gln Leu 50 55 60 Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Cys Ala Asn 65 70 75 80 Arg Tyr Leu Ala Met Arg Glu Asp Gly Arg Leu Gln Ala Ser 85 90 160189PRTTupaia belangeri 160Ala Gly Val Arg Ala Glu Arg Glu Glu Ala Pro Gly Ser Gly Asp Ser 1 5 10 15 Arg Gly Thr Asp Pro Ala Ala Arg Ser Leu Ile Arg Arg Pro Asp Ala 20 25 30 Ala Ala Arg Glu Ala Leu Leu Gly Ala Arg Ser Arg Val Gln Gly Ser 35 40 45 Ser Thr Ser Trp Pro Ala Ser Ser Arg Thr Gly Ile Lys Leu Pro Asp 50 55 60 Asp Ser Gly Gln Gly Met Gly Gly Tyr Pro Leu Asp Arg Pro Ser Arg 65 70 75 80 Ser Thr Gly Arg Gly Leu Gly Gly Ala Pro Asp Pro Ala Val Lys Leu 85 90 95 Gln Leu Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Cys 100 105 110 Ala Asn Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu Leu Ala Ser 115 120 125 Lys Cys Val Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn 130 135 140 Asn Tyr Asn Thr Tyr Arg Ser Arg Lys Tyr Ser Ser Trp Tyr Val Ala 145 150 155 160 Leu Lys Arg Thr Gly Gln Tyr Lys Leu Gly Ser Lys Thr Gly Pro Gly 165 170 175 Gln Lys Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 180 185 161154PRTXenopus silurana tropicalis 161Met Ala Ala Gly Ser Ile Thr Thr Leu Pro Thr Glu Ser Glu Asp Gly 1 5 10 15 Asn Thr Pro Phe Pro Pro Gly Asn Phe Lys Asp Pro Lys Arg Leu Tyr 20 25 30 Cys Lys Asn Gly Gly Tyr Phe Leu Arg Ile Asn Ser Asp Gly Arg Val 35 40 45 Asp Gly Ser Arg Asp Lys Ser Asp Leu His Ile Lys Leu Gln Leu Gln 50 55 60 Ala Val Glu Arg Gly Val Val Ser Ile Lys Gly Ile Thr Ala Asn Arg 65 70 75 80 Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu Thr Ser Leu Lys Cys Ile 85 90 95 Thr Asp Glu Cys Phe Phe Tyr Glu Arg Leu Glu Ala Asn Asn Tyr Asn 100 105 110 Thr Tyr Arg Ser Arg Lys Asn Asn Ser Trp Tyr Val Ala Leu Lys Arg 115 120 125 Thr Gly Gln Tyr Lys Asn Gly Ser Thr Thr Gly Pro Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 145 150 162155PRTLatimeria chalumnae 162Met Ala Ala Gly Gly Ile Thr Thr Leu Pro Ala Val Pro Glu Asp Gly 1 5 10 15 Gly Ser Ser Thr Phe Pro Pro Gly Asn Phe Lys Glu Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Asn Gly Gly Tyr Phe Leu Arg Ile Asn Pro Asp Gly Arg 35 40 45 Val Asp Gly Thr Arg Glu Lys Asn Asp Pro Tyr Ile Lys Leu Gln Leu 50 55 60 Gln Ala Glu Ser Ile Gly Val Val Ser Ile Lys Gly Val Cys Ser Asn 65 70 75 80 Arg Tyr Leu Ala Met Asn Glu Asp Cys Arg Leu Phe Gly Leu Lys Tyr 85 90 95 Pro Thr Asp Glu Cys Phe Phe His Glu Arg Leu Glu Ser Asn Asn Tyr 100 105 110 Asn Thr Tyr Arg Ser Lys Lys Tyr Ser Asp Trp Tyr Val Ala Leu Lys 115 120 125 Arg Thr Gly Gln Tyr Lys Pro Gly Pro Lys Thr Gly Leu Gly Gln Lys 130 135 140 Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Ser 145 150 155 163155PRTTetraodon nigroviridis 163Met Ala Thr Gly Gly Ile Thr Thr Leu Pro Ser Thr Pro Glu Asp Gly 1 5 10 15 Gly Ser Ser Gly Phe Pro Pro Gly Ser Phe Lys Asp Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile Lys Ser Asp Gly Val 35 40 45 Val Asp Gly Ile Arg Glu Lys Ser Asp Pro His Ile Lys Leu Gln Leu 50 55 60 Gln Ala Thr Ser Val Gly Glu Val Val Ile Lys Gly Val Cys Ala Asn 65 70 75 80 Arg Tyr Leu Ala Met Asn Arg Asp Gly Arg Leu Phe Gly Thr Lys Arg 85 90 95 Ala Thr Asp Glu Cys His Phe Leu Glu Arg Leu Glu Ser Asn Asn Tyr 100 105 110 Asn Thr Tyr Arg Ser Arg Lys Tyr Pro Thr Met Phe Val Gly Leu Thr 115 120 125 Arg Thr Gly Gln Tyr Lys Ser Gly Ser Lys Thr Gly Pro Gly Gln Lys 130 135 140 Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Cys 145 150 155 164155PRTGasterosteus aculeatus 164Met Ala Thr Ala Gly Phe Ala Thr Leu Pro Ser Thr Pro Glu Asp Gly 1 5 10 15 Gly Ser Gly Gly Phe Thr Pro Gly Gly Phe Lys Asp Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile Arg Ser Asp Gly Gly 35 40 45 Val Asp Gly Ile Arg Glu Lys Ser Asp Ala His Ile Lys Leu Gln Ile 50 55 60 Gln Ala Thr Ser Val Gly Glu Val Val Ile Lys Gly Val Cys Ala Asn 65 70 75 80 Arg Tyr Leu Ala Met Asn Arg Asp Gly Arg Leu Phe Gly Val Arg Arg 85 90 95 Ala Thr Asp Glu Cys Tyr Phe Leu Glu Arg Leu Glu Ser Asn Asn Tyr 100 105 110 Asn Thr Tyr Arg Ser Arg Lys Tyr Pro Gly Met Tyr Val Ala Leu Lys 115 120 125 Arg Thr Gly Gln Tyr Lys Ser Gly Ser Lys Thr Gly Pro Gly Gln Lys 130 135 140 Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Cys 145 150 155 165155PRTTakifugu rubripes 165Met Ala Thr Gly Gly Ile Thr Thr Leu Pro Ser Thr Pro Glu Asp Gly 1 5 10 15 Gly Ser Gly Gly Phe Pro Pro Gly Ser Phe Lys Asp Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile Arg Ser Asp Gly Ala 35 40 45 Val Asp Gly Thr Arg Glu Lys Thr Asp Pro His Ile Lys Leu Gln Leu 50 55 60 Gln Ala Thr Ser Val Gly Glu Val Val Ile Lys Gly Val Cys Ala Asn 65 70 75 80 Arg Tyr Leu Ala Met Asn Arg Asp Gly Arg Leu Phe Gly Met Lys Arg 85 90 95 Ala Thr Asp Glu Cys His Phe Leu Glu Arg Leu Glu Ser Asn Asn Tyr 100 105 110 Asn Thr Tyr Arg Ser Arg Lys Tyr Pro Asn Met Phe Val Gly Leu Thr 115 120 125 Arg Thr Gly Asn Tyr Lys Ser Gly Thr Lys Thr Gly Pro Cys Gln Lys 130 135 140 Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Tyr 145 150 155 166155PRTOncorhynchus mykiss 166Met Ala Thr Gly Glu Ile Thr Thr Leu Pro Ala Thr Pro Glu Asp Gly 1 5 10 15 Gly Ser Gly Gly Phe Leu Pro Gly Asn Phe Lys Glu Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Asn Gly Gly Tyr Phe Leu Arg Ile Asn Ser Asn Gly Ser 35 40 45 Val Asp Gly Ile Arg Asp Lys Asn Asp Pro His Asn Lys Leu Gln Leu 50 55 60 Gln Ala Thr Ser Val Gly Glu Val Val Ile Lys Gly Val Ser Ala Asn 65 70 75 80 Arg Tyr Leu Ala Met Asn Ala Asp Gly Arg Leu Phe Gly Pro Arg Arg 85 90 95 Thr Thr Asp Glu Cys Tyr Phe Met Glu Arg Leu Glu Ser Asn Asn Tyr 100 105 110 Asn Thr Tyr Arg Ser Arg Lys Tyr Pro Glu Met Tyr Val Ala Leu Lys 115 120 125 Arg Thr Gly Gln Tyr Lys Ser Gly Ser Lys Thr Gly Pro Gly Gln Lys 130 135 140 Ala Ile Leu Phe Leu Pro Met Ser Ala Arg Arg 145 150 155 167150PRTSalmo salar 167Met Ala Thr Gly Glu Ile Thr Thr Leu Pro Ala Thr Pro Glu Asp Gly 1 5 10 15 Gly Ser Gly Gly Phe Pro Pro Gly Asn Phe Lys Asp Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Asn Gly Gly Tyr Phe Leu Arg Ile Asn Ser Asn Gly Ser 35 40 45 Val Asp Gly Ile Arg Glu Lys Asn Asp Pro His Lys Gln Pro Gln Phe 50 55 60 Val Arg Ala Trp Thr Leu Gln Gly Val Lys Arg Ser Thr Gly Met Leu 65 70 75 80 Ala His Val Asp Ser Asn Ala Ser His Asn Cys Val Lys Val Ala Gly 85 90 95 Cys Ser Leu Gly Glu Phe Gly Ser Met Ser Asn Arg Pro His Asn Arg 100 105 110 Arg Pro Arg Val Ala Thr Pro Ala Gln Asp Leu His Ile Arg Leu Leu 115 120 125 His Leu Arg Asp Arg Leu Lys Pro Ala Thr Arg Thr Ala Asp Lys Thr 130 135 140 Glu Glu Tyr Phe Cys Leu 145 150 168154PRTDanio rerio 168Met Ala Thr Gly Gly Ile Thr Thr Leu Pro Ala Ala Pro Asp Ala Glu 1 5 10 15 Asn Ser Ser Phe Pro Ala Gly Ser Phe Arg Asp Pro Lys Arg Leu Tyr 20 25 30 Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile Asn Ala Asp Gly Arg Val 35 40 45 Asp Gly Ala Arg Asp Lys Ser Asp Pro His Ile Arg Leu Gln Leu Gln 50 55 60 Ala Thr Ala Val Gly Glu Val Leu Ile Lys Gly Ile Cys Thr Asn Arg 65 70 75 80 Phe Leu Ala Met Asn Ala Asp Gly Arg Leu Phe Gly Thr Lys Arg Thr 85 90 95 Thr Asp Glu Cys Tyr Phe Leu Glu Arg Leu Glu Ser Asn Asn Tyr Asn 100 105 110 Thr Tyr Arg Ser Arg Lys Tyr Pro Asp Trp Tyr Val Ala Leu Lys Arg 115 120

125 Thr Gly Gln Tyr Lys Ser Gly Ser Lys Thr Ser Pro Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Met Ser Ala Lys Cys 145 150 169155PRTOreochromis niloticus 169Met Ala Thr Gly Gly Ile Thr Thr Leu Pro Ala Thr Pro Glu Asp Gly 1 5 10 15 Gly Ser Ser Gly Phe Pro Pro Gly Asn Phe Lys Asp Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile Lys Ser Asp Gly Gly 35 40 45 Val Asp Gly Ile Arg Glu Lys Asn Asp Pro His Ile Lys Leu Gln Leu 50 55 60 Gln Ala Thr Ser Val Gly Glu Val Val Ile Lys Gly Ile Cys Ala Asn 65 70 75 80 Arg Tyr Leu Ala Met Asn Arg Asp Gly Arg Leu Phe Gly Ala Arg Arg 85 90 95 Ala Thr Asp Glu Cys Tyr Phe Leu Glu Arg Leu Glu Ser Asn Asn Tyr 100 105 110 Asn Thr Tyr Arg Ser Arg Lys Tyr Pro Asn Met Tyr Val Ala Leu Lys 115 120 125 Arg Thr Gly Gln Tyr Lys Ser Gly Ser Lys Thr Gly Pro Gly Gln Lys 130 135 140 Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Cys 145 150 155 170155PRTOryzias latipes 170Met Ala Thr Gly Glu Ile Thr Thr Leu Pro Ser Pro Ala Glu Asn Ser 1 5 10 15 Arg Ser Asp Gly Phe Pro Pro Gly Asn Tyr Lys Asp Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Asn Gly Gly Leu Phe Leu Arg Ile Lys Pro Asp Gly Gly 35 40 45 Val Asp Gly Ile Arg Glu Lys Lys Asp Pro His Val Lys Leu Arg Leu 50 55 60 Gln Ala Thr Ser Ala Gly Glu Val Val Ile Lys Gly Val Cys Ser Asn 65 70 75 80 Arg Tyr Leu Ala Met His Gly Asp Gly Arg Leu Phe Gly Val Arg Gln 85 90 95 Ala Thr Glu Glu Cys Tyr Phe Leu Glu Arg Leu Glu Ser Asn Asn Tyr 100 105 110 Asn Thr Tyr Arg Ser Lys Lys Tyr Pro Asn Met Tyr Val Ala Leu Lys 115 120 125 Arg Thr Gly Gln Tyr Lys Pro Gly Asn Lys Thr Gly Pro Gly Gln Lys 130 135 140 Ala Ile Leu Phe Leu Pro Met Ser Ala Lys Tyr 145 150 155 171468DNAHomo sapiens 171atggcagccg ggagcatcac cacgctgccc gccttgcccg aggatggcgg cagcggcgcc 60ttcccgcccg gccacttcaa ggaccccaag cggctgtact gcaaaaacgg gggcttcttc 120ctgcgcatcc accccgacgg ccgagttgac ggggtccggg agaagagcga ccctcacatc 180aagctacaac ttcaagcaga agagagagga gttgtgtcta tcaaaggagt gtgtgctaac 240cgttacctgg ctatgaagga agatggaaga ttactggctt ctaaatgtgt tacggatgag 300tgtttctttt ttgaacgatt ggaatctaat aactacaata cttaccggtc aaggaaatac 360accagttggt atgtggcact gaaacgaact gggcagtata aacttggatc caaaacagga 420cctgggcaga aagctatact ttttcttcca atgtctgcta agagctga 468172468DNAGorilla 172atggcagccg ggagcatcac cacgctgccc gccttgcccg aggatggcgg cagcggcgcc 60ttcccgcccg gccacttcaa ggaccccaag cggctgtact gcaaaaacgg gggcttcttc 120ctgcgcatcc accccgacgg ccgagttgac ggggtccggg agaagagcga ccctcacatc 180aagctacaac ttcaagcaga agagagagga gttgtgtcta tcaaaggagt gtgtgctaac 240cgttaccttg ctatgaagga agatggaaga ttactggctt ctaaatgtgt tacggatgag 300tgtttctttt ttgaacgatt ggaatctaat aactacaata cttaccggtc aaggaaatac 360accagttggt atgtggcact gaaacgaact gggcagtata aacttggatc caaaacagga 420cctgggcaga aagctatact ttttcttcca atgtctgcta agagctga 468173468DNASumatran orangutan 173atggcagccg ggagcatcac cacgctgccc gccttgcccg aggatggcgg cagcggcgcc 60ttcccgccgg gccacttcaa ggaccccaag cggctgtact gcaaaaacgg gggcttcttc 120ctgcgcatcc accccgacgg ccgagttgac ggggtccgag agaagagcga ccctcacatc 180aaactacaac ttcaagcaga agaaagagga gttgtgtcta tcaaaggagt gtgtgctaac 240cgctaccttg ctatgaagga agatggaaga ttactggctt ctaaatgtgt tacggatgag 300tgtttctttt ttgaacgatt ggaatctaat aactacaata cttaccggtc aaggaaatac 360accagttggt atgtggcact gaaacgaact gggcagtata aacttggatc caaaacagga 420cctgggcaga aagctatact ttttcttcca atgtctgcta agagctga 468174468DNARhesus monkey 174atggcagccg ggagcatcac cacgctgccc gccttgcccg aggatggcgg cagcggcgcc 60ttcccgcctg gccacttcaa ggaccccaag cggctgtact gcaaaaacgg gggcttcttc 120ctgcgcattc accccgacgg ccgagttgac ggggtccggg agaagagcga ccctcacatc 180aaattacaac ttcaagcaga agagagagga gttgtgtcta tcaaaggagt gtgtgctaac 240cgttaccttg ctatgaagga agatggaaga ttactggctt ctaaatgtgt tacagatgag 300tgtttctttt ttgaacgatt ggaatctaat aactacaata cttaccggtc aaggaaatac 360accagttggt atgtggcact gaaacgaact gggcaatata aacttggatc caaaacagga 420cctgggcaga aagctatact ttttcttcca atgtctgcta agagctga 468175468DNAChimpanzee 175atggcagccg ggagcatcac cacgctgccc gccttgcccg aggatggcgg cagcggcgcc 60ttcccgcccg gccacttcaa ggaccccaag cggctgtact gcaaaaacgg gggcttcttc 120ctgcgcatcc accccgacgg ccgagttgac ggggtccggg agaagagcga ccctcacatc 180aagctacaac ttcaagcaga agagagagga gttgtgtcta tcaaaggagt gtgtgctaac 240cgttaccttg ctatgaagga agatggaaga ttactggctt ctaaatgtgt tacggatgag 300tgtttctttt ttgaacgatt ggaatctaat aactacaata cttaccggtc aaggaaatac 360accagttggt atgtggcact gaaacgaact gggcagtata aacttggatc caaaacagga 420cctgggcaga aagctatact ttttcttcca atgtctgcta agagctga 468176468DNAPygmy chimpanzee 176atggcagccg ggagcatcac cacgctgccc gccttgcccg aggatggcgg cagcggcgcc 60ttcccgcccg gccacttcaa ggaccccaag cggctgtact gcaaaaacgg gggcttcttc 120ctgcgcatcc accccgacgg ccgagttgac ggggtccggg agaagagcga ccctcacatc 180aagctacaac ttcaagcaga agagagagga gttgtgtcta tcaaaggagt gtgtgctaac 240cgttaccttg ctatgaagga agatggaaga ttactggctt ctaaatgtgt tacggatgag 300tgtttctttt ttgaacgatt ggaatctaat aactacaata cttaccggtc aaggaaatac 360accagttggt atgtggcact gaaacgaact gggcagtata aacttggatc caaaacagga 420cctgggcaga aagctatact ttttcttcca atgtctgcta agagctga 468177468DNABolivian squirrel monkey 177atggcagccg ggagcatcac cacgctgccc gccctgcccg aagacggcgg cagcggcgcc 60ttcccgcccg gccacttcaa agaccccaag cggctgtact gcaaaaacgg gggcttcttc 120ctgcgaatcc accccgacgg ccgagtggac ggggtccggg agaagagcga ccctcacatc 180aaactacaac ttcaagcaga agagagagga gttgtatcta tcaaaggagt gtgtgctaac 240cgttaccttg ctatgaagga agatggaaga ttactggctt ctaaatgtgt tacggacgag 300tgtttctttt ttgaacgatt ggaatctaat aactacaata cttaccgatc aaggaaatac 360accagttggt atgtggcact gaaacgaact gggcagtata aacttggatc caaaacagga 420cctgggcaga aagctatact ttttcttcca atgtctgcta agagctga 468178468DNANorthern white-cheeked gibbon 178atggcagccg ggagcatcac cacgctgccc gccttgccgg aggatggcgg cagcggcgcc 60ttcccgcccg gccacttcaa ggaccccaag cggctgtact gcaaaaacgg gggtttcttc 120ctgcgcatcc accccgacgg tcgagttgac ggggtccggg agaagagcga ccctcacatc 180aaactacaac ttcaagcaga agagagagga gttgtgtcta tcaaaggagt gtgtgctaac 240cgttaccttg ctatgaagga agatggaaga ttactggctt ctaaatgtgt tacggatgag 300tgtttctttt ttgaacgatt ggaatctaat aactacaata cttaccggtc aaggaaatac 360accagttggt atgtggcact gaaacgaact gggcagtata aacttggatc caaaacagga 420cctgggcaga aagctatact ttttcttcca atgtctgcta agagctga 468179468DNAHorse 179atggcagccg ggagcatcac cacgctgccc gccctgcccg aggacggcgg cagcggcgcc 60ttcccgcccg gccacttcaa ggaccccaag cggctctact gcaaaaacgg gggcttcttc 120ctgcgcatcc accccgacgg ccgagtggac ggggtccggg agaagagcga ccctcacatc 180aaactacaac ttcaagcaga agagagaggg gttgtgtcta tcaaaggagt gtgtgcgaac 240cgttatcttg ctatgaagga agatggaagg ttactggctt ctaaatgtgt tacggacgag 300tgtttctttt ttgaacgatt ggaatctaat aactacaata cttaccggtc aaggaaatac 360tccagttggt atgtggccct gaaacgaacg gggcagtata aacttggacc caaaacagga 420cctggacaga aagctatact ttttcttcca atgtctgcta agagctga 468180468DNACattle 180atggccgccg ggagcatcac cacgctgcca gccctgccgg aggacggcgg cagcggcgct 60ttcccgccgg gccacttcaa ggaccccaag cggctgtact gcaagaacgg gggcttcttc 120ctgcgcatcc accccgacgg ccgagtggac ggggtccgcg agaagagcga cccacacatc 180aaactacaac ttcaagcaga agagagaggg gttgtgtcta tcaaaggagt gtgtgcaaac 240cgttaccttg ctatgaaaga agatggaaga ttactagctt ctaaatgtgt tacagacgag 300tgtttctttt ttgaacgatt ggagtctaat aactacaata cttaccggtc aaggaaatac 360tccagttggt atgtggcact gaaacgaact gggcagtata aacttggacc caaaacagga 420cctgggcaga aagctatact ttttcttcca atgtctgcta agagctga 468181468DNAOlive baboon 181atggcagccg ggagcatcac cacgctgccc gccttgcccg aggatggcgg cagcggcgcc 60ttcccgcccg gccacttcaa ggaccccaag cggctgtact gcaaaaacgg gggcttcttc 120ctgcgcattc accccgacgg ccgagttgac ggggtccggg agaagagcga ccctcacatc 180aaattacaac ttcaagcaga agagagagga gttgtgtcta tcaaaggagt gtgtgctaac 240cgttaccttg ctatgaagga agatggaaga ttactggctt ctaaatgtgt tacggatgag 300tgtttctttt ttgaacgatt ggaatctaat aactacaata cttaccggtc aaggaaatac 360accagttggt atgtggcact gaaacgaact gggcagtata aacttggatc caaaacagga 420cctgggcaga aagctatact ttttcttcca atgtctgcta agagctga 468182468DNAAlpaca 182atggcagctg ggagcatcac cacgctgccc gccctgccgg aggacggcgg cagcggcgcc 60ttcccgcccg gccacttcaa ggaccccaag cggttgtact gcaaaaacgg gggcttcttc 120ctgcgcatcc accccgacgg ccgagtggac ggggtccggg agaagagcga ccctcacatc 180aaactacaac ttcaagcaga agagagaggg gtcgtgtcta tcaaaggagt gtgtgcaaac 240cgttaccttg ctatgaagga agatggaaga ttactggctt ctaaatgtgt cacagacgag 300tgtttctttt ttgaacgatt ggaatctaat aactacaata cttaccggtc aaggaaatac 360tccagttggt atgtggcact gaaacgaact gggcagtaca aacttggacc caaaacagga 420cctgggcaga aagctatact tttccttcca atgtctgcta agagctga 468183468DNASheep 183atggccgccg ggagcatcac cacgctgcca gccctgccgg aggacggcgg cagcagcgct 60ttcccgcccg gccactttaa ggaccccaag cggctgtact gcaagaacgg gggcttcttc 120ctgcgcatcc accccgacgg ccgagtggac ggggtccgcg agaagagcga ccctcacatc 180aaactacaac ttcaagcaga agagagaggg gttgtgtcta tcaaaggagt gtgtgcaaac 240cgttaccttg ctatgaaaga agatggaaga ttactagctt ctaaatgtgt tacagacgag 300tgtttctttt ttgaacgatt ggagtctaat aactacaata cttaccggtc aaggaaatac 360tccagttggt atgtggcact gaaacgaact gggcagtata aacttggacc caaaacagga 420cctgggcaga aagctatact ttttcttcca atgtctgcta agagctga 468184325DNAWestern roe deer 184gcgcatccac cccgacggcc gagtggacgg ggtccgcgag aagagtgacc ctcacatcaa 60actacaactt caagcagaag agagaggggt tgtgtctatc aaaggagtgt gtgcgaaccg 120ttatcttgct atgaaagaag acggaagatt attggcttca aaatgtgtta cagacgaatg 180tttctttttt gaacgattgg agtctaataa ctacaatact taccggtcaa ggaaatactc 240cagttggtat gtggcactga aacgaactgg gcagtataaa cttggaccca aaacaggacc 300tgggcagaaa gctatacttt ttctt 325185288DNAElephant 185gttaaactac agcttcaagc agaagagaga ggtgttgtgt ctatcaaagg agtgtgtgcc 60aaccgttatc tggctatgaa ggaagatgga agattgctgg cttctagatg tgtgacagat 120gaatgtttct tctttgaacg actggaatct aataactaca atacttaccg gtcaaggaaa 180tacaccagtt ggtatgtggc actgaaacga acggggcagt ataaacttgg atccaaaaca 240ggacctggac agaaagctat actttttctt cccatgtctg ctaagagc 288186361DNAPig 186gaacgggggc ttcttcctgc gcatccaccc cgacggccga gtggatgggg tccgggagaa 60gagcgaccct cacatcaaac tacaacttca agcagaagag agaggggttg tgtctatcaa 120aggagtgtgt gcaaaccgtt atcttgctat gaaggaagat ggaagattac tggcttctaa 180atgtgttaca gacgagtgtt tcttttttga acgactggaa tctaataact acaatactta 240ccggtcgagg aaatactcca gttggtatgt ggcactgaaa cgaactgggc agtataaact 300tggacccaaa acaggacctg ggcagaaagc tatacttttt cttccaatgt ctgctaagag 360c 361187288DNAPanda 187gtcaaactgc aacttcaagc ggaagagaga ggggttgtat ccatcaaagg agtatgtgca 60aatcgctatc ttgccatgaa ggaagatgga agattactgg cttctaaatg tgttaccgat 120gagtgtttct tttttgagcg actggaatct aataactaca atacttaccg gtcaaggaaa 180tactccagtt ggtatgtggc actgaaacga actgggcagt ataaacttgg acccaaaaca 240ggacctgggc agaaagctat actttttctt ccaatgtctg ctaagagc 288188468DNASloth 188atggcagccg ggagcatcac cacgctgccc gccctgcccg aggacggagg cagcggcgcc 60ttaccgcccg gccacttcaa agatcccaag cggctctact gcaaaaacgg gggcttcttc 120ctgcgtatcc atcccgacgg cagagtggac ggggtccggg agaagagcga cccccacatc 180aaactacaac ttcaagcaga agagagaggg gttgtgtcta tcaaaggtgt gtgtgcaaac 240cgatatcttg ctatgaagga agatggaaga ttacaggctt ctaaatgtgt aacggacgag 300tgtttctttt ttgaacgatt ggaatctaat aactacaata cgtaccgatc aaggaaatac 360tccagttggt atgtggcact gaaacgaact gggcaatata aacttggacc caaaacagga 420cctgggcaga aagccatact ttttcttcca atgtctgcta agagctga 468189468DNAWater buffalo 189atggccgccg ggagcatcac cacgctgcca cccctgccgg aggacggcgg cagcggcgct 60ttcccgcccg gccacttcaa ggaccccaag cggctgtact gcaagaacgg gggcttcttc 120ctgcgcatcc accccgacgg ccgagtggac ggggtccgcg agaagagcga cccacacatc 180aaactacaac ttcaagcaga agagagaggg gttgtgtcta tcaaaggagt gtgtgcaaac 240cgttaccttg ctatgaaaga agatggaaga ttactagctt ccaaatgtgt tacagacgag 300tgtttctttt ttgaacgatt ggagtctagt aactacaata cttaccggtc aaggaaatac 360tccagttggt atgtggcact gaaacgaact gggcagtata aacttggacc caaaacagga 420cctgggcaga aagctatact ttttcttcca atgtctgcta agagctga 468190468DNADog 190atggcagccg ggagcatcac cacgctgccc gccctgccgg aggacggcgg cagcggcgcc 60ttcccgcccg gccacttcaa ggaccccaag aggctgtact gcaaaaaagg gggcttcttc 120ctgcggatcc accccgacgg ccgggtggac ggggtccggg agaagagcga tccccacgtc 180aaattgcaac ttcaagcaga agagagaggc gttgtgtcca tcaaaggagt atgtgcaaat 240cgctatcttg ctatgaagga agatggaaga ttactggctt ctaaatgtgt tactgacgag 300tgcttctttt ttgaacgatt ggaatctaat aactacaata cttaccggtc aaggaaatac 360tccagttggt atgtggcact gaaacgaact gggcagtata aacttggacc aaaaacagga 420cctgggcaga aagctatact ttttcttcca atgtctgcta agagctga 468191465DNANorway rat 191atggctgccg gcagcatcac ttcgcttccc gcactgccgg aggacggcgg cggcgccttc 60ccacccggcc acttcaagga tcccaagcgg ctctactgca agaacggcgg cttcttcctg 120cgcatccatc cagacggccg cgtggacggc gtccgggaga agagcgaccc acacgtcaaa 180ctacagctcc aagcagaaga gagaggagtt gtgtccatca agggagtgtg tgcgaaccgg 240tacctggcta tgaaggaaga tggacggctg ctggcttcta agtgtgttac agaagagtgt 300ttcttctttg aacgcctgga gtccaataac tacaacactt accggtcacg gaaatactcc 360agttggtatg tggcactgaa acgaactggg cagtataaac tcggatccaa aacggggcct 420ggacagaagg ccatactgtt tcttccaatg tctgctaaga gctga 465192405DNANaked mole-rat 192ccacccggcc acttcaagga cccaaagcgg ctgtactgca aaaacggggg cttcttcctg 60cgcatccacc ccgacggccg cgtggacggg gtccgggaga agagcgaccc tcacgtcaaa 120ctacaacttc aagcagaaga gagaggagtt gtgtctatta agggagtgtg tgcgaaccgt 180taccttgcta tgaaggaaga tggaagatta ctggcttcta aatgtgttac agatgagtgt 240ttcttttttg aacgattgga atctaataac tacaatactt atcggtcaag gaaatactcc 300agttggtatg tggcactgaa acgaactgga caatataaac ttggatccaa aacaggaccg 360gggcagaaag ctatactttt tcttccaatg tctgctaaga gctga 405193468DNABushbaby 193atggcagccg ggagcatcac cacgctgccc tccctgcccg aggacggcgg cagcgacgcc 60tttccgcccg gccacttcaa ggaccccaag cgactgtact gcaaaaacgg gggcttcttc 120ctgcgcatcc accccgacgg ccgagtggac ggggtccggg agaagagcga cccttacatc 180aaactacaac ttcaagcaga agagagagga gttgtgtcta tcaaaggagt gtgtgcgaac 240cgttaccttg ctatgaagga agacggaaga ttgctggctt ctaaattgat tacagacgag 300tgcttctttt ttgaacgact ggaatctaat aactacaata cttaccggtc aagaaaatac 360tccagttggt atgtggcact gaaacgaact ggacagtata aacttggatc caaaacagga 420cctgggcaga aagctatact ttttcttcca atgtctgcta agagctga 468194465DNAHouse mouse 194atggctgcca gcggcatcac ctcgcttccc gcactgccgg aggacggcgg cgccgccttc 60ccaccaggcc acttcaagga ccccaagcgg ctctactgca agaacggcgg cttcttcctg 120cgcatccatc ccgacggccg cgtggatggc gtccgcgaga agagcgaccc acacgtcaaa 180ctacaactcc aagcagaaga gagaggagtt gtgtctatca agggagtgtg tgccaaccgg 240taccttgcta tgaaggaaga tggacggctg ctggcttcta agtgtgttac agaagagtgt 300ttcttctttg aacgactgga atctaataac tacaatactt accggtcacg gaaatactcc 360agttggtatg tggcactgaa acgaactggg cagtataaac tcggatccaa aacgggacct 420ggacagaagg ccatactgtt tcttccaatg tctgctaaga gctga 465195432DNASquirrel 195ctgcccgagg acggcggcgg cggcgccttc ccgcccggcc actttaagga ccccaagcgg 60ctctactgca aaaacggagg cttcttcctg cgcatccacc ccgacggccg agtggacggg 120gtccgggaga agagcgaccc ccacatcaag ctccagcttc aagccgaaga ccgaggggtt 180gtgtccatca agggagtgtg tgcaaaccga tacctggcca tgaaggagga cgggaggctc 240ctggcttcta aatgtgttac ggacgagtgt ttcttttttg aacgactgga atcaaataac 300tacaatactt accggtcaag gaaatactcc agttggtatg tggccctgaa acgaacaggg 360cagtataaac ttggatccaa aacaggacct gggcagaaag ctatactttt tcttccaatg 420tctgctaaga gc 432196318DNADomestic cat 196ccacttcaag gaccccaagc gtctgtactg caaaaacggg ggcttcttcc tgcgcatcca 60ccccgacggc cgagtggatg gggtccggga gaagagcgac cctcacatca aactgcaact 120tcaggcagaa gagagagggg ttgtgtccat caaaggagtc tgtgcaaacc gctatcttgc 180catgaaggaa gatggaagat tactggcttc taaatgtgtt acggacgagt gtttcttttt 240tgaacgattg gaatctaata actacaatac ttatcggtca aggaaatact ccagctggta 300tgtggcactg aaacgaac 318197288DNAGuinea pig 197gttaaactac aacttcaagc cgaagacaga ggagttgtgt ctatcaaggg agtctgtgcg 60aaccgttacc ttgctatgaa ggaagacgga agattattgg cttccaaatg tgttacagat 120gaatgtttct tttttgaacg actggaatct aataactaca acacttaccg gtcaaggaaa 180tactccagtt ggtatgtggc actgaaacga actggacaat ataaacttgg gtccaaaaca 240ggaccagggc agaaagccat actttttctt ccaatgtctg cgaagagc 288198471DNATasmanian devil 198atggccgcgg gcagcatcac cacgttgccg gccctggccg gggatggagc

cagcgggggc 60gcctttcccc cgggccactt ccaggacccc aagcggctgt actgcaagaa cggaggcttc 120ttcttgcgca tccatcccga cggtcacgtg gacggcatcc gcgagaagag cgatccgcac 180attaaacttc agcttcaggc agaagagaga ggagtagtgt ctattaaagg agtttgtgcc 240aaccgctatc ttgccatgaa agaggatggc agattactgg ctctgaaatg tgtgactgaa 300gagtgtttct tctttgaacg tctagagtcc aacaattaca acacttatcg ctcaaggaaa 360tactccaatt ggtatgtggc attgaaacgc acaggccagt ataagcttgg atccaagact 420ggaccagggc agaaagccat ccttttcctt cccatgtctg ctaagagctg a 471199471DNAGray short-tailed opossum 199atggccgcag gcagcatcac cacgctgcca gccctgtccg gggacggagg cggcgggggc 60gcctttcccc cgggccactt caaggacccc aagcggctgt actgcaagaa cggaggcttc 120ttcctgcgca tccaccccga cggccgtgtg gacggcatcc gcgagaagag cgacccgaac 180attaaactac aacttcaggc agaagagaga ggagtggtgt ctattaaagg agtatgtgcc 240aatcgctatc ttgccatgaa ggaagatgga agattattgg ctttgaaata tgtgaccgaa 300gagtgtttct ttttcgaacg cttggagtcc aacaactaca acacttatcg ctcgaggaaa 360tattccaatt ggtacgtggc actgaaacga acggggcagt acaagcttgg atccaagact 420ggcccggggc agaaagccat ccttttcctc cccatgtctg ctaagagctg a 471200468DNARabbit 200atggcagccg agagcatcac cacgctgccc gccctgccgg aggatggagg cagcggcgcc 60ttcccgcccg gccacttcaa ggaccccaag cggctgtact gcaaaaacgg gggtttcttc 120ctgcgtatcc accccgacgg ccgcgtggac ggggtccggg agaagagcga cccacacatc 180aaattacaac ttcaagcaga agagagagga gttgtatcca tcaaaggtgt gtgtgcaaac 240cgttaccttg ctatgaagga agatggaaga ctgctggctt ctaaatgtgt tacagacgag 300tgcttctttt ttgaacgact ggagtctaat aactacaata cttaccggtc aaggaaatat 360tccagctggt atgtggcact gaaacgaact gggcagtata aacttggatc caaaacagga 420cctgggcaga aggctatact ttttcttcca atgtctgcta agagctga 468201375DNATurkey 201cggctctact gtaagaacgg cggcttcttc ctgcgcatca atcccgacgg cagagtggac 60ggcgtccgcg agaagagcga tccgcacatc aaactgcagc ttcaggcaga agaaagagga 120gtggtatcaa tcaaaggtgt aagtgcaaac cgctttctgg ctatgaagga ggatggcaga 180ttgctggcac tgaaatgtgc aacagaagaa tgtttctttt ttgagcgttt ggaatctaat 240aattataaca cttaccggtc acggaagtac tctgattggt atgtggcact gaaaagaact 300ggacagtaca agcccggacc aaaaactgga cctggacaga aagctatcct ttttcttcca 360atgtctgcta aaagc 375202477DNAGallus gallus 202atggcggcgg gggcggcggg gagcatcacc acgctgccgg cgctgcccga cgacgggggc 60ggcggcgctt ttccccccgg gcacttcaag gaccccaagc ggctctactg caagaacggc 120ggcttcttcc tgcgcatcaa ccccgacggc agggtggacg gcgtccgcga gaagagcgat 180ccgcacatca aactgcagct tcaagcagaa gaaagaggag tagtatcaat caaaggcgta 240agtgcaaacc gctttctggc tatgaaggag gatggcagat tgctggcact gaaatgtgca 300acagaggaat gtttcttttt cgagcgcttg gaatctaata actataacac ttaccggtca 360cggaagtact ctgattggta tgtggcactg aaaaggactg gacagtacaa gcccggacca 420aaaactggac ctggacagaa agctatcctt tttcttccaa tgtctgctaa aagctga 477203462DNAZebra finch 203atggcggcgg cggggggcat cgctacgctg cccgacgacg gcggcagcgg cgcctttccc 60ccggggcact tcaaggaccc caagcgcctg tactgcaaga acggcggctt cttcctgcgc 120atcaaccccg acgggaaggt ggacggcgtc cgcgagaaga gcgacccgca catcaagctg 180cagcttcagg cggaggaacg aggagtggtg tccatcaaag gtgtcagtgc caatcgcttc 240ctggccatga aagaggatgg cagattgctg gccttgaaat atgcaacaga agaatgtttc 300ttttttgaac gtttggaatc caataactat aacacttacc ggtcacggaa atactcggat 360tggtatgtgg cactgaaaag aactggacag tacaaacctg gaccaaaaac tggacctgga 420cagaaagcta tccttttcct tcctatgtct gctaaaagct ga 462204468DNAJapanese firebelly newt 204atggctgctg ggagcatcac cagtctccct gccctacccg aggacgggaa tggcggcacc 60ttcacacccg gcggattcaa agagccgaag aggctgtact gcaagaacgg gggcttcttt 120ctccggatca actccgacgg caaggtggac ggagcccggg agaagagcga ctcctacatt 180aaactgcagc ttcaagcaga agagcgcggt gtggtgtcca tcaagggagt atgtgcaaac 240cgctatctcg ctatgaagga tgatggcagg ctgatggcgc tgaaatggat aaccgatgaa 300tgcttctttt tcgagcgact ggagtccaac aactataaca cgtatcgatc acggaaatat 360tccgattggt atgtggcgct gaaaagaact gggcaataca aaaatggatc aaaaaccgga 420gcaggacaga aagcaatcct ttttctaccc atgtcggcca agagttga 468205468DNAAfrican clawed frog 205atggcggcag ggagcatcac aactctgcca actgaatccg aggatggggg aaacactcct 60ttttcaccag ggagttttaa agaccccaag aggctctact gcaagaacgg gggcttcttc 120ctcaggataa actcagacgg gagagtggac gggtcaaggg acaaaagtga ctcgcacata 180aaattacagc tacaagctgt agagcgggga gtggtatcaa taaagggaat cactgcaaat 240cgctaccttg ccatgaagga agatgggaga ttaacatcgc tgaggtgtat aacagatgaa 300tgcttctttt ttgaacgact ggaagctaat aactacaaca cttaccggtc tcggaaatac 360agcagctggt atgtggcact aaagcgaacc gggcagtaca aaaatggatc gagcactgga 420ccgggacaaa aagctatttt atttctccca atgtccgcaa agagctga 468206471DNAWhite-eared opossum 206atggcagcag gcagcatcac cacattgccg gccctgtccg gggacggagg cggcggggga 60gcctttcctc caggccactt caaggacccc aagcggctgt actgcaagaa cggaggcttc 120ttcctgcgca tccaccccga cggccgcgtg gacggcatcc gcgagaagag cgacccgaac 180attaaactac aacttcaggc agaagagaga ggagtagtgt ctattaaagg agtatgtgcc 240aaccgatatc ttgccatgaa ggaggatggc agattattgg ctttgaaata tgtgaccgaa 300gagtgtttct tttttgaacg tttggagtcc aacaactaca acacttatcg ctcaagaaaa 360tattccaatt ggtatgtggc actgaaacga acggggcagt ataagcttgg atccaagact 420ggcccggggc agaaagccat ccttttctcc ccatgtctgc taagatgctg a 471207288DNAMicrobat 207gtcaaactcc aacttcaagc agaagagaga ggggtcgtgt ctatcaaagg agtgtgtgcc 60aaccgctatc tcgctatgaa ggaggacggc cggttacagg cttctaaatg tgttacggat 120gagtgtttct tttttgaacg gttggaatcc aataactaca acacttaccg gtcaagaaag 180tactccagtt ggtatgtggc attgaagcgg aatgggcagt ataaacttgg acccaaaaca 240ggacctggcc agaaagccat actttttctt cccatgtctg ctaagagc 288208420DNAAnole lizard 208gcggcggcgg cctctttccc cccgggcccc ttcaaggacc ccaagcgcct ctactgcaag 60aacgggggct tcttcctgcg gatcaacccc gacggcggcg tggacggcgt ccgagagaag 120agcgacccca acatcaaatt gctgctccag gcagaggaga gaggtgtagt gtccatcaaa 180ggtgtatgcg caaaccgttt cctggctatg aatgaagacg gtcgattgtt agcactgaaa 240tacgtaacag atgaatgctt cttttttgaa cgcttggaat ctaataatta caatacttat 300cggtctcgta aataccgtga ttggtacatt gcactgaaac gaactggtca gtacaaactt 360ggaccaaaaa ctggacgagg ccagaaagct atccttttcc ttccaatgtc tgccaaaagt 420209282DNAArmadillo 209atggcagccg ggagcatcac cacgctgccc gctctgcccg aggacggcgg cagcggcgcc 60ttcccgccgg gccacttcaa ggaccccaag cggctgtact gcaaaaacgg gggcttcttc 120ctgcgcatcc atcccgacgg ccgagtggac ggggtccggg agaagagcga ccctaacatc 180aaactacaac ttcaagcaga agagagaggg gtcgtgtcta tcaaaggcgt gtgtgcgaac 240cgttaccttg ctatgcggga agacggaaga ctccaggcgt ct 282210567DNATree shrew 210gcgggggtta gagctgagag ggaggaggca ccggggagcg gtgacagccg ggggaccgat 60cccgccgcgc gttcgctcat caggaggccg gatgctgcag cgcgagaggc gcttcttgga 120gccaggagcc gggttcaggg cagctccacc tcctggccag cctcgtcacg aaccgggatc 180aagttgccgg acgactcagg tcaaggaatg ggcggctatc ctctggaccg cccgagccgg 240agcacagggc gagggctggg cggtgccccg gaccctgccg taaaactaca gcttcaagcg 300gaagagagag gggtcgtgtc tatcaaagga gtgtgtgcaa accgttacct ggccatgaag 360gaggatgggc gactgctggc ttctaaatgt gttacagatg agtgtttctt ttttgaacga 420ctggaatcta ataactacaa tacttaccgg tcccgaaagt actccagctg gtatgtggca 480ctgaaacgaa ctgggcagta taaacttgga tccaaaacag gacctgggca gaaagctata 540ctttttcttc caatgtctgc taaaagc 567211465DNAWestern clawed frog 211atggcagcag gaagcatcac aaccctacca accgaatctg aggatggaaa cactcctttc 60ccaccgggga actttaagga ccccaagagg ctctactgca agaatggggg ctacttcctc 120aggattaact cagacgggag agtggacgga tcaagggata aaagtgactt acacataaaa 180ttacagctac aagcagtaga gcggggagtg gtatcaataa agggaatcac tgcaaatcgc 240taccttgcca tgaaggaaga tgggagatta acatcgctga agtgtataac agatgaatgc 300ttcttttatg aacgattgga agctaataac tacaacactt accggtctcg gaaaaacaac 360agctggtatg tggcactaaa gcgaactggg cagtataaaa atggatcgac cactggacca 420ggacaaaaag ctattttgtt tctcccaatg tcagcaaaaa gctga 465212468DNACoelacanth 212atggctgcgg gaggaatcac taccctgccg gcggtacctg aggatggagg cagcagcacc 60ttccctccag gaaacttcaa ggagcccaag agactttact gtaagaatgg aggctatttc 120ttaaggataa accccgatgg aagagtggat ggaacaaggg agaaaaatga tccttatata 180aaattacaac tgcaagctga atctatagga gtggtgtcga taaagggagt ttgttcaaac 240cgttacctag cgatgaatga agactgtaga ctttttggat tgaaatatcc aacggatgaa 300tgtttcttcc atgagaggct ggagtccaac aactacaata cttatcgttc aaagaagtat 360tcggattggt atgtggcgct gaaacggact ggtcagtaca aacctgggcc aaaaactgga 420ctgggacaaa aagcaatcct tttccttccg atgtctgcca agagttga 468213468DNASpotted green pufferfish 213atggccacgg gagggatcac gacgcttcca tccacacctg aagacggcgg cagcagcggc 60tttcctcccg gcagcttcaa ggatcccaaa aggctctact gtaaaaacgg aggtttcttc 120ctgaggatca agtccgacgg ggtcgtggac ggaatccggg agaagagtga cccccacata 180aagcttcagc tccaggcgac ctctgtgggg gaggtggtca tcaagggggt gtgcgctaac 240cgctatctgg ccatgaacag agatggacgg ctgttcggaa cgaaacgagc cacggacgaa 300tgccatttct tagagcggct tgagagcaac aactacaaca cttaccgctc caggaagtac 360ccaaccatgt ttgtgggact gacgcggacg ggccagtaca agtctgggag caaaactgga 420ccgggccaaa aggccatcct ttttcttccg atgtccgcca aatgctaa 468214468DNAStickleback 214atggccacgg caggcttcgc gacgcttccc tccacgcccg aagacggcgg cagcggcggc 60ttcacccccg ggggattcaa ggatcccaag aggctgtact gcaaaaacgg gggcttcttc 120ttgaggatca ggtccgacgg aggtgtagat ggaatcaggg agaagagcga cgcccacata 180aagctccaaa tccaggcgac gtcggtgggg gaggtggtca tcaaaggagt ctgtgccaac 240cgctatctgg ccatgaacag agacggccgg ctgttcggag tgagacgggc gacggacgaa 300tgctacttcc tggagcggct ggagagtaac aactacaaca cctaccgctc caggaagtac 360cccggcatgt acgtggctct gaagcggacc ggccagtaca agtccgggag caaaaccgga 420cccggtcaaa aggccattct gttcctcccc atgtcggcta agtgctaa 468215468DNAFugu rubripes 215atggccacgg gagggatcac aacacttcca tccacacctg aagacggcgg cagcggcggt 60tttcctcccg ggagcttcaa ggatcccaaa aggctgtact gtaaaaacgg cggcttcttc 120ctgaggatca ggtccgacgg ggccgtggac ggaacccggg agaagactga cccccacata 180aagcttcagc tccaggcgac ctctgtgggg gaggtggtca tcaagggggt ttgtgctaat 240cgttatctgg ccatgaacag agatggacga ctgtttggaa tgaaacgagc gacggatgaa 300tgccacttct tagagcggct cgagagcaac aactacaaca cctaccgctc caggaagtac 360cccaacatgt ttgtgggact gacgcgaact ggcaactaca agtctgggac taaaactgga 420ccgggccaaa aggccatcct ctttcttccg atgtcggcca aatactaa 468216468DNARainbow trout 216atggccacag gagaaatcac cactctaccc gccacacctg aagatggagg cagtggcggc 60ttccttccag gaaactttaa ggagcccaag aggttgtact gtaaaaatgg aggctacttc 120ttgaggataa actctaacgg aagcgtggac gggatcagag ataagaacga cccccacaat 180aagcttcaac tccaggcgac ctcagtgggg gaagtagtaa tcaaaggggt ctcagccaac 240cgctatctgg ccatgaatgc agatggaaga ctgtttggac cgagacggac aacagatgaa 300tgctacttca tggagaggct ggagagtaac aactacaaca cctaccgctc tcgaaagtac 360cctgaaatgt atgtggcact gaaaaggact ggccagtaca agtcaggatc caaaactgga 420cccggccaaa aagccatcct cttcctcccc atgtcagcca gacgctga 468217453DNASalmon 217atggccacag gagaaatcac cactctaccc gccacacctg aagatggagg cagtggcggc 60ttccctccag gaaactttaa ggatcccaag aggctgtact gtaaaaacgg gggctacttc 120ttgagaataa actctaatgg aagcgtggac gggatccgag agaagaacga cccccacaaa 180cagcctcaat ttgtcagggc atggactctt caaggtgtca aacgttccac agggatgctg 240gcccatgttg actccaacgc ttcccacaat tgtgtcaagg tggctggatg ttctttggga 300gaatttggca gtatgtccaa ccggcctcat aaccgcagac cacgtgtagc tacaccagcc 360caggacctcc acatccggct tcttcatcta cgggatcgtc tgaaaccagc cacccgaaca 420gctgataaaa ctgaggagta tttctgtctg taa 453218465DNAZebrafish 218atggccaccg gagggatcac cacactcccg gccgctccgg acgccgaaaa cagcagcttt 60cccgcgggca gcttcaggga tcccaagcgc ctgtactgca aaaacggagg attcttcctg 120cggatcaacg cggacggccg agtggacgga gcccgagaca agagcgaccc gcacattcgt 180ctgcagctgc aggcgacggc agtgggtgaa gtactcatta aaggcatctg taccaaccgt 240ttccttgcca tgaacgcaga cggacgactg ttcgggacga aaaggaccac agatgaatgt 300tatttcctgg agcgcctgga gtccaacaac tacaacacat acagatcccg caagtatccc 360gactggtacg tggctctgaa gagaaccggc cagtataaaa gcggctctaa aaccagcccg 420ggacagaagg ccatcctgtt tctgcccatg tcggccaaat gctga 465219468DNANile tilapia 219atggccacgg gaggaatcac aacacttccc gctacacctg aagacggcgg cagcagcggc 60tttcctcctg ggaacttcaa ggaccctaaa aggctgtact gtaaaaatgg tggcttcttc 120ttgaggataa aatctgatgg aggagtggat ggaatacgag agaaaaacga cccccacata 180aagcttcaac tccaggcgac ctcagtggga gaagtggtca tcaaagggat ttgtgcaaac 240cgatatctgg caatgaacag agatggacga ctgtttggag cgagaagagc aacagatgag 300tgctacttct tagagcggct cgagagcaac aactacaaca cctaccgctc caggaagtac 360ccaaacatgt acgtggcgct gaagcggact ggccagtaca agtctggaag caaaactgga 420ccgggtcaaa aggcaattct ctttctccca atgtctgcta aatgctaa 468220468DNAMedaka 220atggctacgg gagaaatcac aacacttccc tccccagctg aaaacagcag aagcgatggc 60tttcctccag ggaactacaa ggatcctaag aggctctact gtaaaaatgg aggtttgttt 120ttgaggatta aacctgatgg aggagtggat ggaatccggg aaaaaaaaga tccccacgtt 180aagcttcgcc ttcaggctac ctcagcggga gaggtggtga tcaaaggagt ttgttcaaac 240agatatctgg cgatgcatgg agatggacgt ctatttggag tgagacaagc aacagaggaa 300tgctacttct tggagcgact agagagcaac aactataaca cctatcgctc taaaaagtac 360ccaaacatgt acgtggcact gaagcggaca ggccagtaca aacctggaaa caaaactgga 420ccaggtcaaa aggccattct ctttctgcct atgtctgcca agtactaa 468221206PRTHomo sapiens 221Met Ser Gly Pro Gly Thr Ala Ala Val Ala Leu Leu Pro Ala Val Leu 1 5 10 15 Leu Ala Leu Leu Ala Pro Trp Ala Gly Arg Gly Gly Ala Ala Ala Pro 20 25 30 Thr Ala Pro Asn Gly Thr Leu Glu Ala Glu Leu Glu Arg Arg Trp Glu 35 40 45 Ser Leu Val Ala Leu Ser Leu Ala Arg Leu Pro Val Ala Ala Gln Pro 50 55 60 Lys Glu Ala Ala Val Gln Ser Gly Ala Gly Asp Tyr Leu Leu Gly Ile 65 70 75 80 Lys Arg Leu Arg Arg Leu Tyr Cys Asn Val Gly Ile Gly Phe His Leu 85 90 95 Gln Ala Leu Pro Asp Gly Arg Ile Gly Gly Ala His Ala Asp Thr Arg 100 105 110 Asp Ser Leu Leu Glu Leu Ser Pro Val Glu Arg Gly Val Val Ser Ile 115 120 125 Phe Gly Val Ala Ser Arg Phe Phe Val Ala Met Ser Ser Lys Gly Lys 130 135 140 Leu Tyr Gly Ser Pro Phe Phe Thr Asp Glu Cys Thr Phe Lys Glu Ile 145 150 155 160 Leu Leu Pro Asn Asn Tyr Asn Ala Tyr Glu Ser Tyr Lys Tyr Pro Gly 165 170 175 Met Phe Ile Ala Leu Ser Lys Asn Gly Lys Thr Lys Lys Gly Asn Arg 180 185 190 Val Ser Pro Thr Met Lys Val Thr His Phe Leu Pro Arg Leu 195 200 205 222268PRTHomo sapiens 222Met Ser Leu Ser Phe Leu Leu Leu Leu Phe Phe Ser His Leu Ile Leu 1 5 10 15 Ser Ala Trp Ala His Gly Glu Lys Arg Leu Ala Pro Lys Gly Gln Pro 20 25 30 Gly Pro Ala Ala Thr Asp Arg Asn Pro Arg Gly Ser Ser Ser Arg Gln 35 40 45 Ser Ser Ser Ser Ala Met Ser Ser Ser Ser Ala Ser Ser Ser Pro Ala 50 55 60 Ala Ser Leu Gly Ser Gln Gly Ser Gly Leu Glu Gln Ser Ser Phe Gln 65 70 75 80 Trp Ser Pro Ser Gly Arg Arg Thr Gly Ser Leu Tyr Cys Arg Val Gly 85 90 95 Ile Gly Phe His Leu Gln Ile Tyr Pro Asp Gly Lys Val Asn Gly Ser 100 105 110 His Glu Ala Asn Met Leu Ser Val Leu Glu Ile Phe Ala Val Ser Gln 115 120 125 Gly Ile Val Gly Ile Arg Gly Val Phe Ser Asn Lys Phe Leu Ala Met 130 135 140 Ser Lys Lys Gly Lys Leu His Ala Ser Ala Lys Phe Thr Asp Asp Cys 145 150 155 160 Lys Phe Arg Glu Arg Phe Gln Glu Asn Ser Tyr Asn Thr Tyr Ala Ser 165 170 175 Ala Ile His Arg Thr Glu Lys Thr Gly Arg Glu Trp Tyr Val Ala Leu 180 185 190 Asn Lys Arg Gly Lys Ala Lys Arg Gly Cys Ser Pro Arg Val Lys Pro 195 200 205 Gln His Ile Ser Thr His Phe Leu Pro Arg Phe Lys Gln Ser Glu Gln 210 215 220 Pro Glu Leu Ser Phe Thr Val Thr Val Pro Glu Lys Lys Lys Pro Pro 225 230 235 240 Ser Pro Ile Lys Pro Lys Ile Pro Leu Ser Ala Pro Arg Lys Asn Thr 245 250 255 Asn Ser Val Lys Tyr Arg Leu Lys Phe Arg Phe Gly 260 265 223208PRTHomo sapiens 223Met Ala Leu Gly Gln Lys Leu Phe Ile Thr Met Ser Arg Gly Ala Gly 1 5 10 15 Arg Leu Gln Gly Thr Leu Trp Ala Leu Val Phe Leu Gly Ile Leu Val 20 25 30 Gly Met Val Val Pro Ser Pro Ala Gly Thr Arg Ala Asn Asn Thr Leu 35 40 45 Leu Asp Ser Arg Gly Trp Gly Thr Leu Leu Ser Arg Ser Arg Ala Gly 50 55 60 Leu Ala Gly Glu Ile Ala Gly Val Asn Trp Glu Ser Gly Tyr Leu Val 65 70 75 80 Gly Ile Lys Arg Gln Arg Arg Leu Tyr Cys Asn Val Gly Ile Gly Phe 85 90 95 His Leu Gln Val Leu Pro Asp Gly Arg Ile Ser Gly Thr His Glu Glu 100

105 110 Asn Pro Tyr Ser Leu Leu Glu Ile Ser Thr Val Glu Arg Gly Val Val 115 120 125 Ser Leu Phe Gly Val Arg Ser Ala Leu Phe Val Ala Met Asn Ser Lys 130 135 140 Gly Arg Leu Tyr Ala Thr Pro Ser Phe Gln Glu Glu Cys Lys Phe Arg 145 150 155 160 Glu Thr Leu Leu Pro Asn Asn Tyr Asn Ala Tyr Glu Ser Asp Leu Tyr 165 170 175 Gln Gly Thr Tyr Ile Ala Leu Ser Lys Tyr Gly Arg Val Lys Arg Gly 180 185 190 Ser Lys Val Ser Pro Ile Met Thr Val Thr His Phe Leu Pro Arg Ile 195 200 205 224208PRTHomo sapiens 224Met Ala Pro Leu Gly Glu Val Gly Asn Tyr Phe Gly Val Gln Asp Ala 1 5 10 15 Val Pro Phe Gly Asn Val Pro Val Leu Pro Val Asp Ser Pro Val Leu 20 25 30 Leu Ser Asp His Leu Gly Gln Ser Glu Ala Gly Gly Leu Pro Arg Gly 35 40 45 Pro Ala Val Thr Asp Leu Asp His Leu Lys Gly Ile Leu Arg Arg Arg 50 55 60 Gln Leu Tyr Cys Arg Thr Gly Phe His Leu Glu Ile Phe Pro Asn Gly 65 70 75 80 Thr Ile Gln Gly Thr Arg Lys Asp His Ser Arg Phe Gly Ile Leu Glu 85 90 95 Phe Ile Ser Ile Ala Val Gly Leu Val Ser Ile Arg Gly Val Asp Ser 100 105 110 Gly Leu Tyr Leu Gly Met Asn Glu Lys Gly Glu Leu Tyr Gly Ser Glu 115 120 125 Lys Leu Thr Gln Glu Cys Val Phe Arg Glu Gln Phe Glu Glu Asn Trp 130 135 140 Tyr Asn Thr Tyr Ser Ser Asn Leu Tyr Lys His Val Asp Thr Gly Arg 145 150 155 160 Arg Tyr Tyr Val Ala Leu Asn Lys Asp Gly Thr Pro Arg Glu Gly Thr 165 170 175 Arg Thr Lys Arg His Gln Lys Phe Thr His Phe Leu Pro Arg Pro Val 180 185 190 Asp Pro Asp Lys Val Pro Glu Leu Tyr Lys Asp Ile Leu Ser Gln Ser 195 200 205 225207PRTHomo sapiens 225 Met Ala Glu Val Gly Gly Val Phe Ala Ser Leu Asp Trp Asp Leu His 1 5 10 15 Gly Phe Ser Ser Ser Leu Gly Asn Val Pro Leu Ala Asp Ser Pro Gly 20 25 30 Phe Leu Asn Glu Arg Leu Gly Gln Ile Glu Gly Lys Leu Gln Arg Gly 35 40 45 Ser Pro Thr Asp Phe Ala His Leu Lys Gly Ile Leu Arg Arg Arg Gln 50 55 60 Leu Tyr Cys Arg Thr Gly Phe His Leu Glu Ile Phe Pro Asn Gly Thr 65 70 75 80 Val His Gly Thr Arg His Asp His Ser Arg Phe Gly Ile Leu Glu Phe 85 90 95 Ile Ser Leu Ala Val Gly Leu Ile Ser Ile Arg Gly Val Asp Ser Gly 100 105 110 Leu Tyr Leu Gly Met Asn Glu Arg Gly Glu Leu Tyr Gly Ser Lys Lys 115 120 125 Leu Thr Arg Glu Cys Val Phe Arg Glu Gln Phe Glu Glu Asn Trp Tyr 130 135 140 Asn Thr Tyr Ala Ser Thr Leu Tyr Lys His Ser Asp Ser Glu Arg Gln 145 150 155 160 Tyr Tyr Val Ala Leu Asn Lys Asp Gly Ser Pro Arg Glu Gly Tyr Arg 165 170 175 Thr Lys Arg His Gln Lys Phe Thr His Phe Leu Pro Arg Pro Val Asp 180 185 190 Pro Ser Lys Leu Pro Ser Met Ser Arg Asp Leu Phe His Tyr Arg 195 200 205 226211PRTHomo sapiens 226Met Ala Pro Leu Ala Glu Val Gly Gly Phe Leu Gly Gly Leu Glu Gly 1 5 10 15 Leu Gly Gln Gln Val Gly Ser His Phe Leu Leu Pro Pro Ala Gly Glu 20 25 30 Arg Pro Pro Leu Leu Gly Glu Arg Arg Ser Ala Ala Glu Arg Ser Ala 35 40 45 Arg Gly Gly Pro Gly Ala Ala Gln Leu Ala His Leu His Gly Ile Leu 50 55 60 Arg Arg Arg Gln Leu Tyr Cys Arg Thr Gly Phe His Leu Gln Ile Leu 65 70 75 80 Pro Asp Gly Ser Val Gln Gly Thr Arg Gln Asp His Ser Leu Phe Gly 85 90 95 Ile Leu Glu Phe Ile Ser Val Ala Val Gly Leu Val Ser Ile Arg Gly 100 105 110 Val Asp Ser Gly Leu Tyr Leu Gly Met Asn Asp Lys Gly Glu Leu Tyr 115 120 125 Gly Ser Glu Lys Leu Thr Ser Glu Cys Ile Phe Arg Glu Gln Phe Glu 130 135 140 Glu Asn Trp Tyr Asn Thr Tyr Ser Ser Asn Ile Tyr Lys His Gly Asp 145 150 155 160 Thr Gly Arg Arg Tyr Phe Val Ala Leu Asn Lys Asp Gly Thr Pro Arg 165 170 175 Asp Gly Ala Arg Ser Lys Arg His Gln Lys Phe Thr His Phe Leu Pro 180 185 190 Arg Pro Val Asp Pro Glu Arg Val Pro Glu Leu Tyr Lys Asp Leu Leu 195 200 205 Met Tyr Thr 210 227621DNAHomo sapiens 227atgtcggggc ccgggacggc cgcggtagcg ctgctcccgg cggtcctgct ggccttgctg 60gcgccctggg cgggccgagg gggcgccgcc gcacccactg cacccaacgg cacgctggag 120gccgagctgg agcgccgctg ggagagcctg gtggcgctct cgttggcgcg cctgccggtg 180gcagcgcagc ccaaggaggc ggccgtccag agcggcgccg gcgactacct gctgggcatc 240aagcggctgc ggcggctcta ctgcaacgtg ggcatcggct tccacctcca ggcgctcccc 300gacggccgca tcggcggcgc gcacgcggac acccgcgaca gcctgctgga gctctcgccc 360gtggagcggg gcgtggtgag catcttcggc gtggccagcc ggttcttcgt ggccatgagc 420agcaagggca agctctatgg ctcgcccttc ttcaccgatg agtgcacgtt caaggagatt 480ctccttccca acaactacaa cgcctacgag tcctacaagt accccggcat gttcatcgcc 540ctgagcaaga atgggaagac caagaagggg aaccgagtgt cgcccaccat gaaggtcacc 600cacttcctcc ccaggctgtg a 621228807DNAHomo sapiens 228atgagcttgt ccttcctcct cctcctcttc ttcagccacc tgatcctcag cgcctgggct 60cacggggaga agcgtctcgc ccccaaaggg caacccggac ccgctgccac tgataggaac 120cctagaggct ccagcagcag acagagcagc agtagcgcta tgtcttcctc ttctgcctcc 180tcctcccccg cagcttctct gggcagccaa ggaagtggct tggagcagag cagtttccag 240tggagcccct cggggcgccg gaccggcagc ctctactgca gagtgggcat cggtttccat 300ctgcagatct acccggatgg caaagtcaat ggatcccacg aagccaatat gttaagtgtt 360ttggaaatat ttgctgtgtc tcaggggatt gtaggaatac gaggagtttt cagcaacaaa 420tttttagcga tgtcaaaaaa aggaaaactc catgcaagtg ccaagttcac agatgactgc 480aagttcaggg agcgttttca agaaaatagc tataatacct atgcctcagc aatacataga 540actgaaaaaa cagggcggga gtggtatgtg gccctgaata aaagaggaaa agccaaacga 600gggtgcagcc cccgggttaa accccagcat atctctaccc attttctgcc aagattcaag 660cagtcggagc agccagaact ttctttcacg gttactgttc ctgaaaagaa aaagccacct 720agccctatca agccaaagat tcccctttct gcacctcgga aaaataccaa ctcagtgaaa 780tacagactca agtttcgctt tggataa 807229627DNAHomo sapiens 229atggccctgg gacagaaact gttcatcact atgtcccggg gagcaggacg tctgcagggc 60acgctgtggg ctctcgtctt cctaggcatc ctagtgggca tggtggtgcc ctcgcctgca 120ggcacccgtg ccaacaacac gctgctggac tcgaggggct ggggcaccct gctgtccagg 180tctcgcgcgg ggctagctgg agagattgcc ggggtgaact gggaaagtgg ctatttggtg 240gggatcaagc ggcagcggag gctctactgc aacgtgggca tcggctttca cctccaggtg 300ctccccgacg gccggatcag cgggacccac gaggagaacc cctacagcct gctggaaatt 360tccactgtgg agcgaggcgt ggtgagtctc tttggagtga gaagtgccct cttcgttgcc 420atgaacagta aaggaagatt gtacgcaacg cccagcttcc aagaagaatg caagttcaga 480gaaaccctcc tgcccaacaa ttacaatgcc tacgagtcag acttgtacca agggacctac 540attgccctga gcaaatacgg acgggtaaag cggggcagca aggtgtcccc gatcatgact 600gtcactcatt tccttcccag gatctaa 627230627DNAHomo sapiens 230atggctccct taggtgaagt tgggaactat ttcggtgtgc aggatgcggt accgtttggg 60aatgtgcccg tgttgccggt ggacagcccg gttttgttaa gtgaccacct gggtcagtcc 120gaagcagggg ggctccccag gggacccgca gtcacggact tggatcattt aaaggggatt 180ctcaggcgga ggcagctata ctgcaggact ggatttcact tagaaatctt ccccaatggt 240actatccagg gaaccaggaa agaccacagc cgatttggca ttctggaatt tatcagtata 300gcagtgggcc tggtcagcat tcgaggcgtg gacagtggac tctacctcgg gatgaatgag 360aagggggagc tgtatggatc agaaaaacta acccaagagt gtgtattcag agaacagttc 420gaagaaaact ggtataatac gtactcatca aacctatata agcacgtgga cactggaagg 480cgatactatg ttgcattaaa taaagatggg accccgagag aagggactag gactaaacgg 540caccagaaat tcacacattt tttacctaga ccagtggacc ccgacaaagt acctgaactg 600tataaggata ttctaagcca aagttga 627231624DNAHomo sapiens 231atggcagagg tggggggcgt cttcgcctcc ttggactggg atctacacgg cttctcctcg 60tctctgggga acgtgccctt agctgactcc ccaggtttcc tgaacgagcg cctgggccaa 120atcgagggga agctgcagcg tggctcaccc acagacttcg cccacctgaa ggggatcctg 180cggcgccgcc agctctactg ccgcaccggc ttccacctgg agatcttccc caacggcacg 240gtgcacggga cccgccacga ccacagccgc ttcggaatcc tggagtttat cagcctggct 300gtggggctga tcagcatccg gggagtggac tctggcctgt acctaggaat gaatgagcga 360ggagaactct atgggtcgaa gaaactcaca cgtgaatgtg ttttccggga acagtttgaa 420gaaaactggt acaacaccta tgcctcaacc ttgtacaaac attcggactc agagagacag 480tattacgtgg ccctgaacaa agatggctca ccccgggagg gatacaggac taaacgacac 540cagaaattca ctcacttttt acccaggcct gtagatcctt ctaagttgcc ctccatgtcc 600agagacctct ttcactatag gtaa 624232636DNAHomo sapiens 232atggctccct tagccgaagt cgggggcttt ctgggcggcc tggagggctt gggccagcag 60gtgggttcgc atttcctgtt gcctcctgcc ggggagcggc cgccgctgct gggcgagcgc 120aggagcgcgg cggagcggag cgcgcgcggc gggccggggg ctgcgcagct ggcgcacctg 180cacggcatcc tgcgccgccg gcagctctat tgccgcaccg gcttccacct gcagatcctg 240cccgacggca gcgtgcaggg cacccggcag gaccacagcc tcttcggtat cttggaattc 300atcagtgtgg cagtgggact ggtcagtatt agaggtgtgg acagtggtct ctatcttgga 360atgaatgaca aaggagaact ctatggatca gagaaactta cttccgaatg catctttagg 420gagcagtttg aagagaactg gtataacacc tattcatcta acatatataa acatggagac 480actggccgca ggtattttgt ggcacttaac aaagacggaa ctccaagaga tggcgccagg 540tccaagaggc atcagaaatt tacacatttc ttacctagac cagtggatcc agaaagagtt 600ccagaattgt acaaggacct actgatgtac acttga 636233209PRTHomo sapiens 233Met Asp Ser Asp Glu Thr Gly Phe Glu His Ser Gly Leu Trp Val Ser 1 5 10 15 Val Leu Ala Gly Leu Leu Leu Gly Ala Cys Gln Ala His Pro Ile Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr 35 40 45 Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg 50 55 60 Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu 65 70 75 80 Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val 85 90 95 Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly 100 105 110 Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu 115 120 125 Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu 130 135 140 His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly 145 150 155 160 Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu 165 170 175 Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp 180 185 190 Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala 195 200 205 Ser 234209PRTPongo abelii 234Met Asp Ser Asp Glu Thr Gly Phe Glu His Ser Gly Leu Trp Val Pro 1 5 10 15 Val Leu Ala Gly Leu Leu Leu Gly Ala Cys Gln Ala His Pro Ile Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr 35 40 45 Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg 50 55 60 Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu 65 70 75 80 Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val 85 90 95 Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly 100 105 110 Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu 115 120 125 Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu 130 135 140 His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly 145 150 155 160 Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Pro Pro Glu 165 170 175 Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp 180 185 190 Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala 195 200 205 Ser 235209PRTPan troglodytes 235Met Asp Ser Asp Glu Thr Gly Phe Glu His Ser Gly Leu Trp Val Ser 1 5 10 15 Val Leu Ala Gly Leu Leu Leu Gly Ala Cys Gln Ala His Pro Ile Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr 35 40 45 Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg 50 55 60 Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu 65 70 75 80 Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val 85 90 95 Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly 100 105 110 Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu 115 120 125 Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu 130 135 140 His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly 145 150 155 160 Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Pro Pro Glu 165 170 175 Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp 180 185 190 Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr Thr 195 200 205 Ser 236209PRTCanis lupus familiaris 236Met Gly Trp Ala Glu Ala Gly Phe Glu His Leu Gly Leu Trp Val Pro 1 5 10 15 Val Leu Ala Val Leu Leu Leu Glu Ala Cys Arg Ala His Pro Ile Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr 35 40 45 Leu Tyr Thr Asp Asp Ala Gln Glu Thr Glu Ala His Leu Glu Ile Arg 50 55 60 Ala Asp Gly Thr Val Val Gly Ala Ala Arg Gln Ser Pro Glu Ser Leu 65 70 75 80 Leu Glu Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val 85 90 95 Lys Thr Ser Arg Phe Leu Cys Gln Gly Pro Asp Gly Thr Leu Tyr Gly 100 105 110 Ser Leu His Phe Asp Pro Val Ala Cys Ser Phe Arg Glu Leu Leu Leu 115 120 125 Glu Asp Gly Tyr Asn Ile Tyr His Ser Glu Thr Leu Gly Leu Pro Leu 130 135 140 Arg Leu Arg Pro His Asn Ser Ala Tyr Arg Asp Leu Ala Pro Arg Gly 145 150 155 160 Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Leu Pro Ala Pro Pro Glu 165 170 175 Pro Pro Gly Ile Leu Ala Pro Glu Pro Pro Asp Val Gly Ser Ser Asp 180 185 190 Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala 195 200 205 Ser 237209PRTBos taurus 237Met Gly Trp Asp Glu Ala Lys Phe Lys His Leu Gly Leu Trp Val Pro 1 5 10 15 Val Leu Ala Val Leu Leu Leu Gly Thr Cys Arg Ala His Pro Ile Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr 35 40 45 Leu Tyr Thr Asp Asp Ala Gln Glu Thr Glu Ala His Leu Glu Ile Arg 50 55 60

Ala Asp Gly Thr Val Val Gly Ala Ala Arg Gln Ser Pro Glu Ser Leu 65 70 75 80 Leu Glu Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val 85 90 95 Lys Thr Ser Arg Phe Leu Cys Gln Gly Pro Asp Gly Lys Leu Tyr Gly 100 105 110 Ser Leu His Phe Asp Pro Lys Ala Cys Ser Phe Arg Glu Leu Leu Leu 115 120 125 Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Thr Leu Gly Leu Pro Leu 130 135 140 Arg Leu Pro Pro Gln Arg Ser Ser Asn Arg Asp Pro Ala Pro Arg Gly 145 150 155 160 Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Ala Ala Pro Pro Asp 165 170 175 Pro Pro Gly Ile Leu Ala Pro Glu Pro Pro Asp Val Gly Ser Ser Asp 180 185 190 Pro Leu Ser Met Val Gly Pro Ser Tyr Gly Arg Ser Pro Ser Tyr Thr 195 200 205 Ser 238209PRTEquus caballus 238Met Asp Trp Asp Lys Thr Gly Phe Lys Tyr Gln Gly Leu Trp Val Pro 1 5 10 15 Val Leu Ala Val Leu Leu Leu Gly Ala Cys Gln Ser His Pro Ile Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg His 35 40 45 Leu Tyr Thr Asp Asp Ala Gln Glu Thr Glu Ala His Leu Glu Ile Arg 50 55 60 Ala Asp Gly Thr Val Ala Gly Ala Val His Arg Ser Pro Glu Ser Leu 65 70 75 80 Leu Glu Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val 85 90 95 Lys Thr Ser Arg Phe Leu Cys Gln Gly Pro Asp Gly Thr Leu Tyr Gly 100 105 110 Ser Leu His Phe Asp Pro Val Ala Cys Ser Phe Arg Glu Leu Leu Leu 115 120 125 Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Thr Leu Gly Leu Pro Leu 130 135 140 Arg Leu Pro His His Ser Ser Pro Tyr Gln Asp Pro Ala Pro Arg Ala 145 150 155 160 Pro Ala Arg Phe Leu Pro Leu Pro Gly Phe Pro Pro Ala Pro Pro Glu 165 170 175 Pro Pro Gly Ile Pro Ala Pro Glu Pro Pro Asp Val Gly Ser Ser Asp 180 185 190 Pro Leu Ser Met Val Gly Pro Ser Arg Ser Arg Ser Pro Ser Tyr Thr 195 200 205 Ser 239209PRTAiluropoda melanoleuca 239Met Gly Trp Asp Glu Ala Arg Ser Glu Gln Leu Gly Leu Trp Val Pro 1 5 10 15 Val Leu Ala Val Leu Leu Leu Glu Ala Cys Gln Ala His Pro Ile Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr 35 40 45 Leu Tyr Thr Asp Asp Ala Gln Glu Thr Glu Ala His Leu Ala Ile Arg 50 55 60 Ala Asp Gly Thr Val Val Gly Ala Ala Ser Arg Ser Pro Glu Ser Leu 65 70 75 80 Leu Glu Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val 85 90 95 Lys Thr Ser Arg Phe Leu Cys Gln Gly Pro Asp Gly Thr Leu Tyr Gly 100 105 110 Ser Val Arg Phe Asp Pro Val Ala Cys Ser Phe Arg Glu Leu Leu Leu 115 120 125 Glu Asp Gly Tyr Asn Ile Tyr His Ser Glu Thr Leu Gly Leu Pro Leu 130 135 140 Arg Leu Pro Ala His Asn Ser Pro Tyr Arg Asp Ser Ala Pro Arg Gly 145 150 155 160 Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Leu Pro Val Pro Pro Asp 165 170 175 Pro Pro Gly Ile Leu Gly Pro Glu Pro Pro Asp Val Gly Ser Ser Asp 180 185 190 Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala 195 200 205 Ser 240209PRTOryctolagus cuniculus 240Met Asp Trp Gly Lys Ala Lys Cys Arg Pro Pro Gly Leu Trp Val Pro 1 5 10 15 Ala Leu Ala Ala Leu Leu Leu Gly Ala Cys Gln Ala His Pro Ile Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Asp Gln Val Arg Gln Gln His 35 40 45 Leu Tyr Thr Asp Asp Ala Gln Glu Thr Glu Ala His Leu Glu Ile Arg 50 55 60 Ala Asp Gly Thr Val Val Gly Ala Ala Arg Arg Ser Pro Glu Ser Leu 65 70 75 80 Leu Gln Met Lys Ala Leu Gln Pro Gly Ile Ile Gln Ile Leu Gly Val 85 90 95 Gln Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Thr Leu Tyr Gly 100 105 110 Ser Leu His Phe Asp Arg Glu Ala Cys Ser Phe Arg Glu Leu Leu Arg 115 120 125 Glu Asp Gly Tyr Asn Val Tyr Leu Ser Glu Ala Leu Gly Leu Pro Leu 130 135 140 Arg Leu Ser Pro Gly Ser Ser Pro Arg Arg Ala Pro Ala Pro Arg Gly 145 150 155 160 Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Asp Leu Pro Glu 165 170 175 Pro Pro Gly Leu Leu Ala Ala Ala Pro Pro Asp Val Asp Ser Pro Asp 180 185 190 Pro Leu Ser Met Val Gln Pro Ala Leu Asp Gln Ser Pro Ser Tyr Thr 195 200 205 Ser 241209PRTGorilla gorilla 241Met Asp Ser Asp Glu Thr Gly Phe Glu His Ser Gly Leu Trp Val Ser 1 5 10 15 Val Leu Ala Gly Leu Leu Leu Gly Ala Cys Gln Ala His Pro Ile Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr 35 40 45 Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg 50 55 60 Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu 65 70 75 80 Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val 85 90 95 Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly 100 105 110 Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu 115 120 125 Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu 130 135 140 His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly 145 150 155 160 Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Pro Pro Glu 165 170 175 Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp 180 185 190 Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala 195 200 205 Ser 242209PRTNomascus leucogenys 242Met Asp Ser Asp Glu Thr Gly Phe Glu His Ser Gly Leu Trp Val Pro 1 5 10 15 Val Leu Ala Gly Leu Leu Leu Gly Ala Cys Gln Ala His Pro Ile Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr 35 40 45 Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg 50 55 60 Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu 65 70 75 80 Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val 85 90 95 Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly 100 105 110 Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu 115 120 125 Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu 130 135 140 His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly 145 150 155 160 Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Pro Pro Glu 165 170 175 Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp 180 185 190 Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala 195 200 205 Ser 243209PRTProcavia capensis 243Met Asp Trp Ala Lys Phe Gly Ile Glu His Pro Gly Leu Trp Val Pro 1 5 10 15 Val Met Ala Val Leu Leu Leu Gly Ala Cys Gln Gly Tyr Pro Ile Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr 35 40 45 Leu Tyr Thr Asp Asp Ala Gln Glu Thr Glu Ala His Leu Glu Ile Arg 50 55 60 Ala Asp Gly Thr Val Val Gly Ala Ala His Arg Ser Pro Glu Ser Leu 65 70 75 80 Leu Glu Leu Lys Ala Leu Lys Pro Gly Ile Ile Gln Ile Leu Gly Val 85 90 95 Lys Thr Ser Arg Phe Leu Cys Gln Gly Pro Asp Gly Val Leu Tyr Gly 100 105 110 Ser Leu Arg Phe Asp Pro Val Ala Cys Ser Phe Arg Glu Leu Leu Leu 115 120 125 Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu 130 135 140 Arg Leu Pro Ser His Asn Ser Pro Gln Arg Asp Leu Ala Ser Arg Val 145 150 155 160 Pro Ala Arg Phe Leu Pro Leu Pro Gly Arg Leu Thr Val Leu Pro Glu 165 170 175 Pro Ser Gly Val Leu Gly Pro Glu Pro Pro Asp Val Asp Ser Ser Asp 180 185 190 Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala 195 200 205 Ser 244209PRTCavia porcellus 244Met Asp Trp Ala Arg Thr Glu Cys Glu Arg Pro Arg Leu Trp Val Ser 1 5 10 15 Met Leu Ala Ile Leu Leu Val Gly Ala Cys Gln Ala His Pro Ile Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr 35 40 45 Leu Tyr Thr Asp Asp Ala Gln Asp Thr Glu Val His Leu Glu Ile Arg 50 55 60 Ala Asp Gly Ser Val Arg Gly Ile Ala His Arg Ser Pro Glu Ser Leu 65 70 75 80 Leu Glu Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Ile 85 90 95 Arg Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ser Leu Tyr Gly 100 105 110 Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu 115 120 125 Ala Asp Gly Tyr Asn Val Tyr Lys Ser Glu Ala His Gly Leu Pro Leu 130 135 140 His Leu Leu Arg Gly Asp Ser Leu Ser Gln Glu Pro Ala Pro Pro Gly 145 150 155 160 Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Ala Thr Pro Pro Glu 165 170 175 Pro Pro Arg Met Leu Pro Pro Gly Pro Pro Asp Val Gly Ser Ser Asp 180 185 190 Pro Leu Ser Met Val Gly Pro Leu Trp Asp Arg Ser Pro Ser Tyr Thr 195 200 205 Ser 245209PRTTupaia belangeri 245Met Gly Trp Asp Lys Ala Arg Phe Glu His Leu Gly Ala Trp Ala Pro 1 5 10 15 Val Leu Ala Val Leu Leu Leu Gly Ala Cys Gln Ala Tyr Pro Ile Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr 35 40 45 Leu Tyr Thr Asp Asp Thr Gln Asp Thr Glu Ala His Leu Glu Ile Arg 50 55 60 Ala Asp Gly Thr Val Val Gly Ala Ala His Gln Ser Pro Glu Ser Leu 65 70 75 80 Leu Glu Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val 85 90 95 Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly 100 105 110 Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu 115 120 125 Glu Asp Gly Tyr Asn Ile Tyr Gln Ser Glu Ala Arg Gly Leu Pro Leu 130 135 140 Arg Leu Pro Pro His Asp Ser Pro His Arg Asp Arg Thr Pro Arg Gly 145 150 155 160 Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Leu Val Pro Pro Glu 165 170 175 Leu Pro Gly Val Leu Ala Leu Glu Pro Pro Asp Val Gly Ser Ser Asp 180 185 190 Pro Leu Ser Met Met Gly Pro Ser Gln Gly Gln Ser Pro Ser Tyr Ala 195 200 205 Ser 246210PRTSorex araneus 246Met Val Trp Asp Lys Ala Arg Gly Gln Gln Leu Gly Leu Trp Ala Pro 1 5 10 15 Met Leu Leu Gly Leu Leu Leu Gly Ala Cys Gln Ala His Pro Leu Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Leu Arg Phe 35 40 45 Leu Tyr Thr Asp Asp Ala Gln Arg Thr Gly Ala His Leu Glu Ile Arg 50 55 60 Ala Asp Gly Thr Val Gln Gly Ala Ala His Arg Thr Pro Glu Cys Leu 65 70 75 80 Leu Glu Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val 85 90 95 Ser Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Val Leu Tyr Gly 100 105 110 Ser Leu Arg Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu 115 120 125 Gln Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala Leu Gly Leu Pro Leu 130 135 140 Tyr Leu His Pro Pro Ser Ala Pro Val Ser Gln Glu Pro Ala Ser Arg 145 150 155 160 Gly Ala Val Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Ser Leu 165 170 175 Glu Pro Pro Arg Pro Pro Ala Pro Val Pro Pro Asp Val Gly Ser Ser 180 185 190 Asp Pro Leu Ser Met Val Gly Pro Pro Glu Arg His Ser Pro Ser Tyr 195 200 205 Thr Ser 210 247208PRTIctidomys tridecemlineatus 247Met Asp Trp Val Lys Ala Lys Leu Glu Pro Leu Gly Leu Trp Val Leu 1 5 10 15 Val Leu Ala Ala Leu Val Leu Gly Ala Cys Gln Ala Tyr Pro Ile Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr 35 40 45 Leu Tyr Thr Asp Asp Ala Gln Glu Thr Glu Ala His Leu Glu Ile Arg 50 55 60 Ala Asp Gly Thr Val Val Gly Ala Ala His Gln Ser Pro Glu Ser Leu 65 70 75 80 Leu Glu Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val 85 90 95 Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Val Leu Tyr Gly 100 105 110 Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Gln Leu Leu 115 120 125 Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ser His Gly Leu Pro Val 130 135 140 Arg Leu Pro Pro Asn Ser Pro Tyr Arg Asp Pro Ala Pro Pro Gly Pro 145 150 155 160 Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Ala Leu Glu Pro 165 170 175 Pro Gly Ile Leu Gly Pro Glu Pro Pro Asp Val Gly Ser Ser Asp Pro 180 185 190 Leu Ser Met Val Gly Pro Leu Gln Gly Arg Ser Pro Ser Tyr Ala Ser 195 200 205 248208PRTLoxodonta africana 248Met Asp Trp Ala Lys Phe Gly Leu Glu His Pro Gly Leu Trp Val Pro 1 5 10 15 Val Met Ala Val Leu Leu Leu Gly Ala Cys Gln Gly His Pro Ile Pro 20 25 30 Asp

Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr 35 40 45 Leu Tyr Thr Asp Asp Gln Glu Thr Glu Ala His Leu Glu Ile Arg Ala 50 55 60 Asp Gly Thr Val Ala Gly Ala Ala His Arg Ser Ser Glu Ser Leu Leu 65 70 75 80 Glu Leu Lys Ala Leu Lys Pro Gly Ile Ile Gln Ile Leu Gly Val Lys 85 90 95 Thr Ser Arg Phe Leu Cys Gln Gly Pro Asp Gly Val Leu Tyr Gly Ser 100 105 110 Leu His Phe Asp Pro Ala Ala Cys Ser Phe Arg Glu Leu Leu Leu Glu 115 120 125 Asp Gly Tyr Asn Val Tyr Trp Ser Glu Ala His Gly Leu Pro Ile Arg 130 135 140 Leu Pro Ser His Asn Ser Pro Tyr Arg Asp Pro Ala Ser Arg Val Pro 145 150 155 160 Ala Arg Phe Leu Pro Leu Pro Gly Leu Leu Pro Met Leu Gln Glu Pro 165 170 175 Pro Gly Val Leu Ala Pro Glu Pro Pro Asp Val Asp Ser Ser Asp Pro 180 185 190 Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 195 200 205 249208PRTSus scrofa 249Met Gly Trp Ala Glu Ala Lys Phe Glu Arg Leu Gly Leu Trp Val Pro 1 5 10 15 Val Leu Ala Val Leu Leu Gly Ala Cys Gln Ala Arg Pro Ile Pro Asp 20 25 30 Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu 35 40 45 Tyr Thr Asp Asp Ala Gln Glu Thr Glu Ala His Leu Glu Ile Arg Ala 50 55 60 Asp Gly Thr Val Ala Gly Val Ala Arg Gln Ser Pro Glu Ser Leu Leu 65 70 75 80 Glu Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Gln 85 90 95 Thr Ser Arg Phe Leu Cys Gln Gly Pro Asp Gly Arg Leu Tyr Gly Ser 100 105 110 Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu Glu 115 120 125 Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala Leu Gly Leu Pro Leu Arg 130 135 140 Leu Pro Pro His Arg Ser Ser Asn Arg Asp Leu Ala Pro Arg Gly Pro 145 150 155 160 Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Pro Pro Glu Pro 165 170 175 Pro Gly Ile Leu Ala Pro Glu Pro Pro Asp Val Gly Ser Ser Asp Pro 180 185 190 Leu Ser Met Val Gly Pro Ser His Gly Arg Ser Pro Ser Tyr Thr Ser 195 200 205 250208PRTFelis catus 250Met Asp Trp Asp Glu Ala Gly Ser Gln Arg Leu Gly Leu Trp Val Val 1 5 10 15 Leu Gly Val Leu Leu Pro Glu Ala Cys Gln Ala His Pro Ile Pro Asp 20 25 30 Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Phe Leu 35 40 45 Tyr Thr Asp Asp Ala Gln Glu Thr Glu Val His Leu Glu Ile Lys Ala 50 55 60 Asp Gly Thr Val Val Gly Thr Ala Arg Arg Ser Pro Glu Ser Leu Leu 65 70 75 80 Glu Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys 85 90 95 Thr Ser Arg Phe Leu Cys Gln Gly Pro Asp Gly Thr Leu Tyr Gly Ser 100 105 110 Leu Arg Phe Asp Pro Ala Ala Cys Ser Phe Arg Glu Leu Leu Leu Glu 115 120 125 Asp Gly Tyr Asn Ile Tyr His Ser Glu Thr Leu Gly Leu Pro Leu Arg 130 135 140 Leu Pro Pro His Asn Ser Pro Tyr Arg Asp Leu Ala Pro Arg Ala Pro 145 150 155 160 Ala Arg Phe Leu Pro Leu Pro Gly Leu Leu Pro Ala Pro Pro Glu Pro 165 170 175 Pro Gly Ile Leu Ala Pro Glu Pro Pro Asp Val Gly Ser Ser Asp Pro 180 185 190 Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 195 200 205 251208PRTOtolemur garnettii 251Asp Lys Ala Arg Thr Gly Phe Lys His Pro Gly Pro Trp Phe Pro Leu 1 5 10 15 Leu Ala Val Leu Leu Leu Gly Ala Cys Gln Ala His Pro Ile Pro Asp 20 25 30 Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu 35 40 45 Tyr Thr Asp Asp Ala Gln Glu Thr Glu Ala His Leu Glu Ile Arg Glu 50 55 60 Asp Gly Thr Val Val Gly Ala Ala Gln Gln Ser Pro Glu Ser Leu Leu 65 70 75 80 Glu Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val Lys 85 90 95 Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Gly Leu Tyr Gly Ser 100 105 110 Leu Tyr Phe Asp Pro Lys Ala Cys Ser Phe Arg Glu Leu Leu Leu Glu 115 120 125 Asp Gly Tyr Asn Val Tyr Trp Ser Glu Thr Tyr Gly Leu Pro Leu His 130 135 140 Leu Pro Pro Ala Asn Ser Pro Tyr Trp Gly Pro Ser Leu Arg Ser Pro 145 150 155 160 Ala Arg Phe Leu Pro Leu Pro Gly Pro Pro Ala Ala Ser Pro Glu Leu 165 170 175 Pro Gly Ile Leu Ala Leu Glu Pro Pro Asp Val Gly Ser Ser Asp Pro 180 185 190 Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 195 200 205 252208PRTRattus norvegicus 252Met Asp Trp Met Lys Ser Arg Val Gly Ala Pro Gly Leu Trp Val Cys 1 5 10 15 Leu Leu Leu Pro Val Phe Leu Leu Gly Val Cys Glu Ala Tyr Pro Ile 20 25 30 Ser Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg 35 40 45 Tyr Leu Tyr Thr Asp Asp Asp Gln Asp Thr Glu Ala His Leu Glu Ile 50 55 60 Arg Glu Asp Gly Thr Val Val Gly Thr Ala His Arg Ser Pro Glu Ser 65 70 75 80 Leu Leu Glu Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly 85 90 95 Val Lys Ala Ser Arg Phe Leu Cys Gln Gln Pro Asp Gly Thr Leu Tyr 100 105 110 Gly Ser Pro His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu 115 120 125 Leu Lys Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro 130 135 140 Leu Arg Leu Pro Gln Lys Asp Ser Gln Asp Pro Ala Thr Arg Gly Pro 145 150 155 160 Val Arg Phe Leu Pro Met Pro Gly Leu Pro His Glu Pro Gln Glu Gln 165 170 175 Pro Gly Val Leu Pro Pro Glu Pro Pro Asp Val Gly Ser Ser Asp Pro 180 185 190 Leu Ser Met Val Glu Pro Leu Gln Gly Arg Ser Pro Ser Tyr Ala Ser 195 200 205 253210PRTMus musculus 253Met Glu Trp Met Arg Ser Arg Val Gly Thr Leu Gly Leu Trp Val Arg 1 5 10 15 Leu Leu Leu Ala Val Phe Leu Leu Gly Val Tyr Gln Ala Tyr Pro Ile 20 25 30 Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg 35 40 45 Tyr Leu Tyr Thr Asp Asp Asp Gln Asp Thr Glu Ala His Leu Glu Ile 50 55 60 Arg Glu Asp Gly Thr Val Val Gly Ala Ala His Arg Ser Pro Glu Ser 65 70 75 80 Leu Leu Glu Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly 85 90 95 Val Lys Ala Ser Arg Phe Leu Cys Gln Gln Pro Asp Gly Ala Leu Tyr 100 105 110 Gly Ser Pro His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu 115 120 125 Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro 130 135 140 Leu Arg Leu Pro Gln Lys Asp Ser Pro Asn Gln Asp Ala Thr Ser Trp 145 150 155 160 Gly Pro Val Arg Phe Leu Pro Met Pro Gly Leu Leu His Glu Pro Gln 165 170 175 Asp Gln Ala Gly Phe Leu Pro Pro Glu Pro Pro Asp Val Gly Ser Ser 180 185 190 Asp Pro Leu Ser Met Val Glu Pro Leu Gln Gly Arg Ser Pro Ser Tyr 195 200 205 Ala Ser 210 254107PRTVicugna pacos 254Met Asp Trp Asp Glu Ala Lys Phe Glu His Arg Gly Leu Trp Val Pro 1 5 10 15 Val Leu Thr Val Leu Leu Leu Gly Ala Cys Gln Ala Arg Pro Ile Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr 35 40 45 Leu Tyr Thr Asp Asp Ala Gln Glu Thr Glu Ala His Leu Glu Ile Arg 50 55 60 Ala Asp Gly Thr Val Val Gly Val Ala Arg Gln Pro Glu Gly Ile Pro 65 70 75 80 Pro Glu Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly 85 90 95 Pro Ser Tyr Ser Arg Ser Pro Ser Tyr Thr Ser 100 105 255211PRTAnolis carolinensis 255Cys Lys Ser Lys Gly Gly Gly Lys Gly Gly Glu Arg Met Trp Val Asp 1 5 10 15 Leu Val Phe Trp Ala Ala Leu Leu Arg Thr Ala Pro Ala Leu Pro Leu 20 25 30 Arg Asn Ser Asn Pro Ile Tyr Gln Phe Asp Gly Gln Val Arg Leu Arg 35 40 45 His Leu Tyr Thr Ala Asp Glu Gln Thr His Leu His Leu Glu Ile Leu 50 55 60 Pro Asp Gly Thr Val Gly Gly Ser Arg Phe Gln Asn Pro Phe Ser Leu 65 70 75 80 Met Glu Ile Lys Ala Val Lys Pro Gly Val Ile Arg Met Gln Ala Lys 85 90 95 Lys Thr Ser Arg Phe Leu Cys Met Lys Pro Asn Gly Arg Leu Tyr Gly 100 105 110 Ser Leu Phe Tyr Ser Glu Glu Ala Cys Asn Phe His Glu Lys Val Leu 115 120 125 Ser Asp Gly Tyr Asn Leu Tyr Tyr Ser Glu Asn Tyr Asn Ile Pro Val 130 135 140 Ser Leu Ser Ser Ala Gly Asn Leu Gly Gln Ser Arg Gln Leu Pro Pro 145 150 155 160 Phe Ser Gln Phe Leu Pro Leu Val Asn Lys Ile Pro Leu Glu Pro Val 165 170 175 Leu Glu Asp Phe Asp Phe Tyr Gly His Gln Leu Asp Val Glu Ser Ala 180 185 190 Asp Pro Leu Ser Ile Leu Gly Gln Asn Pro Gly Phe Met Ser Pro Ser 195 200 205 Tyr Val Phe 210 256188PRTGadus morhua 256Leu Leu Leu Ala Thr Leu Leu His Ile Gly Leu Ser Phe Tyr Val Pro 1 5 10 15 Asp Ser Gly Pro Leu Leu Trp Leu Gly Asp Gln Val Arg Glu Arg His 20 25 30 Leu Tyr Thr Ala Glu Ser His Arg Arg Gly Leu Phe Leu Glu Met Ser 35 40 45 Pro Asp Gly Gln Val Thr Gly Ser Ala Ala Gln Thr Pro Leu Ser Val 50 55 60 Leu Glu Leu Arg Ser Val Arg Ala Gly Asp Thr Val Ile Arg Ala Arg 65 70 75 80 Leu Ser Ser Leu Tyr Leu Cys Val Asp Arg Ala Gly His Leu Thr Gly 85 90 95 Gln Arg Gln Tyr Thr Glu Ser Asp Cys Thr Phe Arg Glu Val Ile Leu 100 105 110 Glu Asp Gly Tyr Thr His Phe Leu Ser Val His His Gly Leu Pro Ile 115 120 125 Ser Leu Ala Pro Arg His Ser Pro Gly Arg Gln Gly Leu Arg Phe Ser 130 135 140 Arg Phe Leu Pro Leu Arg Ser Ser Leu Ser Glu Asp Arg Val Ala Glu 145 150 155 160 Pro Pro Asp Ser Pro Leu Asn Leu Asp Ser Glu Asp Pro Leu Gly Met 165 170 175 Gly Leu Gly Ser Leu Leu Ser Pro Ala Phe Ser Met 180 185 257216PRTLatimeria chalumnae 257Met Leu Cys Gln Ser Phe Val Ile Leu Ser Gln Lys Phe Ile Phe Gly 1 5 10 15 Leu Phe Leu Thr Gly Leu Gly Leu Thr Gly Leu Ala Trp Thr Arg Pro 20 25 30 Phe Gln Asp Ser Asn Pro Ile Leu Gln Tyr Ser Asp Ser Ile Arg Leu 35 40 45 Arg His Leu Tyr Thr Ala Ser Glu Ser Arg His Leu His Leu Gln Ile 50 55 60 Asn Ser Asp Gly Gln Val Gly Gly Thr Thr Lys Gln Ser Pro Tyr Ser 65 70 75 80 Leu Leu Glu Met Lys Ala Val Lys Thr Gly Phe Val Val Ile Arg Gly 85 90 95 Lys Lys Ser Ala Arg Tyr Leu Cys Met Glu Arg Ser Gly Arg Leu Tyr 100 105 110 Gly Ser Leu Gln Tyr Thr Glu Lys Asp Cys Thr Phe Lys Glu Val Val 115 120 125 Leu Ala Asp Gly Tyr Asn Leu Tyr Val Ser Glu Glu His Gln Ala Thr 130 135 140 Val Thr Leu Ser Pro Met Arg Ala Arg Ile Ala Gln Gly Lys Lys Ile 145 150 155 160 Pro Pro Phe Ser His Phe Leu Pro Met Val Asn Lys Val Pro Val Glu 165 170 175 Asp Val Ala Ala Glu Met Glu Phe Val Gln Val Leu Arg Glu Met Thr 180 185 190 Ala Asp Val Asp Ser Pro Asp Pro Phe Gly Met Thr Trp Glu Glu Ser 195 200 205 Val His Ser Pro Ser Phe Phe Ala 210 215 258192PRTTursiops truncates 258Met Gly Trp Asp Lys Thr Lys Leu Glu His Leu Gly Leu Trp Val Pro 1 5 10 15 Val Leu Ala Val Leu Leu Gly Pro Cys Gln Ala His Pro Ile Pro Asp 20 25 30 Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr Leu 35 40 45 Tyr Thr Asp Asp Ala Gln Glu Thr Glu Ala His Leu Glu Ile Arg Ala 50 55 60 Asp Gly Thr Val Val Gly Thr Ala Arg Arg Ser Pro Glu Gly Val Lys 65 70 75 80 Thr Ser Arg Phe Leu Cys Gln Gly Pro Glu Gly Arg Leu Tyr Gly Ser 85 90 95 Leu His Phe Asn Pro Gln Ala Cys Ser Phe Arg Glu Leu Leu Leu Glu 100 105 110 Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala Leu Gly Ile Pro Leu Arg 115 120 125 Leu Pro Pro His Arg Ser Ser Asn Trp Asp Leu Ala Pro Arg Gly Pro 130 135 140 Ala Arg Phe Leu Pro Leu Pro Gly Phe Leu Pro Pro Pro Leu Glu Pro 145 150 155 160 Pro Gly Ile Leu Ala Pro Glu Pro Pro Asn Val Gly Ser Ser Asp Pro 165 170 175 Leu Ser Met Val Gly Pro Ser His Gly Arg Ser Pro Ser Tyr Thr Ser 180 185 190 259209PRTMustela putorius furo 259Met Gly Trp Glu Glu Ala Arg Ser Glu His Leu Gly Leu Trp Val Pro 1 5 10 15 Val Leu Ala Val Leu Leu Leu Gly Ala Cys Gln Ala Tyr Pro Ile Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr 35 40 45 Leu Tyr Thr Asp Asp Ala Gln Glu Thr Glu Ala His Leu Glu Ile Arg 50 55 60 Ala Asp Gly Thr Val Val Gly Ala Ala Arg Arg Ser Pro Glu Ser Leu 65 70 75 80 Leu Glu Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val 85 90 95 Lys Thr Ser Arg Phe Leu Cys Gln Gly Pro Asn Gly Thr Leu Tyr Gly 100 105 110 Ser Phe His Phe Asp Pro Val Ala Cys Ser Phe Arg Glu Val Leu Leu 115 120 125 Glu Asp Gly Tyr Asn Ile Tyr His Ser Glu Thr Leu

Gly Leu Pro Leu 130 135 140 Arg Leu Pro Pro His Asn Ser Pro His Arg Asp Leu Ala Pro Arg Gly 145 150 155 160 Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Leu Pro Ala Thr Pro Glu 165 170 175 Ser Arg Gly Ile Pro Ala Pro Glu Pro Pro Asn Val Gly Ser Ser Asp 180 185 190 Pro Leu Ser Met Val Gly Pro Leu Gln Gly Gln Ser Pro Ser Tyr Thr 195 200 205 Ser 260198PRTTakifugu rubripes 260Phe Ile Tyr Leu Phe Ile Gln Thr Ala Leu Phe Ser Pro Ser Lys Trp 1 5 10 15 Phe Asn Phe Tyr Leu Pro Asp Ser Asn Pro Leu Leu Ser Phe Asp Ser 20 25 30 His Gly Arg Gly Ile His Leu Tyr Thr Asp Asn Gln Arg Arg Gly Met 35 40 45 Tyr Leu Gln Met Ser Thr Asp Gly Ser Val Ser Gly Ser Asp Val Gln 50 55 60 Thr Ala Asn Ser Val Leu Glu Leu Lys Ser Val Arg Asn Gly His Val 65 70 75 80 Val Ile Arg Gly Lys Ser Ser Ser Leu Phe Leu Cys Met Asp Ser Arg 85 90 95 Gly Arg Leu Trp Gly Gln Arg His Pro Thr Glu Ala Asp Cys Thr Phe 100 105 110 Arg Glu Val Leu Leu Ala Asp Gly Tyr Thr Arg Phe Leu Ser Leu His 115 120 125 Asn Gly Thr Pro Val Ser Leu Ala Pro Lys Gln Ser Pro Asp Gln His 130 135 140 Thr Val Pro Phe Thr Arg Phe Leu Pro Leu Arg Asn Thr Leu Ala Glu 145 150 155 160 Glu Ser Met Ser Glu Pro Pro Ser Asn Gln Gln Arg Tyr Phe Asn Ile 165 170 175 Asp Ser Asp Asp Leu Leu Gly Met Asp Leu Asn Ala Met Val Ser Pro 180 185 190 Gln Phe Ser Gly Asp Lys 195 261203PRTDipodomys ordii 261Met Asp Gln Ala Lys Thr Arg Val Gly Ala Arg Gly Leu Gly Gly Leu 1 5 10 15 Val Leu Ala Val Ile Ile Leu Gly Ala Cys Lys Ala Arg Pro Ile Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Leu Arg His 35 40 45 Leu Tyr Thr Asp Asp Thr Gln Glu Thr Glu Ala His Leu Glu Ile Arg 50 55 60 Ala Asp Gly Thr Val Val Gly Thr Ala His Arg Ser Pro Glu Ser Leu 65 70 75 80 Leu Glu Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Ile 85 90 95 Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Thr Leu Tyr Gly 100 105 110 Ser Leu His Phe Asp Pro Glu Val Cys Ser Phe Gln Glu Leu Leu Leu 115 120 125 Glu Asp Gly Tyr Asn Ile Tyr Arg Ser Glu Ala Leu Gly Leu Pro Leu 130 135 140 Arg Leu Ser Pro Asp Pro Ala Pro Trp Gly Pro Ala Arg Phe Leu Pro 145 150 155 160 Leu Pro Gly Val Pro Pro Ala Pro Pro Glu Pro Pro Gly Ile Leu Ala 165 170 175 Pro Glu Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly 180 185 190 Leu Leu Gln Gly Arg Ser Pro Ser Tyr Ala Ser 195 200 262184PRTEchinops telfairi 262Met Gly Cys Thr Lys Ser Gly Trp Lys Ser Pro Gly Leu Trp Val Pro 1 5 10 15 Val Leu Ala Ser Leu Leu Leu Gly Gly Cys Gly Ala His Pro Ile Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr 35 40 45 Leu Tyr Thr Asp Asp Ala Gln Thr Thr Glu Ala His Leu Glu Ile Arg 50 55 60 Ala Asp Gly Thr Val Gly Gly Val Ala His Gln Ser Pro Glu Lys Phe 65 70 75 80 Leu Ser Gln Trp Arg Glu Lys Pro Leu Arg Ser Leu His Phe Asp Pro 85 90 95 Ala Ala Cys Ser Phe Arg Glu Lys Leu Leu Glu Asp Gly Tyr Asn Leu 100 105 110 Tyr His Ser Glu Thr His Gly Leu Pro Leu Arg Leu Pro Pro Arg Gly 115 120 125 Gly Asp Pro Ser Ser Gln Pro Gly Ala Arg Phe Pro Pro Leu Pro Gly 130 135 140 Gln Leu Pro Gln Leu Gln Glu Thr Pro Gly Val Leu Ala Pro Glu Pro 145 150 155 160 Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro Trp Arg 165 170 175 Gly Gln Ser Pro Ser Tyr Ala Ser 180 263210PRTMacaca mulatta 263Met Asp Ser Asp Glu Thr Gly Phe Glu His Ser Gly Leu Trp Val Pro 1 5 10 15 Val Leu Ala Gly Leu Leu Leu Gly Ala Cys Gln Ala His Pro Ile Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr 35 40 45 Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg 50 55 60 Glu Asp Gly Thr Val Gly Gly Ala Ala His Gln Ser Pro Glu Ser Glu 65 70 75 80 Cys Gly Pro Glu Pro Gly Ser Glu Gly Gly Gly Ala Val Gly Gly Ala 85 90 95 Glu Gly Pro Gly Leu Leu Gly Leu Arg Glu Ala Gly Leu Gly Pro Gly 100 105 110 Ser Trp Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu 115 120 125 Leu Glu Asn Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro 130 135 140 Leu His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro Ala Ser Gln 145 150 155 160 Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Pro Pro 165 170 175 Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser 180 185 190 Asp Pro Leu Ser Met Val Gly Pro Ser Gln Ala Arg Ser Pro Ser Tyr 195 200 205 Ala Ser 210 264193PRTMicrocebus murinus 264Met Gly Trp Asp Glu Ala Gly Ala Gly Phe Glu His Pro Gly Leu Trp 1 5 10 15 Phe Pro Met Leu Gly Val Leu Leu Leu Gly Ala Cys Gln Ala Tyr Pro 20 25 30 Ile Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln 35 40 45 Arg His Leu Tyr Thr Asp Asp Ile Gln Glu Thr Glu Ala His Leu Glu 50 55 60 Ile Arg Ala Asp Gly Thr Val Val Gly Ala Ala Arg Gln Ser Pro Glu 65 70 75 80 Leu Glu Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val 85 90 95 Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly 100 105 110 Ser Leu His Phe Asp Pro Glu Cys Ser Phe Arg Glu Leu Leu Leu Glu 115 120 125 Asp Gly Tyr Asn Val Tyr Cys Pro Tyr Leu Pro Leu His Leu Ser Pro 130 135 140 Arg Ile Glu Leu Ala Gly Ser Arg Ser Ala Leu Pro Leu Pro Pro Ala 145 150 155 160 Pro Glu Arg Arg Ile Leu Ala Pro Glu Pro Pro Asp Gly Ser Ser Asp 165 170 175 Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala 180 185 190 Ser 265204PRTOchotona princeps 265Lys Asp Met Asp Gly Leu Gln Pro Pro Gly Leu Arg Val Pro Val Leu 1 5 10 15 Ala Ala Leu Leu Leu Gly Val Gly Gln Ala Arg Pro Ile Pro Asp Ser 20 25 30 Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg His Leu Tyr 35 40 45 Thr Asp Asp Ala Gln Glu Ser Glu Val His Leu Glu Ile Arg Ala Asp 50 55 60 Gly Thr Val Ala Gly Thr Ala Arg Arg Ser Pro Glu Ser Leu Leu Glu 65 70 75 80 Met Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val His Thr 85 90 95 Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Thr Leu Tyr Gly Ser Leu 100 105 110 His Phe Asp His Lys Ala Cys Ser Phe Arg Glu Gln Leu Leu Glu Asp 115 120 125 Gly Tyr Asn Val Tyr His Ser Glu Thr His Gly Leu Pro Leu Arg Leu 130 135 140 Ser Pro Asp Arg Ala Pro Arg Gly Pro Ala Arg Phe Leu Pro Leu Pro 145 150 155 160 Gly Pro Pro Pro Asp Leu Leu Val Pro Pro Leu Pro Pro Asp Val Leu 165 170 175 Ala Pro Glu Pro Pro Asp Val Asp Ser Pro Asp Pro Leu Ser Met Val 180 185 190 Gly Pro Leu Gln Gly Gln Ser Pro Ser Tyr Thr Ser 195 200 266182PRTXiphophorus maculatus 266Cys Pro Phe Pro Phe Leu Phe Leu Ile Leu Ser Leu Pro Phe Phe Ser 1 5 10 15 Ser Ser Phe Tyr Ile Pro Glu Ser Asn Pro Ile Phe Ala Phe Arg Asn 20 25 30 Gln Leu Arg Glu Val His Leu Tyr Thr Glu Asn His Arg Arg Gly Leu 35 40 45 Tyr Val Glu Ile His Leu Asp Gly Arg Val Thr Gly Ser Asp Ala Gln 50 55 60 Ser Pro Tyr Ser Val Leu Gln Ile Lys Ser Val Lys Pro Gly His Val 65 70 75 80 Val Ile Lys Gly Gln Thr Ser Ser Leu Phe Leu Cys Met Asp Asp Ser 85 90 95 Gly Asn Leu Arg Gly Gln Thr Thr Tyr Asp Glu Ala Asp Cys Ser Phe 100 105 110 Arg Glu Leu Leu Leu Ala Asp Gly Tyr Thr Arg Phe Leu Asn Ser Gln 115 120 125 His Gly Val Pro Leu Ser Leu Ala Ser Arg Asn Ser Pro Asp Arg His 130 135 140 Ser Val Pro Phe Thr Arg Phe Leu Pro Leu Arg Asn Thr Leu Thr Val 145 150 155 160 Ser Glu Glu Ser Thr Lys Thr Gln Arg Asp Phe Asn Leu Asp Ser Asp 165 170 175 Asp Leu Leu Gly Met Gly 180 267192PRTGasterosteus aculeatus 267Ser Leu Leu Leu Met Val Pro Leu Pro Phe Cys Ser Ser Phe Tyr Leu 1 5 10 15 Thr Asp Ser Ser Pro Leu Leu Pro Phe Asn Asn Gln Val Lys Glu Val 20 25 30 His Leu Tyr Thr Ala Glu Asn His Arg Arg Ala Met Tyr Leu Gln Ile 35 40 45 Ala Leu Asp Gly Ser Val Ser Gly Ser Asp Ala Arg Ser Thr Tyr Ser 50 55 60 Val Leu Gln Leu Lys Ser Ile Gln Pro Gly His Val Val Ile Arg Gly 65 70 75 80 Lys Ala Ser Ser Met Phe Leu Cys Val Asp Ser Gly Gly Arg Leu Arg 85 90 95 Gly Gln Gly Pro Tyr Ser Glu Ala Asp Cys Ser Phe Arg Glu Leu Leu 100 105 110 Leu Gly Asp Gly Tyr Thr Arg Phe Leu Ser Ser Gln His Gly Ser Pro 115 120 125 Leu Ser Leu Ala Ser Arg Pro Ser Pro Asp Pro Asn Ser Val Pro Phe 130 135 140 Thr Arg Phe Leu Pro Ile Arg Thr Ala Pro Glu Ala Glu Ser Val Ile 145 150 155 160 Glu Glu Pro Pro Ser Asn Gln Arg Tyr Val Asn Val Asp Ser Glu Asp 165 170 175 Leu Leu Gly Met Gly Leu Asn Thr Val Val Ser Pro Gln Phe Ser Ala 180 185 190 268165PRTSarcophilus harrisii 268Val Ser Ala Met Gly Leu Arg Glu Arg Ala Pro Arg Tyr Leu Ala Pro 1 5 10 15 Leu Leu Ser Leu Leu Leu Ala Cys Arg Ala Ser Gly His Pro Leu Pro 20 25 30 Asp Ser Ser Pro Met Leu Leu Phe Gly Gly Gln Val Arg Leu Arg His 35 40 45 Leu Tyr Thr Asp Val Gly Gln Glu Ala Glu Ala His Val Glu Leu Ala 50 55 60 Ser Asp Gly Thr Val Arg Ala Ala Ala Arg Arg Ser Pro Asn Ser Leu 65 70 75 80 Leu Glu Leu Lys Ala Val Lys Pro Gly Ile Val Arg Ile Leu Ala Val 85 90 95 His Ser Ser Arg Phe Leu Cys Met Arg Pro Asn Gly Glu Leu Tyr Gly 100 105 110 Ala Ile His Tyr Asp Pro Ser Ala Cys Asn Phe Arg Glu Arg Leu Leu 115 120 125 Gly Asp Gly Tyr Asn Val Tyr Glu Ser Glu Ala His Gly Arg Thr Leu 130 135 140 Arg Leu Pro Pro Lys Ala Ala Pro Gly Pro Ala Gly Pro Ser Arg Phe 145 150 155 160 Leu Pro Leu Pro Gly 165 269208PRTMacropus eugenii 269Thr Glu Glu Pro Ser Thr Gly Ser Arg His Leu Gly Gln Trp Ala Pro 1 5 10 15 Gly Leu Pro Gly Pro Leu Leu Ser Leu Leu Leu Ala Tyr Arg Gly Trp 20 25 30 Gly Ser Pro Ile Pro Asp Ser Ser Pro Met Leu Leu Phe Gly Gly Gln 35 40 45 Val Arg Leu Arg His Leu Tyr Thr Asp Asp Gly Gln Asp Thr Glu Ala 50 55 60 His Val Glu Leu Gly Pro Asp Gly Val Val Arg Ala Val Ala Glu Arg 65 70 75 80 Ser Pro Asn Ser Leu Leu Glu Leu Lys Ala Val Lys Pro Gly Val Ile 85 90 95 Arg Ile Leu Ala Val Gln Ser Ser Arg Phe Leu Cys Met Arg Pro Asn 100 105 110 Gly Glu Leu Tyr Gly Ala Val His Tyr Asp Pro Ser Ala Cys Asn Phe 115 120 125 Arg Glu His Leu Leu Gly Asp Gly Tyr Asn Val Tyr Glu Ser Glu Thr 130 135 140 His Arg Arg Thr Leu Arg Leu Ser Pro Ser Leu Gly Gln Ala Gly Pro 145 150 155 160 Ser Arg Phe Leu Pro Leu Pro Gly Asp Trp Leu Pro Gly Pro Asp Pro 165 170 175 Pro Trp Ala Gln Gly Pro Glu Pro Pro Asp Val Gly Ser Ala Asp Pro 180 185 190 Leu Ser Met Val Gly Ala Val Gln Gly Leu Ser Pro Ser Tyr Ser Ser 195 200 205 270160PRTXenopus tropicalis 270Arg Gly Gly Arg Thr Lys Lys Lys Thr Leu Leu Arg Lys Trp Leu Cys 1 5 10 15 Leu Leu Ala Ile Met Leu Ser Arg Ser Arg Phe Ser Leu Ala Asn Pro 20 25 30 Ile Gln Asn Ser Asn Pro Ile Leu Ser Asn Asp Asn Gln Val Arg Thr 35 40 45 Gln Tyr Leu Tyr Thr Asp Asn Asn Asn Met His Leu Tyr Leu Gln Ile 50 55 60 Thr His Asn Gly Val Val Thr Gly Thr Glu Glu Lys Asn Asp Tyr Gly 65 70 75 80 Val Leu Glu Ile Lys Ala Val Lys Ala Gly Val Val Val Ile Lys Gly 85 90 95 Ile Arg Ser Asn Leu Tyr Leu Cys Met Asp Ser Arg His Gln Leu Tyr 100 105 110 Ala Ser Ala Tyr Asp Lys Asp Asp Cys His Phe His Glu Lys Ile Thr 115 120 125 Pro Asp Asn Tyr Asn Met Tyr Ser Ser Glu Lys His Ser Glu Tyr Val 130 135 140 Ser Leu Ala Pro Leu Lys Gly Ser Gln Met Ala Arg Phe Leu Pro Ile 145 150 155 160 271194PRTDanio rerio 271Met Leu Leu Ala Cys Phe Phe Ile Phe Phe Ala Leu Phe Pro His Leu 1 5 10 15 Arg Trp Cys Met Tyr Val Pro Ala Gln Asn Val Leu Leu Gln Phe Gly 20 25 30 Thr Gln Val Arg Glu Arg Leu Leu Tyr Thr Asp Gly Leu Phe Leu Glu 35 40 45 Met Asn Pro Asp Gly Ser Val Lys Gly Ser Pro Glu Lys Asn Leu Asn 50 55 60 Cys Val Leu Glu Leu Arg Ser Val Lys Ala Gly Glu Thr Val Ile Gln 65 70 75

80 Ser Ala Ala Thr Ser Leu Tyr Leu Cys Val Asp Asp Gln Asp Lys Leu 85 90 95 Lys Gly Gln His His Tyr Ser Ala Leu Asp Cys Thr Phe Gln Glu Leu 100 105 110 Leu Leu Asp Gly Tyr Ser Phe Phe Leu Ser Pro His Thr Asn Leu Pro 115 120 125 Val Ser Leu Leu Ser Lys Arg Gln Lys His Gly Asn Pro Leu Ser Arg 130 135 140 Phe Leu Pro Val Ser Arg Ala Glu Asp Ser Arg Thr Gln Glu Val Lys 145 150 155 160 Gln Tyr Ile Gln Asp Ile Asn Leu Asp Ser Asp Asp Pro Leu Gly Met 165 170 175 Gly His Arg Ser His Leu Gln Thr Val Phe Ser Pro Ser Leu His Thr 180 185 190 Lys Lys 272209PRTBos grunniens mutus 272Met Gly Trp Asp Glu Ala Lys Phe Lys His Leu Gly Leu Trp Val Pro 1 5 10 15 Val Leu Ala Val Leu Leu Leu Gly Thr Cys Arg Ala His Pro Ile Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr 35 40 45 Leu Tyr Thr Asp Asp Ala Gln Glu Thr Glu Ala His Leu Glu Ile Arg 50 55 60 Ala Asp Gly Thr Val Val Gly Ala Ala Arg Gln Ser Pro Glu Ser Leu 65 70 75 80 Leu Glu Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val 85 90 95 Lys Thr Ser Arg Phe Leu Cys Gln Gly Pro Asp Gly Lys Leu Tyr Gly 100 105 110 Ser Leu His Phe Asp Pro Lys Ala Cys Ser Phe Arg Glu Leu Leu Leu 115 120 125 Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Thr Leu Gly Leu Pro Leu 130 135 140 Arg Leu Pro Pro Gln Arg Ser Ser Asn Arg Asp Pro Ala Pro Arg Gly 145 150 155 160 Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Ala Glu Pro Pro Asp 165 170 175 Pro Pro Gly Ile Leu Ala Pro Glu Pro Pro Asp Val Gly Ser Ser Asp 180 185 190 Pro Leu Ser Met Val Gly Pro Ser Tyr Gly Arg Ser Pro Ser Tyr Thr 195 200 205 Ser 273209PRTSaimiri boliviensis boliviensis 273Met Gly Ser Glu Glu Val Ala Leu Glu Arg Pro Ala Leu Trp Val Ser 1 5 10 15 Val Leu Ala Gly Leu Leu Leu Gly Thr Cys Gln Ala Tyr Pro Ile Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr 35 40 45 Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg 50 55 60 Glu Asp Gly Thr Val Ala Gly Ala Ala His Gln Ser Pro Glu Ser Leu 65 70 75 80 Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val 85 90 95 Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly 100 105 110 Ser Leu Tyr Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu 115 120 125 Glu Asp Gly Tyr Asn Val Tyr Gln Ser Val Ala His Ser Leu Pro Leu 130 135 140 His Leu Pro Gly Gly Arg Ser Pro Pro Trp Asp Pro Ala Pro Arg Gly 145 150 155 160 Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Glu Pro Pro Glu 165 170 175 Ala Pro Gly Ile Leu Ala Pro Glu Pro Pro Asp Val Gly Ser Ser Asp 180 185 190 Pro Leu Ser Met Val Gly Pro Ser Gln Gly Gln Ser Pro Ser Tyr Thr 195 200 205 Ser 274210PRTCallithrix jacchusmisc_feature(64)..(64)Xaa can be any naturally occurring amino acid 274Met Gly Ser Glu Glu Val Gly Leu Glu His Pro Ala Leu Trp Val Ser 1 5 10 15 Val Leu Ala Gly Leu Leu Leu Gly Thr Cys Gln Ala His Pro Ile Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr 35 40 45 Leu Tyr Thr Asp Asp Ala Gln Gln Lys Glu Ala His Leu Glu Ile Xaa 50 55 60 Glu Asp Gly Thr Val Ala Gly Ala Ala Thr Lys Val Pro Lys Val Ser 65 70 75 80 Leu Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly 85 90 95 Val Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr 100 105 110 Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu 115 120 125 Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser Val Ala His Gly Leu Pro 130 135 140 Leu His Leu Pro Glu Ser Arg Ser Pro Pro Arg Asp Pro Ala Pro Arg 145 150 155 160 Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Glu Pro Pro 165 170 175 Glu Pro Pro Gly Ile Leu Ala Pro Glu Pro Pro Asp Val Gly Ser Ser 180 185 190 Asp Pro Leu Ser Met Val Gly Pro Ser Gln Gly Gln Ser Pro Ser Tyr 195 200 205 Ala Ser 210 275209PRTTupaia chinensis 275Met Gly Trp Asp Lys Ala Arg Phe Glu His Leu Gly Ala Trp Ala Pro 1 5 10 15 Val Leu Ala Val Leu Leu Leu Gly Ala Cys Gln Ala Tyr Pro Ile Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr 35 40 45 Leu Tyr Thr Asp Asp Thr Gln Asp Thr Glu Ala His Leu Glu Ile Arg 50 55 60 Ala Asp Gly Thr Val Val Gly Ala Ala His Gln Ser Pro Glu Ser Leu 65 70 75 80 Leu Glu Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val 85 90 95 Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly 100 105 110 Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu 115 120 125 Glu Asp Gly Tyr Asn Ile Tyr Gln Ser Glu Ala Arg Gly Leu Pro Leu 130 135 140 Arg Leu Pro Pro His Asp Ser Pro His Arg Asp Arg Thr Pro Gln Gly 145 150 155 160 Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Leu Val Pro Pro Glu 165 170 175 Leu Pro Gly Val Leu Ala Leu Glu Pro Pro Asp Val Gly Ser Ser Asp 180 185 190 Pro Leu Ser Met Met Gly Pro Ser Gln Gly Gln Ser Pro Ser Tyr Ala 195 200 205 Ser 276188PRTPapio Anubis 276Met Asp Ser Asp Glu Thr Gly Phe Glu His Ser Gly Leu Trp Val Pro 1 5 10 15 Val Leu Ala Gly Leu Leu Leu Gly Ala Cys Gln Ala His Pro Ile Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr 35 40 45 Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg 50 55 60 Glu Asp Gly Thr Val Gly Gly Ala Ala His Gln Ser Pro Glu Ser Lys 65 70 75 80 Cys Gly Pro Glu Pro Gly Ser Glu Gly Gly Gly Ala Leu His Phe Asp 85 90 95 Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu Glu Asn Gly Tyr Asn 100 105 110 Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu His Leu Pro Gly Asn 115 120 125 Lys Ser Pro His Arg Asp Pro Ala Ser Arg Gly Pro Ala Arg Phe Leu 130 135 140 Pro Leu Pro Gly Leu Pro Pro Ala Pro Pro Glu Pro Pro Gly Ile Leu 145 150 155 160 Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val 165 170 175 Gly Pro Ser Gln Ala Arg Ser Pro Ser Tyr Ala Ser 180 185 277208PRTPteropus alecto 277Met Gly Trp Gly Lys Ala Arg Leu Gln His Pro Gly Leu Trp Gly Pro 1 5 10 15 Val Leu Ala Val Leu Leu Gly Ala Cys Gln Ala His Pro Ile Leu Asp 20 25 30 Ser Ser Pro Leu Phe Gln Phe Gly Ser Gln Val Arg Arg Arg Tyr Leu 35 40 45 Tyr Thr Asp Asp Ala Gln Asp Thr Glu Ala His Leu Glu Ile Arg Ala 50 55 60 Asp Gly Thr Val Ala Gly Ala Ala Arg Arg Ser Pro Glu Ser Leu Leu 65 70 75 80 Glu Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Val Leu Gly Val Lys 85 90 95 Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Thr Leu Tyr Gly Ser 100 105 110 Leu His Phe Asp Pro Ala Ala Cys Ser Phe Arg Glu Leu Leu Leu Lys 115 120 125 Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala Leu Ala Arg Pro Leu Arg 130 135 140 Leu Pro Pro Tyr Ser Ser Pro Ser Ser Asp Pro Ala Arg Arg Gly Pro 145 150 155 160 Ala Arg Phe Leu Pro Leu Pro Gly Pro Pro Pro Glu Pro Pro Gln Pro 165 170 175 Pro Gly Arg Leu Ala Pro Glu Pro Pro Asp Val Gly Ser Ser Asp Pro 180 185 190 Leu Ser Met Val Trp Pro Ser Arg Gly Arg Ser Pro Ser Tyr Thr Ser 195 200 205 278210PRTHeterocephalus glaber 278Met Asp Trp Ala Arg Ala Glu Ser Glu Arg Pro Gly Leu Trp Val Pro 1 5 10 15 Ala Val Leu Ala Val Leu Leu Leu Gly Ala Cys Gln Ala His Pro Ile 20 25 30 Pro Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg 35 40 45 His Leu Tyr Thr Asp Asp Ala Gln Asp Thr Glu Val His Leu Glu Ile 50 55 60 Arg Ala Asp Gly Ser Val Gly Gly Ala Ala His Arg Ser Pro Glu Ser 65 70 75 80 Leu Leu Glu Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly 85 90 95 Val Arg Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Thr Leu Tyr 100 105 110 Gly Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu 115 120 125 Leu Ala Asp Gly Tyr Asn Ile Tyr Gln Ser Glu Ala Tyr Gly Leu Pro 130 135 140 Leu Arg Met Leu Pro Ser Asp Ser Ala Ser Arg Asp Pro Val Pro Pro 145 150 155 160 Gly Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu His Pro Pro Pro Leu 165 170 175 Glu Pro Pro Gly Met Leu Pro Pro Glu Pro Pro Asp Val Gly Ser Ser 180 185 190 Asp Pro Leu Ser Met Val Gly Pro Leu Gln Gly Arg Ser Pro Ser Tyr 195 200 205 Ala Phe 210 279209PRTCricetulus griseus 279Met Asp Trp Met Lys Ser Gly Val Gly Val Pro Gly Leu Trp Val Pro 1 5 10 15 Leu Leu Pro Ile Phe Leu Leu Gly Val Ser Gln Ala His Pro Ile Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg His Arg His 35 40 45 Leu Tyr Thr Asp Asp Asn Gln Glu Thr Glu Val His Leu Glu Ile Arg 50 55 60 Gln Asp Gly Thr Val Ile Gly Thr Thr His Arg Ser Pro Glu Ser Leu 65 70 75 80 Leu Glu Leu Lys Ala Leu Lys Pro Glu Val Ile Pro Val Leu Gly Val 85 90 95 Lys Ala Ser Arg Phe Leu Cys Gln Gln Pro Asp Gly Thr Leu Tyr Gly 100 105 110 Ser Pro His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu 115 120 125 Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Val His Gly Leu Pro Leu 130 135 140 Arg Leu Pro Gln Arg Asp Ser Pro Asn Gln Ala Pro Ala Ser Trp Gly 145 150 155 160 Pro Val Pro Pro Leu Pro Val Pro Gly Leu Leu His Gln Pro Gln Glu 165 170 175 Leu Pro Gly Phe Leu Ala Pro Glu Pro Pro Asp Val Gly Ser Ser Asp 180 185 190 Pro Leu Ser Met Val Gly Pro Leu Gln Gly Arg Ser Pro Ser Tyr Ala 195 200 205 Ser 280192PRTOvis aries 280Met Gly Trp Asp Glu Ala Lys Phe Lys His Leu Gly Leu Trp Val Pro 1 5 10 15 Val Leu Ala Val Leu Leu Leu Gly Thr Cys Arg Ala His Pro Ile Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr 35 40 45 Leu Tyr Thr Asp Asp Ala Gln Glu Thr Glu Ala His Leu Glu Ile Arg 50 55 60 Ala Asp Gly Thr Val Val Gly Ala Ala Arg Gln Ser Pro Glu Ser Leu 65 70 75 80 Leu Glu Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Phe Gly Val 85 90 95 Lys Thr Ser Arg Phe Leu Cys Gln Gly Pro Asp Gly Lys Leu Tyr Gly 100 105 110 Ser Leu His Phe Asp Pro Lys Ala Cys Ser Phe Arg Glu Leu Leu Leu 115 120 125 Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Thr Leu Gly Leu Pro Leu 130 135 140 Arg Leu Pro Pro Gln Arg Ser Ser Asn Arg Asp Pro Ala Pro Arg Gly 145 150 155 160 Pro Pro Lys Pro Gln Leu His Phe Leu Lys Thr Ser Ala Val Gln Tyr 165 170 175 Trp Pro Arg Tyr Glu Lys Val Pro Ala Phe Leu His Pro Phe Pro Gly 180 185 190 281135PRTPan paniscus 281Met Asp Ser Asp Glu Thr Gly Phe Glu His Ser Gly Leu Trp Val Ser 1 5 10 15 Val Leu Ala Gly Leu Leu Leu Gly Ala Cys Gln Ala His Pro Ile Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr 35 40 45 Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg 50 55 60 Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu 65 70 75 80 Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val 85 90 95 Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly 100 105 110 Ser Val Ser Phe Gln Asp Pro Pro His His Pro Pro Cys Ser Ser Tyr 115 120 125 Met Ser Pro Ser Gln Pro Gly 130 135 282116PRTMacaca fascicularis 282Met Asp Ser Asp Glu Thr Gly Phe Glu His Ser Gly Leu Trp Val Pro 1 5 10 15 Val Leu Ala Gly Leu Leu Leu Gly Ala Cys Gln Ala His Pro Ile Pro 20 25 30 Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr 35 40 45 Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg 50 55 60 Glu Asp Gly Thr Val Gly Gly Ala Ala His Gln Ser Pro Glu Ser Leu 65 70 75 80 Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val 85 90 95 Lys Thr Ser Arg Phe Leu Cys Gln Lys Pro Asp Gly Ala Leu Tyr Gly 100 105 110 Ser Val Ser Phe 115 283104PRTMesocricetus auratus 283Val Ile Gln Ile Leu Gly Val Lys Ala Ala Arg Phe Pro Cys Gln Gln 1 5 10 15 Pro Asp Gly Ser Leu Tyr Gly Ser Pro His Phe Asp Pro Glu Ala Cys 20 25 30 Ser Phe Arg Glu Leu Leu Leu Glu Asp Gly Tyr Asn Val Tyr Gln Ser 35

40 45 Glu Ala His Gly Leu Pro Leu Arg Leu Pro Gln Arg Asp Ala Pro Ser 50 55 60 Gln Pro Pro Ala Ser Trp Gly Pro Val Arg Phe Leu Pro Val Pro Gly 65 70 75 80 Leu Phe Gln Pro Pro His Asp Leu Pro Gly Arg Pro Ala Pro Glu Pro 85 90 95 Pro Asp Val Gly Ser Ser Asp Pro 100 284151PRTOreochromis niloticus 284Met Tyr Leu Gln Met Asn Met Asp Gly Arg Val Thr Gly Ser Asp Ala 1 5 10 15 Gln Thr Pro Tyr Ser Leu Met Gln Leu Lys Ser Val Lys Pro Gly His 20 25 30 Val Ile Ile Lys Gly Pro Ser Ser Ser Leu Phe Leu Cys Val Asp Ser 35 40 45 Glu Gly Asn Leu Arg Gly Gln Ser His Tyr Ser Glu Thr Ser Cys Thr 50 55 60 Phe Arg Glu Met Leu Leu Ala Asp Gly Tyr Thr Arg Phe Ile Ser Ser 65 70 75 80 Gln Tyr Gly Phe Pro Met Ser Leu Ala Ser Arg His Ser Pro Asp Arg 85 90 95 His Ala Leu Pro Phe Thr Arg Phe Leu Pro Leu Arg Asn Asn Leu Lys 100 105 110 Thr Asp Ser Val Ser Glu Gln Leu Pro Asn Asn Gln Arg Leu Phe Asn 115 120 125 Val Asp Ser Asp Asp Leu Leu Gly Met Gly Leu Asn Ser Met Gly Ser 130 135 140 Pro Gln Phe Ser Met Asp Lys 145 150 285630DNAHomo sapiens 285atggactcgg acgagaccgg gttcgagcac tcaggactgt gggtttctgt gctggctggt 60cttctgctgg gagcctgcca ggcacacccc atccctgact ccagtcctct cctgcaattc 120gggggccaag tccggcagcg gtacctctac acagatgatg cccagcagac agaagcccac 180ctggagatca gggaggatgg gacggtgggg ggcgctgctg accagagccc cgaaagtctc 240ctgcagctga aagccttgaa gccgggagtt attcaaatct tgggagtcaa gacatccagg 300ttcctgtgcc agcggccaga tggggccctg tatggatcgc tccactttga ccctgaggcc 360tgcagcttcc gggagctgct tcttgaggac ggatacaatg tttaccagtc cgaagcccac 420ggcctcccgc tgcacctgcc agggaacaag tccccacacc gggaccctgc accccgagga 480ccagctcgct tcctgccact accaggcctg ccccccgcac tcccggagcc acccggaatc 540ctggcccccc agccccccga tgtgggctcc tcggaccctc tgagcatggt gggaccttcc 600cagggccgaa gccccagcta cgcttcctga 630286630DNAPongo abelii 286atggactcgg acgagaccgg gttcgagcac tcaggactgt gggttcctgt gctggctggt 60cttctgctgg gagcctgcca ggcacacccc atccctgact ccagtcctct cctgcaattc 120gggggccaag tccggcagcg gtacctctac acagatgatg cccagcagac agaagcccac 180ctggagatca gggaggatgg gacggtgggg ggcgctgctg accagagccc cgaaagtctc 240ctgcagctga aagccttgaa gccgggagtt attcaaatct tgggagtcaa gacatccagg 300ttcctgtgcc agaggccaga tggggccctg tatggatcgc tccactttga ccctgaggcc 360tgcagcttcc gggagctgct tcttgaggac ggatacaatg tttatcagtc cgaggcccat 420ggcctcccgc tgcacctgcc gggaaacaag tccccacacc gggaccctgc accccgagga 480ccagctcgct tcctgccact accaggcctg ccccccgcac ccccagagcc gcccggaatc 540ctggcccccc agccccccga tgtgggctcc tcggaccctc tgagcatggt gggaccttcc 600cagggccgaa gccccagcta tgcttcctga 630287630DNAPan troglodytes 287atggactcgg acgagaccgg gttcgagcac tcaggactgt gggtttctgt gctggctggt 60cttctgctag gagcctgcca ggcacacccc atccctgact ccagtcctct cctgcaattc 120gggggccaag tccggcagcg gtacctctac acagatgatg cccagcagac agaagcccac 180ctggagatca gggaggatgg gacggtgggg ggcgctgctg accagagccc cgaaagtctc 240ctgcagctga aagccttgaa gccgggagtt attcaaatct tgggagtcaa gacatccagg 300ttcctgtgcc agaggccaga tggggccctg tatggatcgc tccactttga ccctgaggcc 360tgcagcttcc gggagctgct tcttgaggac ggatacaatg tttaccagtc cgaggcccac 420ggcctcccgc tgcacctgcc ggggaacaag tccccacacc gggaccctgc accccgagga 480ccagctcgct tcctgccact accaggcctg ccccccgcac ccccggagcc acccggaatc 540ctggcccccc agccccccga tgtgggctcc tcagaccctc tgagcatggt gggaccttcc 600cagggccgaa gccccagcta cacttcctga 630288630DNACanis lupus familiaris 288atgggctggg ccgaggccgg gttcgagcac ctgggactgt gggtccctgt gctggctgtg 60cttttgctgg aagcctgccg ggcacatccg atccctgact ccagccccct cctacaattt 120ggaggtcaag ttcgacagcg gtacctctac accgacgatg cccaggagac agaggcccac 180ctagagatca gggccgatgg cacagtggtg ggggctgccc gccagagccc tgaaagtctc 240ctggagctga aagccctaaa gccaggggtc attcaaatct tgggagtcaa aacatccagg 300ttcctgtgcc agggcccaga tgggacacta tatggctcgc tccatttcga ccctgtggcc 360tgcagtttcc gagaactgct tcttgaggat gggtacaaca tctaccactc cgagaccctt 420ggtctcccgc ttcgcctgcg cccccacaac tccgcatacc gggacttggc accccgcggg 480cctgcccgct tcctgccact gccaggcctg cttccagcac ccccagagcc tccagggatc 540ctggccccgg agcctcctga cgtgggctcc tcggaccctc tgagcatggt ggggccttca 600cagggccgga gtcccagcta tgcttcctaa 630289630DNABos taurus 289atgggctggg acgaggccaa gttcaagcac ttgggactgt gggtccctgt gctggctgtc 60ctcctgctag gaacctgccg ggcgcatccc attccagact ccagccccct cctccagttt 120gggggccaag tccgccagcg gtacctctac acggatgatg cccaggagac agaggcccac 180ctggagatca gggccgatgg cacagtggtg ggggcagccc gccagagccc cgaaagtctc 240ttggagctga aagccctgaa gccaggcgtc attcagatct tgggagttaa aacatccagg 300tttctctgcc aggggccaga tgggaagctg tacggatcgc tgcactttga ccccaaagcc 360tgcagctttc gggagctgct tcttgaagat ggatacaacg tctaccagtc ggagaccctg 420ggccttccac tccgcctgcc cccccagcgc tcgtccaacc gggacccggc cccgcgggga 480cctgctcgct tccttccact gccgggcctg cccgcggcgc ccccggatcc tccagggatc 540ttggcccccg agcctcccga cgtgggctcc tcggatcccc tgagtatggt gggaccctcg 600tatggccgaa gccccagcta cacttcttga 630290630DNAEquus caballus 290atggactggg acaagacggg gttcaagtac cagggactgt gggtccctgt gctggctgtc 60cttctgctgg gagcctgcca gtcacacccc atccctgact ccagtcccct cctccaattc 120gggggccaag tcaggcagcg ccacctctac acagatgatg cccaggagac agaggcgcac 180ctggagatca gggctgacgg cactgtggca ggggctgtcc accggagccc agaaagtctc 240ttggagctga aagccctgaa gccaggggta attcaaatct tgggagtcaa gacatccagg 300tttctgtgcc aggggccaga cgggacgctg tacggatcgc tccacttcga ccccgtggcc 360tgcagcttcc gggagctgct tctcgaagac ggctacaacg tttaccagtc tgagaccctt 420ggcctcccac tccgcctgcc ccaccacagc tccccatacc aggatccggc ccctcgggca 480cccgcccgct tcctgccgct gccaggcttt cccccagcac ccccggagcc tccagggatc 540ccggcccccg agcccccgga cgtgggctcc tcggaccccc tgagcatggt ggggccttca 600cgcagccgga gccccagcta cacttcctga 630291630DNAAiluropoda melanoleuca 291atgggctggg acgaggccag gtccgagcag ctggggctgt gggtccctgt gctggctgtc 60cttttgctgg aagcttgcca ggcacaccct atccctgact ccagccccct cctccaattc 120ggaggccaag ttcgacagcg gtacctctac acggacgatg cccaggagac agaggcccac 180ctagcgatca gggctgatgg cacagtggtg ggggctgcca gccggagccc agaaagtctc 240ttggagctga aagccctgaa accgggggtc attcaaatcc tgggagtgaa aacatctagg 300ttcctgtgcc agggcccaga tgggacactg tacggatcgg tccgcttcga ccccgtagcc 360tgcagcttcc gggaactgct cctggaggat gggtacaaca tctaccactc tgagaccctc 420ggcctcccac ttcgcctgcc cgcccacaac tctccatacc gggactcggc gccccggggg 480cctgcccgct tcctgcccct gccaggcctg cttccggtcc ccccggaccc cccagggatc 540ctgggccccg agcctcccga cgtgggctcc tcggaccccc tgagcatggt ggggccttca 600cagggccgaa gtcccagcta cgcttcctga 630292630DNAOryctolagus cuniculus 292atggactggg gcaaggccaa gtgccggccc ccggggctgt gggtccccgc gctcgctgcc 60ctgctgctgg gggcctgcca ggcacacccc atccccgact ccagccccct cctccagttt 120ggggaccaag tgcggcagca gcacctgtac acggacgatg cgcaggaaac agaagcccac 180ctggagatca gggcggatgg cacggtggtg ggggctgccc ggaggagccc agaaagtctc 240ttgcagatga aagccttaca accggggatc attcagatct tgggggtcca gacgtccagg 300ttcctctgcc agaggccgga tggcacgctc tacggctcgc tccacttcga ccgcgaggcc 360tgcagcttcc gggagctgct gcgtgaggat gggtacaacg tttacctctc ggaggccctg 420ggcctgcccc tgcgcctgtc ccccggcagc tccccacgca gggcgccggc cccccgggga 480ccagcccgct tcctgccgct gcccggcctg ccgccagacc ttccggaacc gccaggcctc 540ctggccgccg cgccccccga tgtcgactcc ccggaccccc tgagcatggt gcagcctgcg 600ctggaccaga gccccagcta cacctcctga 630293630DNAGorilla gorilla 293atggactcgg acgagaccgg gttcgagcac tcaggactgt gggtttctgt gctggctggt 60cttctgctgg gagcctgcca ggcacacccc atccctgact ccagtcctct cctgcaattc 120gggggccaag tccggcagcg gtacctctac acagatgatg cccagcagac agaagcccac 180ctggagatca gggaggatgg gacggtgggg ggtgctgctg accagagccc tgaaagtctc 240ctgcagctga aagccttgaa gccgggagtt attcaaatct tgggagtcaa gacatccagg 300ttcctgtgcc agaggccaga tggggccctg tatggatcgc tccactttga ccctgaggcc 360tgcagcttcc gggagctgct tcttgaggac ggatacaatg tttaccagtc cgaggcccac 420ggcctcccgc tgcacctgcc ggggaacaag tccccacacc gggaccctgc accccgagga 480ccagctcgct tcctgccact accaggcctg ccccccgcac ccccggagcc acccggaatc 540ctggcccccc agccccccga tgtgggctcc tcggaccctc tgagcatggt gggaccttcc 600cagggccgaa gccccagcta cgcttcctga 630294630DNANomascus leucogenys 294atggactcgg acgagaccgg gttcgagcac tcaggactgt gggttcctgt gctggctggt 60cttctgctgg gagcctgcca ggcacacccc atccctgact ccagtcctct cctgcaattc 120gggggccaag tccggcagcg gtacctctac acagatgatg cccagcagac agaagcccac 180ctggagatca gggaggatgg gacggtgggg ggcgctgctg accagagccc tgaaagtctc 240ctgcagctga aagccttgaa gccgggagtt attcaaatct tgggagtcaa gacatccagg 300ttcctatgcc agaggccaga tggggccctg tatggatcgc tccactttga ccctgaggcc 360tgcagcttcc gggagctgct tcttgaggac ggatacaatg tttaccagtc cgaggcccat 420ggcctcccgc tgcacctgcc ggggaacaag tccccacacc gggaccctgc accccgagga 480ccagctcgct tcctgccact accaggcctg ccccctgcac ccccagagcc gcccggaatc 540ctggcccccc agccccccga tgtgggctcc tcggaccctc tgagcatggt gggaccttcc 600cagggccgaa gccccagcta cgcttcctga 630295630DNAProcavia capensis 295atggactggg ccaagtttgg gatcgagcac ccgggactgt gggtcccggt gatggcagta 60cttctgctgg gagcctgcca aggataccct attcctgact ccagccccct tctccaattc 120ggaggccagg tccggcaacg ttacctctac acagatgacg cgcaggagac cgaggcccac 180ctggagatcc gagcagacgg cacggtggtg ggggctgccc accggagccc cgagagtctc 240ttggagctga aagctttgaa gcccggcata attcagatct tgggagtcaa gacatccaga 300ttcctctgcc agggtcctga tggggtgctg tatggatcgc tccgttttga cccagtggcc 360tgcagcttcc gggagctgct tcttgaagat ggatacaatg tttaccagtc tgaggcccac 420ggcctcccgc ttcgcctacc atcccacaat tccccacaga gggacctggc gtcccgggtg 480ccagcccgct tcctgccact gccaggccgg ctcacggtgc tcccagaacc ttcgggggtc 540ctgggccctg agccccccga tgtggactcc tcagaccccc tgagcatggt ggggccttcg 600cagggccgaa gccccagtta cgcctcctga 630296630DNACavia porcellus 296atggactggg cccggactga gtgtgagcgc ccaaggctgt gggtctccat gctggccatc 60cttctggtgg gagcctgcca ggcacaccct atccctgact ccagccccct cctccagttt 120gggggccagg tccggcagcg gtacctctac acagatgatg ctcaggacac tgaagtgcac 180ctggagatca gggccgatgg ctcagtacgg ggcattgccc acaggagccc tgaaagtctc 240ctggagctga aagccttgaa gccaggagtc attcagatct tgggaatcag gacttccagg 300ttcctgtgcc agaggcccga tgggagtctg tatggatcac tccactttga tcctgaggcc 360tgcagcttcc gggagctgct gcttgctgat ggctacaatg tctacaagtc tgaagcccac 420ggcctccctc tgcacctgct gcgcggtgac tctctatcgc aggaaccagc acccccagga 480ccagcccgat ttctgccact accaggcctg cccgcaacac ccccggagcc acccaggatg 540ctgcccccag ggcccccaga tgtgggctcc tcggaccctt tgagcatggt ggggccttta 600tgggaccgaa gccccagcta tacttcctga 630297583DNATupaia belangeri 297atgggctggg acaaggcccg gttcgagcac ctgggagcgt gggctcctgt gctggctgtc 60ctcctcctgg gagcctgcca ggcatacccc atccctgact ccagccccct cctacaattc 120gggggccagg tccggcagcg gtacctctac acggacgaca cgcaggacac agaagcccac 180cttgagatca gggccgacgg caccgtggtg ggggccgccc accaaagccc ggaaagtctc 240ctggagctga aagccttgaa gccgggggtc attcaaatcc tgggagtcaa gacctccagg 300ttcctgtgcc agaggccaga cggggccctg tacgggtcgc ttcacttcga ccccgaggcc 360tgcagcttcc gggagctgct tctcgaggat ggatacaaca tttaccagtc tgaggctcgt 420ggcctccccc tgcgcctgcc gccccacgac tccccacatc gggaccggac ccctcgggga 480ccagctcgtt tcctgccgct gcctggcctg cccctggttc ctccagagct gccaggggtc 540ctggcccttg agccccccga cgtgggctcc tcagacccgc tga 583298586DNASorex araneus 298atggtctggg acaaggccag ggggcagcag ttgggactgt gggcccccat gctgctgggc 60ttgctgctgg gtgcctgcca ggcacacccc ctccctgact ccagccccct cctccaattt 120gggggccaag tccgactgag gttcctgtac accgacgatg cccagaggac aggggcgcac 180ctggagatca gggccgacgg cacagtgcag ggtgcggccc acaggacccc agaatgtctc 240ctggagctga aagccttgaa gccaggcgta attcaaatcc ttggggtcag cacatccaga 300ttcctgtgcc agcggcccga tggggtcctg tatggatcgc ttcgctttga cccagaggcc 360tgcagtttcc gggaacttct tctccaggat ggatataacg tttaccagtc tgaggccctg 420ggtctcccgc tctacctaca cccgcccagt gccccagtgt cccaggaacc agcctcacgg 480ggcgccgtcc gcttcctgcc actgccagga ctgccacctg cctccctgga gccccccagg 540ccccccgccc cggtgcctcc agacgtgggt tcctcagacc ccctga 586299546DNAIctidomys tridecemlineatus 299atgtacccca tccctgactc aagccccctc ctccaatttg ggggccaagt ccggcagcgg 60tacctgtaca cagatgatgc ccaggagact gaggcccacc tggagatcag ggctgatggc 120accgtggtgg gggctgccca tcaaagcccg gaaagtctct tggaactgaa agccttgaag 180cctggggtca ttcaaatctt gggggtcaaa acatccaggt tcctgtgcca gaggccagat 240ggagtgctgt atggatcgct ccactttgac cctgaggcct gcagcttccg ggagcagctt 300ctggaggacg ggtacaacgt ttaccagtca gaatcccacg gcctccccgt gcgcctgccc 360cctaactcac cataccggga cccagcgccg ccaggaccag cccgcttcct tccactgcca 420ggcctgcccc cagcagccct ggagccgcca gggatcctgg gccctgagcc ccctgatgtg 480ggctcctccg acccactcag catggtgggg cctttgcagg gccgaagccc cagttacgct 540tcctga 546300627DNALoxodonta Africana 300atggactggg ccaagtttgg gttggagcac ccaggactgt gggtccctgt gatggctgtc 60cttctgctgg gagcctgcca gggacacccc atccctgact ccagccccct cctccaattc 120gggggccagg tccggcaacg ttacctctac acagatgatc aggagaccga ggcccacctg 180gagatcagag cagatggcac agtggcggga gccgctcacc ggagctctga gagtctcttg 240gagctgaaag ctttgaagcc tggaataatt cagatcttgg gggtcaagac atcccggttc 300ctgtgccagg ggcctgatgg ggtgctgtac ggatcgctcc atttcgaccc agccgcctgc 360agcttccggg agctgcttct tgaagatgga tacaatgttt actggtccga ggcccatgga 420ctcccaatcc gcctgccctc ccacaactcc ccatataggg acccagcatc ccgggtacca 480gcccgcttcc tgccactgcc aggcctgctc ccaatgctcc aagaacctcc aggggtcctg 540gcccctgagc cccctgatgt ggactcctca gaccccctga gcatggtggg gccttcacag 600ggccgaagcc ccagctatgc ctcctga 627301627DNASus scrofa 301atgggctggg ccgaggccaa gttcgagcgc ttgggactgt gggtccctgt gctggctgtc 60ctgctgggag cctgccaggc acgtcccatt cctgactcca gccccctcct ccaatttggg 120ggccaagtgc gccaacgata cctctacacg gatgatgccc aggaaactga agcccacctg 180gagatcagag ctgatggcac cgtggcaggg gtagcccgcc agagccctga aagtctcttg 240gagctgaaag ccctgaagcc aggggtcatt caaattttgg gagtccagac atcccggttc 300ctgtgccagg ggccagacgg gagactgtac ggatcgctcc acttcgaccc tgaggcctgc 360agcttccggg agctgcttct tgaggatggc tacaacgttt accagtctga ggcccttggc 420ctcccactcc ggctgcctcc gcaccgctcc tccaaccggg acctggcccc ccggggacct 480gctcgcttcc tgccactgcc aggcctgccc ccggcacccc cggagccgcc agggatcttg 540gcccctgaac ctcccgacgt gggctcctcg gaccccctga gcatggtggg gccttcacac 600ggccggagcc ccagctacac ttcttga 627302627DNAFelis catus 302atgggctggg acgaggccgg gtcccagcgc ctgggactgt gggtcgtgct gggggtcctt 60ttgccggaag cctgccaggc acaccctatc cctgactcca gccccctcct ccaattcggg 120ggccaagttc gacagcggtt cctctacacg gacgacgccc aggagacaga ggtccacctc 180gagatcaagg ctgatggcac agtggtgggg accgctcgcc ggagccctga gagtctcttg 240gagctaaaag ccctgaagcc gggggtaatt caaatcttgg gggtcaaaac gtccaggttc 300ctgtgccagg gcccagatgg gacactgtat ggatcgctcc gctttgaccc cgcagcctgc 360agcttccggg aactgctcct ggaggacgga tacaacatct accactcgga gaccctcggg 420ctcccactcc gcctgccccc ccacaactcc ccataccggg acttggcccc ccgggcacct 480gcccgcttcc tgccgctgcc aggcctgctt ccggcacccc cggagcctcc agggatcctg 540gcccccgagc ccccggacgt gggctcctcg gaccctctga gcatggtggg gccttcccag 600ggccgaagtc ccagctacgc ttcctga 627303627DNAOtolemur garnettii 303gacaaggcca ggactgggtt caagcaccca ggaccatggt ttcccctgct ggctgtactt 60ttgttgggag cctgccaggc acaccctatc cctgactcca gccccctact ccagtttggt 120ggccaagtcc ggcagcggta cctctacaca gatgatgccc aggagacaga agcccacctg 180gagatcaggg aagatggcac agtggtgggg gctgcacaac agagccctga aagtctcttg 240gagctgaaag ctttaaagcc aggggtcatt caaatcttgg gagtcaagac atccaggttc 300ctgtgccaga ggccagatgg gggcctatat ggatcgctct actttgaccc caaggcctgc 360agtttccggg agctgcttct tgaggatgga tacaacgttt actggtctga gacctatggc 420ctcccactgc acctgcctcc tgccaattcc ccatactggg gcccatccct tcggagccca 480gcccgcttcc tgccactgcc aggccctcct gcagcatccc cagagctgcc ggggatcttg 540gccctggaac cccccgatgt gggctcctcg gaccctctga gcatggtggg gccttcgcag 600ggccgaagcc ccagctatgc ttcctga 627304627DNARattus norvegicus 304atggactgga tgaaatctag agttggggcc ccgggactgt gggtctgtct cctgctgcct 60gtcttcctgc tgggggtgtg cgaggcatac cccatctctg actccagccc cctcctccag 120tttgggggtc aagtccgaca gaggtatctc tacacagatg acgaccagga caccgaagcc 180cacctggaga tcagggagga cggaacagtg gtgggcacag cacaccgcag tccagaaagt 240ctcctggagc tcaaagcctt gaagccaggg gtcattcaaa tcctgggtgt caaagcctct 300aggtttcttt gccaacaacc agatggaact ctctatggat cgcctcactt tgatcctgag 360gcctgcagtt tcagagagct gctgcttaag gacggataca atgtgtacca gtctgaggcc 420catggcctgc ccctgcgtct gccccagaag gactcccagg atccagcaac ccggggacct 480gtgcgcttcc tgcccatgcc aggcctgccc cacgagcccc aagagcaacc aggagtcctt 540cccccagagc ccccagatgt gggttcctcc gaccccctga gcatggtaga gcctttgcaa 600ggccgaagcc ccagctatgc atcttga 627305633DNAMus musculus 305atggaatgga

tgagatctag agttgggacc ctgggactgt gggtccgact gctgctggct 60gtcttcctgc tgggggtcta ccaagcatac cccatccctg actccagccc cctcctccag 120tttgggggtc aagtccggca gaggtacctc tacacagatg acgaccaaga cactgaagcc 180cacctggaga tcagggagga tggaacagtg gtaggcgcag cacaccgcag tccagaaagt 240ctcctggagc tcaaagcctt gaagccaggg gtcattcaaa tcctgggtgt caaagcctct 300aggtttcttt gccaacagcc agatggagct ctctatggat cgcctcactt tgatcctgag 360gcctgcagct tcagagaact gctgctggag gacggttaca atgtgtacca gtctgaagcc 420catggcctgc ccctgcgtct gcctcagaag gactccccaa accaggatgc aacatcctgg 480ggacctgtgc gcttcctgcc catgccaggc ctgctccacg agccccaaga ccaagcagga 540ttcctgcccc cagagccccc agatgtgggc tcctctgacc ccctgagcat ggtagagcct 600ttacagggcc gaagccccag ctatgcgtcc tga 633306324DNAVicugna pacos 306atggactggg acgaggccaa gttcgagcat cggggactgt gggtcccagt gctcactgtc 60cttctgctgg gagcctgcca ggcacgcccc attcctgact ccagccccct cctccaattc 120gggggccaag tccggcagcg gtacctctac acggatgacg cccaggagac agaagcccac 180ctggagatca gggctgatgg cacagtggtg ggggtggccc gccagcccga aggaattcct 240cccgagcctc ctgacgtggg ctcctcagac cccctgagca tggtggggcc ttcatacagc 300agaagcccca gctacacttc ctga 324307633DNAAnolis carolinensis 307tgtaaaagca agggaggagg gaagggggga gagaggatgt gggtagacct agttttctgg 60gctgccttgc tccgcacagc tcctgctctt cccttgcgga attccaaccc catctaccaa 120tttgatgggc aggtccggct tcggcacctc tacacagcag atgaacagac gcacctccac 180ttggagatct tgccagacgg taccgtgggt ggatccaggt ttcagaatcc cttcagtttg 240atggagatca aagctgtgaa gccaggagtc attcgcatgc aggccaagaa gacctctaga 300tttctctgta tgaaacccaa tggacgactg tatggctcgc tgttctactc tgaggaggca 360tgcaacttcc atgagaaggt tctcagcgat ggctacaacc tctactattc tgaaaactac 420aacatacctg tcagcctcag ctcggcaggg aacctgggtc agagccgtca gttgcctccc 480ttctcccaat tcctgccgtt agtcaacaaa attcctcttg agcctgtgct tgaagacttt 540gacttctatg gacatcaatt ggatgttgaa tcagctgatc ctttgagcat tttaggacaa 600aaccctggtt tcatgagtcc gagctatgtc ttc 633308564DNAGadus morhua 308ctcctcctcg ccaccctcct ccacatcggc ctctccttct acgtccccga ctccggcccc 60ctgctgtggc tgggcgacca ggtcagggag agacacctct acacagcaga gagccaccgg 120agggggctgt tcctggagat gagcccggac ggtcaggtga caggaagtgc tgctcagacg 180ccgctcagtg ttctggagct gaggtcggtc agagcaggag atacggtcat cagagcgcgc 240ctctcctctc tctacctgtg tgtggacagg gcaggtcacc tgacaggaca gagacagtac 300acagagtccg actgcacctt cagagaggtc atccttgagg acggctacac ccacttcctg 360tccgtgcacc acggacttcc tatttcgctg gcgccgagac actccccagg gagacagggg 420ctgcgcttca gcaggttcct cccgctgagg agcagtctgt cagaggatag ggtcgccgag 480cccccagaca gcccactgaa cctggactct gaagaccccc tggggatggg tctgggttcg 540ctcctcagcc cggccttctc catg 564309648DNALatimeria chalumnae 309atgttatgcc agagttttgt gatattaagt cagaaattca tttttgggct ctttttgact 60ggattggggc taacaggatt ggcttggaca aggcccttcc aggattccaa tcccatcctg 120cagtattccg attccatccg gctccgacat ctgtacactg ccagtgagag tcggcacctt 180cacctacaaa tcaactcgga tggacaggtg ggagggacaa ccaagcaaag cccttacagt 240ctgttggaga tgaaggcggt gaagacaggt tttgtggtca tcaggggcaa gaaaagcgcc 300cgttacctct gtatggaacg tagtggacgg ctctatggat cgctgcagta tacagaaaaa 360gactgcacct tcaaagaggt tgtgttggca gatggataca acctgtatgt ctcagaggaa 420caccaggcca cagtgacgct gagccccatg agggcgagga tagcgcaagg gaaaaagatc 480ccaccctttt cccatttcct tccaatggtg aacaaggtgc ctgtggagga tgttgccgct 540gagatggagt ttgtccaggt gctgcgggaa atgacggccg acgtggactc tccggatccc 600tttggaatga cctgggaaga atcggttcac agtccgagct tttttgcc 648310579DNATursiops truncates 310atgggctggg acaagaccaa actcgagcac ctgggactgt gggtccctgt gctagctgtc 60ctgctgggac cctgccaggc acatcccatt cctgactcca gccccctcct ccaatttggg 120ggccaagtcc gccagcgata cctctacacg gatgacgccc aggagacgga ggcccacctg 180gagatcaggg ctgatggcac agtggtgggg acggcccgcc ggagccccga aggagttaaa 240acatccaggt tcctgtgcca ggggccagag gggaggctgt atggatcgct ccacttcaac 300ccccaggcct gcagcttccg ggagctgctt cttgaggatg gatacaacgt ttaccagtct 360gaggctcttg gcattcccct ccgcctgccc ccgcaccgct cctccaactg ggacctggcc 420ccccggggac ctgctcgctt cctgccgctg ccaggcttcc tcccgccacc cctggagcct 480ccagggatct tggcccccga gcctcccaac gtaggttcct cggacccctt gagcatggtg 540ggaccttcac atggccgaag ccccagctac acttcctga 579311630DNAMustela putorius furo 311atgggctggg aagaggccag gtccgagcac ctggggctgt gggtccctgt gctggcggtc 60cttttgctgg gagcctgcca ggcataccct attcctgact ccagccccct cctccaattt 120ggaggccaag ttcgacagcg gtacctctac acagacgacg ctcaggagac ggaggcccac 180ctagagatca gggctgatgg cacggtggtg ggggctgccc gccggagccc cgaaagtctc 240ttggagctga aagccctgaa gccaggggtc attcagatct tgggagtgaa aacatccagg 300ttcctgtgcc agggcccgaa tgggacactg tacggatcgt tccacttcga ccccgtagcc 360tgcagcttcc gggaagtgct tctggaagat ggatacaaca tctaccactc tgagaccctg 420ggcctcccac tgcgcctgcc cccccacaac tccccacaca gggacctggc gccccggggg 480cctgcccgct tcctgcccct gccaggcctg cttccggcca ccccggagtc ccgggggatc 540ccagcccccg agcctcccaa cgtgggctcc tcagaccccc tgagcatggt ggggcctttg 600cagggtcaaa gtcccagcta cacttcctga 630312597DNATakifugu rubripes 312tttatttatt tatttattca aactgcactt ttttcccctt ccaaatggtt caacttttat 60ctccctgact ccaacccgct cttatccttt gacagtcatg gcagaggcat ccacctctac 120acagataatc aaaggcgagg gatgtatctg cagatgagca cagatggaag cgtttccggg 180agtgatgtcc agacggcgaa cagtgtgctg gaactgaagt cagtcagaaa cggccacgtc 240gtcatccgag gaaaatcgtc ttctctgttt ctctgtatgg acagcagagg ccgtttatgg 300gggcagaggc accccactga ggccgactgc actttcaggg aagtgttgct ggcagatgga 360tacactcgct tcctgtccct gcacaacgga actcctgtgt ctctggcacc taaacaatct 420ccagaccagc acacagtccc cttcactcgt ttcctgccgc tcaggaatac actggcagag 480gagagcatgt ctgaaccacc atcaaaccaa cagagatatt ttaacattga ctctgatgat 540cttcttggaa tggatttaaa tgcgatggtc agtcctcagt tttcagggga caagtga 597313612DNADipodomys ordii 313atggaccagg caaagaccag ggttggggcc cgggggctgg ggggccttgt gctggctgtc 60ataattctgg gagcatgcaa ggcacggcct atccctgact ccagccccct cctccaattt 120gggggtcaag ttcggcttcg gcacctctac acagatgaca ctcaggagac ggaagcccat 180ctggagatca gggcagatgg cacggtagtg gggactgccc accggagccc tgaaagtctc 240ttggagctga aagccttgaa gccaggagtc attcaaatct tagggatcaa gacatccaga 300ttcttatgcc agagaccaga cgggacactg tatggatcac tccactttga ccctgaggtt 360tgcagcttcc aggagctgct tctggaagat ggatacaaca tttaccgttc tgaagccctg 420ggtctccccc tgcgcctgtc cccagatcca gcaccctggg ggccagcccg cttcctgccc 480ctgcctggtg tgccccccgc accgccggag ccccccggga tcctggctcc cgaaccccct 540gatgtcggct cctccgaccc tctgagtatg gtgggactgt tgcagggccg aagccccagc 600tatgcatcct ga 612314555DNAEchinops telfairi 314atgggttgca ccaaatctgg gtggaagtcc ccgggactgt gggtccctgt gctggccagc 60cttctgctgg gaggctgcgg agcacacccc atccctgact ccagccccct cctccaattc 120gggggccaag tccggcagcg atacctctat acggatgacg cccagaccac cgaggcccac 180ctggagatca gagcggatgg cacagtgggg ggcgtcgccc accagagccc agagaagttc 240ctgagtcaat ggcgtgaaaa gcccctgaga tcactccatt tcgacccagc cgcctgcagc 300ttccgggaga agcttctaga agacggatac aacttgtacc actctgagac ccacggcctc 360cccctccgcc tcccaccccg tgggggcgac ccctcttctc agcctggggc ccgcttccca 420ccgctgccgg gccagctccc acaactccaa gagacgccag gggtcctcgc ccccgaaccc 480cccgacgtgg gctcttcaga ccccctgagc atggtggggc cttggcgagg gcaaagtccc 540agttatgcct cctga 555315633DNAMacaca mulatta 315atggactcgg acgagaccgg gttcgagcac tcaggactgt gggttcctgt gctggctggt 60cttctgctgg gagcctgcca ggcacacccc atccctgact ccagtcctct cctgcaattc 120gggggccaag tccggcaacg gtacctctac acagatgatg cccagcagac agaagcccac 180ctggagatca gggaggatgg gacagtgggg ggcgctgctc accagagccc cgaaagtgag 240tgtgggccag agcctgggtc tgagggagga ggggctgtgg gaggtgctga gggacctgga 300ctcctgggtc tgagggaggc agggctgggg cctggatcct ggctccactt tgaccctgag 360gcctgcagct tccgggagct gcttcttgag aacggataca atgtttacca gtccgaggcc 420cacggcctcc cactgcacct gccgggaaac aagtccccac accgggaccc tgcatcccaa 480ggaccagctc gcttcctgcc actaccaggc ctgccccccg cacccccgga gccgccagga 540atcctcgccc cccagccccc cgatgtgggc tcctcggacc ctctgagcat ggtgggacct 600tcccaggccc gaagccccag ctatgcttcc tga 633316582DNAMicrocebus murinus 316atgggctggg acgaggccgg cgccgggttc gagcacccag gactgtggtt tcccatgctg 60ggtgtcctgc tgctgggagc ctgccaggcg taccccatcc ctgactccag ccccctcctc 120caatttggcg gccaagtccg gcagcggcac ctctacacag acgatatcca ggagacagaa 180gcccacctgg agatcagggc ggacggcaca gtggtggggg ccgcccgaca gagccctgag 240ttggagctga aagccttaaa gccaggggtc attcaaatct tgggagtcaa gacctccagg 300ttcctgtgcc agaggccaga cggggccctg tacggatcgc tccactttga ccccgagtgc 360agcttccggg agctgcttct tgaggatgga tacaacgtct actgtcccta cctcccgctg 420cacctgtccc cacgcatcga actggccgga tcacgctctg cgctgccact gcccccagca 480cctgaacgca ggattttggc cccggagccc ccggatggct cctcggaccc tctgagcatg 540gtggggcctt cgcagggccg aagtcccagc tatgcttcct ga 582317615DNAOchotona princeps 317aaagacatgg acgggctcca gcctccgggg ctgcgggttc ctgtgctggc tgccctgctt 60ttgggagttg gccaggcacg ccccatccct gattctagcc ctctcctcca attcgggggc 120caggtccggc agaggcacct ctacacggat gacgcccagg aatcggaagt acacctggag 180atccgggcag acggcaccgt ggcagggact gcccgccgga gccctgaaag tctcttagaa 240atgaaagcgt tgaagccagg cgtcattcag atcctggggg tccacacatc caggttcctg 300tgccagagac cagacgggac gctgtacggc tcgctccact tcgaccacaa ggcctgcagc 360ttccgggagc agctgctgga ggatgggtac aacgtgtacc actcagagac acacggcctc 420ccgctgcgcc tgtctccaga ccgagccccc cggggcccag cccgcttcct gccactgcca 480ggccctcctc ctgacctcct ggtgccaccc ctgccaccgg acgtcctagc ccctgagccc 540cccgacgtgg actccccaga ccccctgagc atggtggggc ccttgcaggg ccaaagcccc 600agctacactt cctga 615318546DNAXiphophorus maculates 318tgcccgttcc ccttcctttt cttaatcctc tctcttccct ttttctcttc ctcgttttac 60atcccagaat ccaacccaat ctttgccttc aggaatcagc tcagagaggt gcatctctac 120acagaaaatc acagacgggg tttgtatgtg gagatacatc tggatgggag agtgactgga 180agtgatgctc agagtcctta tagtgtgttg cagataaagt ctgttaaacc gggtcatgtg 240gtcataaagg gacagacatc gtccctgttc ctctgcatgg acgactccgg gaatctaaga 300ggacagacaa cctatgacga ggctgactgc tccttcaggg aactgctgct ggccgatggc 360tacacccgtt tcctgaactc acaacatggc gttcctttat cactggcatc cagaaactct 420ccagatcgac actccgttcc tttcacaaga tttttacctc tcaggaatac tttaacggtt 480tcagaagaat caacaaaaac tcagagggac ttcaacctgg actcggacga ccttctcggg 540atggga 546319576DNAGasterosteus aculeatus 319tctctcctcc tcatggtccc acttcctttc tgttcatcct tttatctcac tgactccagc 60ccacttctac ccttcaataa tcaagtcaaa gaggtgcacc tctacacagc agagaatcac 120agaagagcga tgtacctgca gatcgctctg gacgggagcg tgtcgggaag cgacgctcgg 180tccacttaca gtgtgctgca gctgaaatct atccagccgg gccacgtggt catcagaggg 240aaggcctcct ccatgttcct ctgcgtggac agcgggggcc gtttgagagg acaggggccg 300tactcagagg ccgactgcag cttcagggag ctgctgctgg gggatggcta cacccggttc 360ctgtcctcgc agcacgggtc cccgctgtct ctggcgtcga ggccttcccc ggatcccaac 420tcggtgccct tcactcgatt cctacccatc cggaccgccc ccgaggctga gagcgtgatc 480gaagagccac cgagcaatca gagatacgtc aacgtggact ccgaggatct tcttggaatg 540ggcctgaaca ctgtggtcag tcctcagttc tcggcg 576320495DNASarcophilus harrisii 320gtgtctgcca tgggcctgag ggagcgagct cccaggtacc tggccccgct gctgtccttg 60ctcttggcct gcagggcctc gggtcacccc ctcccggatt ccagccccat gctcctgttt 120ggggggcagg tccgcctccg gcacctctac acggatgtgg gccaggaggc cgaggcccac 180gtggaactgg cgtccgacgg cacagtccgg gcggcagcgc ggaggagtcc caacagtctc 240ctggagctga aggctgtgaa gccgggcatc gtccgaatcc tggccgtcca cagctctcgg 300tttctgtgta tgaggcccaa cggggagctg tacggagcga tacactacga cccttccgcc 360tgcaactttc gggagcgcct gctgggggac ggctacaacg tgtacgagtc cgaggctcac 420gggaggaccc tccgcctgcc ccccaaggcc gcaccgggac ccgccggacc ttctcgcttc 480ctgccgctcc ccggc 495321627DNAMacropus eugenii 321acagaggagc cttctactgg gtccaggcac ctgggacaat gggctcccgg gctgcctggt 60cctctgctgt ccttgctcct ggcctacagg ggctggggct cccccatccc tgattccagc 120cccatgctcc tgtttggtgg ccaggtccgc ctccgacacc tgtacacaga tgatggccag 180gacacggagg cccatgtgga gctggggcca gatggagtgg ttcgagctgt ggctgagagg 240agccccaaca gtcttctgga actgaaggcg gtgaagcctg gagtcatccg aatcctcgct 300gtccagagct ctcggtttct gtgtatgagg cccaacgggg aactgtatgg agcggtacac 360tatgaccctt ctgcctgcaa ctttcgggaa catctgctgg gggatggtta taatgtgtat 420gaatcagaga ctcacagaag gaccctccgt ctgtccccat ccctgggtca ggctggcccc 480tctcgcttcc tgccacttcc aggcgactgg ctgcccggcc ctgatccacc ttgggcacag 540ggccctgagc ccccagacgt gggctctgca gaccccctga gcatggtggg ggccgtgcag 600ggcctcagcc ccagctactc ctcctga 627322480DNAXenopus tropicalis 322agagggggta ggaccaaaaa aaagacgtta ctcaggaaat ggctttgcct tttagccatt 60atgttgagta ggtcaaggtt ttctttagca aatcctatcc agaattcgaa cccaatctta 120tccaacgaca accaagtacg gactcagtat ttatacacag ataacaataa catgcacctg 180tatcttcaga tcacccacaa tggagtagta actggtaccg aagaaaagaa tgactatggt 240gtgctggaaa taaaggcagt aaaagctggg gttgtagtta taaaaggaat tcgaagcaat 300ctctacctat gcatggattc tagacaccaa ttgtatgcgt cggcatatga taaagatgac 360tgccatttcc atgaaaagat cacaccagat aattacaaca tgtatagctc agagaagcat 420tcagaatacg tgtccttagc tccattaaaa ggaagccaga tggctcgttt tctacctata 480323585DNADanio rerio 323atgcttcttg cctgcttttt tatatttttt gctctttttc ctcatcttcg gtggtgtatg 60tatgttcctg cacagaacgt gcttctgcag tttggcacac aagtcaggga acgcctgctt 120tacacagatg ggttgtttct tgaaatgaat ccagatggct ccgtcaaagg ctctcctgaa 180aagaatctaa attgtgtgct ggagctgcgt tcagtcaaag cgggtgaaac cgtcatccag 240agtgcagcta catctctcta cctctgcgtc gatgatcaag acaagctgaa aggacagcat 300cattactctg cactagactg cacctttcag gaattgctac tggatggata ttcgtttttc 360ctttctccac acactaatct tcccgtatcg ctcctctcga aacgtcagaa acacggcaat 420cctctttctc gcttcctccc tgttagcaga gcagaggaca gccggacaca ggaggtgaaa 480cagtatattc aggatataaa cctggactct gacgacccac taggaatggg acatcggtca 540cacttacaga ccgtcttcag tcccagtctg catactaaaa aatga 585324630DNABos grunniens mutus 324atgggctggg atgaagcgaa atttaaacat ctgggcctgt gggtgccggt gctggcggtg 60ctgctgctgg gcacctgccg cgcgcatccg attccggata gcagcccgct gctgcagttt 120ggcggccagg tgcgccagcg ctatctgtat accgatgatg cgcaggaaac cgaagcgcat 180ctggaaattc gcgcggatgg caccgtggtg ggcgcggcgc gccagagccc ggaaagcctg 240ctggaactga aagcgctgaa accgggcgtg attcagattc tgggcgtgaa aaccagccgc 300tttctgtgcc agggcccgga tggcaaactg tatggcagcc tgcattttga tccgaaagcg 360tgcagctttc gcgaactgct gctggaagat ggctataacg tgtatcagag cgaaaccctg 420ggcctgccgc tgcgcctgcc gccgcagcgc agcagcaacc gcgatccggc gccgcgcggc 480ccggcgcgct ttctgccgct gccgggcctg ccggcggaac cgccggatcc gccgggcatt 540ctggcgccgg aaccgccgga tgtgggcagc agcgatccgc tgagcatggt gggcccgagc 600tatggccgca gcccgagcta taccagctaa 630325630DNASaimiri boliviensis boliviensis 325atgggctcgg aggaggtcgc gttggagcgc cctgcactgt gggtctctgt gttggctggt 60ctcctgctgg gaacctgcca ggcatacccc atccctgact ctagtcccct cctgcaattt 120ggaggccaag tccggcagcg gtacctctac acagatgacg ctcagcagac agaagcccac 180ctggagatca gggaagatgg cacggtggcg ggggctgccc accagagccc cgaaagtctc 240ttgcagctga aagccttaaa gccaggggtt attcaaatct tgggagtcaa gacctccagg 300ttcctgtgcc agaggccgga cggggccctg tacggatcgc tctactttga ccccgaggcc 360tgcagcttcc gggagctgct tcttgaggac ggatacaatg tgtaccagtc cgtggcccac 420agcctcccgc tgcacctgcc agggggcagg tccccaccct gggaccctgc acctcgagga 480ccagctcgct tcctgccgct accaggcctg ccccccgaac cccccgaggc gccaggaatc 540ctggcccccg agccccccga tgtgggctcc tcagaccctc tgagcatggt ggggccttcc 600caaggccaaa gccccagcta cacttcctga 630326633DNACallithrix jacchusmisc_feature(190)..(190)n is a, c, g, or t 326atgggctcgg aggaggtcgg gttggagcac cctgcactgt gggtttctgt gctggctggt 60ctcctgctgg gaacctgcca ggcgcacccc atccctgact ccagtcccct cctgcaattt 120ggaggccaag tccggcagcg gtacctctac acagatgacg cccagcagaa agaagcccac 180ctggagatcn aggaagatgg cacagtggcc ggggctgcca ccaaagtccc gaaagtgagt 240ctcttgcagc tgaaagcctt aaagccaggg gttattcaaa tcttgggagt caagacatcc 300aggttcctgt gccagaggcc agacggggcg ctgtatggat cgctccactt tgaccccgag 360gcctgcagct tccgggagct gcttcttgag gacggataca atgtgtacca gtctgtggcc 420cacggcctcc cgctgcacct gccagagagc aggtcaccac cccgggaccc tgcaccccga 480ggaccagctc gcttcctgcc actaccaggc ctgccccctg aacccccaga gccgccagga 540atcctggccc ctgagccccc cgacgtgggc tcctcagacc ctctgagcat ggtggggcct 600tcccaaggcc aaagccccag ctacgcttcc tga 633327630DNATupaia chinensis 327atgggctggg ataaagcgcg ctttgaacat ctgggcgcgt gggcgccggt gctggcggtg 60ctgctgctgg gcgcgtgcca ggcgtatccg attccggata gcagcccgct gctgcagttt 120ggcggccagg tgcgccagcg ctatctgtat accgatgata cccaggatac cgaagcgcat 180ctggaaattc gcgcggatgg caccgtggtg ggcgcggcgc atcagagccc ggaaagcctg 240ctggaactga aagcgctgaa accgggcgtg attcagattc tgggcgtgaa aaccagccgc 300tttctgtgcc agcgcccgga tggcgcgctg tatggcagcc tgcattttga tccggaagcg 360tgcagctttc gcgaactgct gctggaagat ggctataaca tttatcagag cgaagcgcgc 420ggcctgccgc tgcgcctgcc gccgcatgat agcccgcatc gcgatcgcac cccgcagggc 480ccggcgcgct ttctgccgct gccgggcctg ccgctggtgc cgccggaact gccgggcgtg 540ctggcgctgg aaccgccgga tgtgggcagc agcgatccgc tgagcatgat gggcccgagc 600cagggccaga gcccgagcta tgcgagctaa 630328567DNAPapio anubis 328atggactcgg acgagaccgg gttcgagcac tcaggactgt gggttcctgt gctggctggt 60cttctgctgg gagcctgcca ggcacacccc atccctgact ccagtcctct cctgcaattc 120gggggccaag tccggcaacg gtacctctac acagatgatg cccagcagac agaagcccac 180ctggagatca gggaggatgg gacagtgggg ggcgctgctc accagagccc cgaaagtaag 240tgtgggccag

agcctgggtc tgagggagga ggggctctcc actttgaccc tgaggcctgc 300agcttccgcg agctgcttct tgagaacgga tacaatgttt accagtccga ggcccacggc 360ctcccactgc acctgccggg aaacaagtcc ccacaccggg accctgcatc ccgaggacca 420gctcgcttcc tgccactacc aggcctgccc cccgcacccc cagagccacc aggaatcctc 480gccccccagc cccccgatgt gggctcctcg gaccctctga gcatggtggg accttcccag 540gcccgaagcc ctagctacgc ttcctga 567329627DNAPteropus alecto 329atgggctggg gcaaagcgcg cctgcagcat ccgggcctgt ggggcccggt gctggcggtg 60ctgctgggcg cgtgccaggc gcatccgatt ctggatagca gcccgctgtt tcagtttggc 120agccaggtgc gccgccgcta tctgtatacc gatgatgcgc aggataccga agcgcatctg 180gaaattcgcg cggatggcac cgtggcgggc gcggcgcgcc gcagcccgga aagcctgctg 240gaactgaaag cgctgaaacc gggcgtgatt caggtgctgg gcgtgaaaac cagccgcttt 300ctgtgccagc gcccggatgg caccctgtat ggcagcctgc attttgatcc ggcggcgtgc 360agctttcgcg aactgctgct gaaagatggc tataacgtgt atcagagcga agcgctggcg 420cgcccgctgc gcctgccgcc gtatagcagc ccgagcagcg atccggcgcg ccgcggcccg 480gcgcgctttc tgccgctgcc gggcccgccg ccggaaccgc cgcagccgcc gggccgcctg 540gcgccggaac cgccggatgt gggcagcagc gatccgctga gcatggtgtg gccgagccgc 600ggccgcagcc cgagctatac cagctaa 627330633DNAHeterocephalus glaber 330atggattggg cgcgcgcgga aagcgaacgc ccgggcctgt gggtgccggc ggtgctggcg 60gtgctgctgc tgggcgcgtg ccaggcgcat ccgattccgg atagcagccc gctgctgcag 120tttggcggcc aggtgcgcca gcgccatctg tataccgatg atgcgcagga taccgaagtg 180catctggaaa ttcgcgcgga tggcagcgtg ggcggcgcgg cgcatcgcag cccggaaagc 240ctgctggaac tgaaagcgct gaaaccgggc gtgattcaga ttctgggcgt gcgcaccagc 300cgctttctgt gccagcgccc ggatggcacc ctgtatggca gcctgcattt tgatccggaa 360gcgtgcagct ttcgcgaact gctgctggcg gatggctata acatttatca gagcgaagcg 420tatggcctgc cgctgcgcat gctgccgagc gatagcgcga gccgcgatcc ggtgccgccg 480ggcccggcgc gctttctgcc gctgccgggc ctgcatccgc cgccgctgga accgccgggc 540atgctgccgc cggaaccgcc ggatgtgggc agcagcgatc cgctgagcat ggtgggcccg 600ctgcagggcc gcagcccgag ctatgcgttt taa 633331630DNACricetulus griseus 331atggactgga tgaaatctgg agttggggtc ccgggactgt gggtccctct gctgcctatc 60ttcctgctgg gggtctccca ggcacacccc atccctgact ccagccccct cctccagttt 120gggggtcaag tccggcacag gcacctctac acagatgaca accaggaaac tgaagtccac 180ctggagatta ggcaggatgg cacggtgata gggaccacac accgcagccc agaaagtctc 240ctggagctca aagccttgaa gccagaggtc atcccagtgc tgggtgtcaa ggcctccagg 300tttctttgcc aacaaccaga cggaaccctg tatggatcgc ctcactttga tcctgaggcc 360tgcagtttca gggagctctt gcttgaggat ggatacaatg tgtaccaatc tgaagtccat 420ggcctgcccc tgcgcctgcc ccagagggac tctccaaacc aggccccagc atcctgggga 480cctgtgcccc ccctgccagt gccaggactg ctccaccagc cccaggagct accagggttc 540ctggccccag aacctccaga tgtgggctcc tctgacccac tgagcatggt gggacctttg 600cagggccgaa gccccagcta tgcttcctga 630332579DNAOvis aries 332atgggctggg acgaggccaa gttcaagcac ttgggactgt gggtccctgt gctggctgtc 60ctcctgctag gaacctgccg ggcgcatcca attccagact ccagccccct cctccagttt 120gggggccaag tccgccagcg gtacctctac acggatgatg cccaggagac agaggcccac 180ctggagatca gggccgatgg cacagtggtg ggggcggccc gccagagtcc cgaaagtctc 240ttggagctga aagccctgaa gccaggagtc attcagatct ttggagttaa aacatccagg 300ttcctgtgcc aggggccaga tgggaagctg tatggatcgc tgcactttga ccccaaagcc 360tgcagcttcc gggagctgct tcttgaagat gggtacaatg tctaccagtc ggagaccctg 420ggccttccac tccgcctgcc gccgcagcgc tcatccaacc gggacccggc cccgcgggga 480cctccgaagc cccagctaca cttcttgaag acgtccgctg tgcagtactg gccacgttat 540gagaaggtcc cagcttttct gcaccccttc cccggctga 579333405DNAPan paniscus 333atggactcgg acgagaccgg gttcgagcac tcaggactgt gggtttctgt gctggctggt 60cttctgctgg gagcctgcca ggcacacccc atccctgact ccagtcctct cctgcaattc 120gggggccaag tccggcagcg gtacctctac acagatgatg cccagcagac agaagcccac 180ctggagatca gggaggatgg gacggtgggg ggcgctgctg accagagccc cgaaagtctc 240ctgcagctga aagccttgaa gccgggagtt attcaaatct tgggagtcaa gacatccagg 300ttcctgtgcc agaggccaga tggggccctg tatggatcgg tgagtttcca ggaccctcct 360caccacccac catgctcctc ctatatgtcg ccctcacagc ctggg 405334351DNAMacaca fascicularis 334atggatagcg atgaaaccgg ctttgaacat agcggcctgt gggtgccggt gctggcgggc 60ctgctgctgg gcgcgtgcca ggcgcatccg attccggata gcagcccgct gctgcagttt 120ggcggccagg tgcgccagcg ctatctgtat accgatgatg cgcagcagac cgaagcgcat 180ctggaaattc gcgaagatgg caccgtgggc ggcgcggcgc atcagagccc ggaaagcctg 240ctgcagctga aagcgctgaa accgggcgtg attcagattc tgggcgtgaa aaccagccgc 300tttctgtgcc agaaaccgga tggcgcgctg tatggcagcg tgagctttta a 351335314DNAMesocricetus auratus 335ggtcatccaa atcctgggtg tcaaggctgc taggtttcct tgccagcaac cagacggaag 60cctgtacgga tcgcctcact tcgatcccga ggcctgcagt ttccgggagc tcctgcttga 120ggatggatac aatgtgtacc agtcggaagc ccacggcctg cccctgcgcc tgccccagag 180ggacgctccg agccagcccc cagcatcctg gggaccggtg cgcttcctgc cagtgcccgg 240actgttccag ccgccccacg acctcccagg gcgcccggcc ccagagcctc cggacgtggg 300ctcctccgac ccac 314336456DNANile tilapia 336atgtatttgc agatgaacat ggatgggaga gtcacaggaa gtgatgctca gacaccttac 60agtttgatgc agctgaaatc agttaaacca ggccatgtaa tcattaaagg accatcatca 120tctctttttc tctgtgtgga cagcgaaggc aatctgagag ggcagagtca ctactcagaa 180accagctgca ccttcagaga aatgctgctg gctgacggat acacccgttt catttcctca 240caatatggat ttcccatgtc actggcatca agacattccc cagatcgaca cgcgcttccc 300tttacgcggt tcctaccact gaggaataac ttgaaaacgg atagcgtatc agagcagctg 360ccaaacaatc agagactctt caacgtggac tctgatgacc ttcttggaat gggtctaaat 420tctatgggca gtcctcagtt ttctatggac aaataa 456337216PRTHomo sapiens 337Met Arg Ser Gly Cys Val Val Val His Val Trp Ile Leu Ala Gly Leu 1 5 10 15 Trp Leu Ala Val Ala Gly Arg Pro Leu Ala Phe Ser Asp Ala Gly Pro 20 25 30 His Val His Tyr Gly Trp Gly Asp Pro Ile Arg Leu Arg His Leu Tyr 35 40 45 Thr Ser Gly Pro His Gly Leu Ser Ser Cys Phe Leu Arg Ile Arg Ala 50 55 60 Asp Gly Val Val Asp Cys Ala Arg Gly Gln Ser Ala His Ser Leu Leu 65 70 75 80 Glu Ile Lys Ala Val Ala Leu Arg Thr Val Ala Ile Lys Gly Val His 85 90 95 Ser Val Arg Tyr Leu Cys Met Gly Ala Asp Gly Lys Met Gln Gly Leu 100 105 110 Leu Gln Tyr Ser Glu Glu Asp Cys Ala Phe Glu Glu Glu Ile Arg Pro 115 120 125 Asp Gly Tyr Asn Val Tyr Arg Ser Glu Lys His Arg Leu Pro Val Ser 130 135 140 Leu Ser Ser Ala Lys Gln Arg Gln Leu Tyr Lys Asn Arg Gly Phe Leu 145 150 155 160 Pro Leu Ser His Phe Leu Pro Met Leu Pro Met Val Pro Glu Glu Pro 165 170 175 Glu Asp Leu Arg Gly His Leu Glu Ser Asp Met Phe Ser Ser Pro Leu 180 185 190 Glu Thr Asp Ser Met Asp Pro Phe Gly Leu Val Thr Gly Leu Glu Ala 195 200 205 Val Arg Ser Pro Ser Phe Glu Lys 210 215 338651DNAHomo sapiens 338atgcggagcg ggtgtgtggt ggtccacgta tggatcctgg ccggcctctg gctggccgtg 60gccgggcgcc ccctcgcctt ctcggacgcg gggccccacg tgcactacgg ctggggcgac 120cccatccgcc tgcggcacct gtacacctcc ggcccccacg ggctctccag ctgcttcctg 180cgcatccgtg ccgacggcgt cgtggactgc gcgcggggcc agagcgcgca cagtttgctg 240gagatcaagg cagtcgctct gcggaccgtg gccatcaagg gcgtgcacag cgtgcggtac 300ctctgcatgg gcgccgacgg caagatgcag gggctgcttc agtactcgga ggaagactgt 360gctttcgagg aggagatccg cccagatggc tacaatgtgt accgatccga gaagcaccgc 420ctcccggtct ccctgagcag tgccaaacag cggcagctgt acaagaacag aggctttctt 480ccactctctc atttcctgcc catgctgccc atggtcccag aggagcctga ggacctcagg 540ggccacttgg aatctgacat gttctcttcg cccctggaga ccgacagcat ggacccattt 600gggcttgtca ccggactgga ggccgtgagg agtcccagct ttgagaagta a 651339192PRTArtificialChimeric protein 339Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe 1 5 10 15 Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser 20 25 30 Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly 35 40 45 Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu 50 55 60 Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr Leu 65 70 75 80 Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu 85 90 95 Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr 100 105 110 Ile Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Asp Gln 115 120 125 Asn Gly Ser Cys Val Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala 130 135 140 Ile Leu Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro 145 150 155 160 Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro 165 170 175 Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 180 185 190 340168PRTArtificialChimeric protein 340Lys Pro Lys Leu Leu Tyr Cys Ser Asn Gly Gly His Phe Leu Arg Ile 1 5 10 15 Leu Pro Asp Gly Thr Val Asp Gly Thr Arg Asp Arg Ser Asp Gln His 20 25 30 Ile Gln Leu Gln Leu Ser Ala Glu Ser Val Gly Glu Val Tyr Ile Lys 35 40 45 Ser Thr Glu Thr Gly Gln Tyr Leu Ala Met Asp Thr Asp Gly Leu Leu 50 55 60 Tyr Gly Ser Gln Thr Pro Asn Glu Glu Cys Leu Phe Leu Glu Arg Leu 65 70 75 80 Glu Glu Asn His Tyr Asn Thr Tyr Ile Ser Lys Lys His Ala Glu Lys 85 90 95 Asn Trp Phe Val Gly Leu Asp Gln Asn Gly Ser Cys Val Arg Gly Pro 100 105 110 Arg Thr His Tyr Gly Gln Lys Ala Ile Leu Phe Leu Pro Leu Pro Gly 115 120 125 Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln Pro 130 135 140 Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro Ser Gln 145 150 155 160 Gly Arg Ser Pro Ser Tyr Ala Ser 165 341193PRTArtificialChimeric protein 341Met Ala Ala Gly Ser Ile Thr Thr Leu Pro Ala Leu Pro Glu Asp Gly 1 5 10 15 Gly Ser Gly Ala Phe Pro Pro Gly His Phe Lys Asp Pro Lys Arg Leu 20 25 30 Tyr Cys Lys Asn Gly Gly Phe Phe Leu Arg Ile His Pro Asp Gly Arg 35 40 45 Val Asp Gly Val Arg Glu Lys Ser Asp Pro His Ile Lys Leu Gln Leu 50 55 60 Gln Ala Glu Glu Arg Gly Val Val Ser Ile Lys Gly Val Cys Ala Asn 65 70 75 80 Arg Tyr Leu Ala Met Lys Glu Asp Gly Arg Leu Leu Ala Ser Lys Cys 85 90 95 Val Thr Asp Glu Cys Phe Phe Phe Glu Arg Leu Glu Ser Asn Asn Tyr 100 105 110 Asn Thr Tyr Arg Ser Arg Lys Tyr Thr Ser Trp Tyr Val Ala Leu Asp 115 120 125 Gln Thr Gly Gln Tyr Val Leu Gly Ser Lys Thr Gly Pro Gly Gln Lys 130 135 140 Ala Ile Leu Phe Leu Pro Met Pro Gly Leu Pro Pro Ala Leu Pro Glu 145 150 155 160 Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp 165 170 175 Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala 180 185 190 Ser 342169PRTArtificialChimeric protein 342His Phe Lys Asp Pro Lys Arg Leu Tyr Cys Lys Asn Gly Gly Phe Phe 1 5 10 15 Leu Arg Ile His Pro Asp Gly Arg Val Asp Gly Val Arg Glu Lys Ser 20 25 30 Asp Pro His Ile Lys Leu Gln Leu Gln Ala Glu Glu Arg Gly Val Val 35 40 45 Ser Ile Lys Gly Val Cys Ala Asn Arg Tyr Leu Ala Met Lys Glu Asp 50 55 60 Gly Arg Leu Leu Ala Ser Lys Cys Val Thr Asp Glu Cys Phe Phe Phe 65 70 75 80 Glu Arg Leu Glu Ser Asn Asn Tyr Asn Thr Tyr Arg Ser Arg Lys Tyr 85 90 95 Thr Ser Trp Tyr Val Ala Leu Asp Gln Thr Gly Gln Tyr Val Leu Gly 100 105 110 Ser Lys Thr Gly Pro Gly Gln Lys Ala Ile Leu Phe Leu Pro Met Pro 115 120 125 Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro Gln 130 135 140 Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro Ser 145 150 155 160 Gln Gly Arg Ser Pro Ser Tyr Ala Ser 165 343576DNAArtificialNucleic acid sequence encoding chimeric protein 343atggctgaag gggaaatcac caccttcaca gccctgaccg agaagtttaa tctgcctcca 60gggaattaca agaagcccaa actcctctac tgtagcaacg ggggccactt cctgaggatc 120cttccggatg gcacagtgga tgggacaagg gacaggagcg accagcacat tcagctgcag 180ctcagtgcgg aaagcgtggg ggaggtgtat ataaagagta ccgagactgg ccagtacttg 240gccatggaca ccgacgggct tttatacggc tcacagacac caaatgagga atgtttgttc 300ctggaaaggc tggaggagaa ccattacaac acctatatat ccaagaagca tgcagagaag 360aattggtttg ttggcctcga tcagaatggg agctgcgttc gcggtcctcg gactcactat 420ggccagaaag caatcttgtt tctccccctg ccaggcctgc cccccgcact cccggagcca 480cccggaatcc tggcccccca gccccccgat gtgggctcct cggaccctct gagcatggtg 540ggaccttccc agggccgaag ccccagctac gcttcc 576344504DNAArtificialNucleic acid sequence encoding chimeric protein 344aagcccaaac tcctctactg tagcaacggg ggccacttcc tgaggatcct tccggatggc 60acagtggatg ggacaaggga caggagcgac cagcacattc agctgcagct cagtgcggaa 120agcgtggggg aggtgtatat aaagagtacc gagactggcc agtacttggc catggacacc 180gacgggcttt tatacggctc acagacacca aatgaggaat gtttgttcct ggaaaggctg 240gaggagaacc attacaacac ctatatatcc aagaagcatg cagagaagaa ttggtttgtt 300ggcctcgatc agaatgggag ctgcgttcgc ggtcctcgga ctcactatgg ccagaaagca 360atcttgtttc tccccctgcc aggcctgccc cccgcactcc cggagccacc cggaatcctg 420gccccccagc cccccgatgt gggctcctcg gaccctctga gcatggtggg accttcccag 480ggccgaagcc ccagctacgc ttcc 504345579DNAArtificialNucleic acid sequence encoding chimeric protein 345atggcagccg ggagcatcac cacgctgccc gccttgcccg aggatggcgg cagcggcgcc 60ttcccgcccg gccacttcaa ggaccccaag cggctgtact gcaaaaacgg gggcttcttc 120ctgcgcatcc accccgacgg ccgagttgac ggggtccggg agaagagcga ccctcacatc 180aagctacaac ttcaagcaga agagagagga gttgtgtcta tcaaaggagt gtgtgctaac 240cgttacctgg ctatgaagga agatggaaga ttactggctt ctaaatgtgt tacggatgag 300tgtttctttt ttgaacgatt ggaatctaat aactacaata cttaccggtc aaggaaatac 360accagttggt atgtggcact ggatcagact gggcagtatg ttcttggatc caaaacagga 420cctgggcaga aagctatact ttttcttcca atgccaggcc tgccccccgc actcccggag 480ccacccggaa tcctggcccc ccagcccccc gatgtgggct cctcggaccc tctgagcatg 540gtgggacctt cccagggccg aagccccagc tacgcttcc 579346507DNAArtificialNucleic acid sequence encoding chimeric protein 346cacttcaagg accccaagcg gctgtactgc aaaaacgggg gcttcttcct gcgcatccac 60cccgacggcc gagttgacgg ggtccgggag aagagcgacc ctcacatcaa gctacaactt 120caagcagaag agagaggagt tgtgtctatc aaaggagtgt gtgctaaccg ttacctggct 180atgaaggaag atggaagatt actggcttct aaatgtgtta cggatgagtg tttctttttt 240gaacgattgg aatctaataa ctacaatact taccggtcaa ggaaatacac cagttggtat 300gtggcactgg atcagactgg gcagtatgtt cttggatcca aaacaggacc tgggcagaaa 360gctatacttt ttcttccaat gccaggcctg ccccccgcac tcccggagcc acccggaatc 420ctggcccccc agccccccga tgtgggctcc tcggaccctc tgagcatggt gggaccttcc 480cagggccgaa gccccagcta cgcttcc 5073471044PRTHomo sapiens 347Met Lys Pro Gly Cys Ala Ala Gly Ser Pro Gly Asn Glu Trp Ile Phe 1 5 10 15 Phe Ser Thr Asp Glu Ile Thr Thr Arg Tyr Arg Asn Thr Met Ser Asn 20 25 30 Gly Gly Leu Gln Arg Ser Val Ile Leu Ser Ala Leu Ile Leu Leu Arg 35 40 45 Ala Val Thr Gly Phe Ser Gly Asp Gly Arg Ala Ile Trp Ser Lys Asn 50 55 60 Pro Asn Phe Thr Pro Val Asn Glu Ser Gln Leu Phe Leu Tyr Asp Thr 65 70 75 80 Phe Pro Lys Asn Phe Phe Trp Gly Ile Gly Thr Gly Ala Leu Gln Val 85 90 95 Glu Gly Ser Trp Lys Lys Asp Gly Lys Gly Pro Ser Ile Trp Asp His 100 105 110 Phe Ile His Thr His Leu Lys Asn

Val Ser Ser Thr Asn Gly Ser Ser 115 120 125 Asp Ser Tyr Ile Phe Leu Glu Lys Asp Leu Ser Ala Leu Asp Phe Ile 130 135 140 Gly Val Ser Phe Tyr Gln Phe Ser Ile Ser Trp Pro Arg Leu Phe Pro 145 150 155 160 Asp Gly Ile Val Thr Val Ala Asn Ala Lys Gly Leu Gln Tyr Tyr Ser 165 170 175 Thr Leu Leu Asp Ala Leu Val Leu Arg Asn Ile Glu Pro Ile Val Thr 180 185 190 Leu Tyr His Trp Asp Leu Pro Leu Ala Leu Gln Glu Lys Tyr Gly Gly 195 200 205 Trp Lys Asn Asp Thr Ile Ile Asp Ile Phe Asn Asp Tyr Ala Thr Tyr 210 215 220 Cys Phe Gln Met Phe Gly Asp Arg Val Lys Tyr Trp Ile Thr Ile His 225 230 235 240 Asn Pro Tyr Leu Val Ala Trp His Gly Tyr Gly Thr Gly Met His Ala 245 250 255 Pro Gly Glu Lys Gly Asn Leu Ala Ala Val Tyr Thr Val Gly His Asn 260 265 270 Leu Ile Lys Ala His Ser Lys Val Trp His Asn Tyr Asn Thr His Phe 275 280 285 Arg Pro His Gln Lys Gly Trp Leu Ser Ile Thr Leu Gly Ser His Trp 290 295 300 Ile Glu Pro Asn Arg Ser Glu Asn Thr Met Asp Ile Phe Lys Cys Gln 305 310 315 320 Gln Ser Met Val Ser Val Leu Gly Trp Phe Ala Asn Pro Ile His Gly 325 330 335 Asp Gly Asp Tyr Pro Glu Gly Met Arg Lys Lys Leu Phe Ser Val Leu 340 345 350 Pro Ile Phe Ser Glu Ala Glu Lys His Glu Met Arg Gly Thr Ala Asp 355 360 365 Phe Phe Ala Phe Ser Phe Gly Pro Asn Asn Phe Lys Pro Leu Asn Thr 370 375 380 Met Ala Lys Met Gly Gln Asn Val Ser Leu Asn Leu Arg Glu Ala Leu 385 390 395 400 Asn Trp Ile Lys Leu Glu Tyr Asn Asn Pro Arg Ile Leu Ile Ala Glu 405 410 415 Asn Gly Trp Phe Thr Asp Ser Arg Val Lys Thr Glu Asp Thr Thr Ala 420 425 430 Ile Tyr Met Met Lys Asn Phe Leu Ser Gln Val Leu Gln Ala Ile Arg 435 440 445 Leu Asp Glu Ile Arg Val Phe Gly Tyr Thr Ala Trp Ser Leu Leu Asp 450 455 460 Gly Phe Glu Trp Gln Asp Ala Tyr Thr Ile Arg Arg Gly Leu Phe Tyr 465 470 475 480 Val Asp Phe Asn Ser Lys Gln Lys Glu Arg Lys Pro Lys Ser Ser Ala 485 490 495 His Tyr Tyr Lys Gln Ile Ile Arg Glu Asn Gly Phe Ser Leu Lys Glu 500 505 510 Ser Thr Pro Asp Val Gln Gly Gln Phe Pro Cys Asp Phe Ser Trp Gly 515 520 525 Val Thr Glu Ser Val Leu Lys Pro Glu Ser Val Ala Ser Ser Pro Gln 530 535 540 Phe Ser Asp Pro His Leu Tyr Val Trp Asn Ala Thr Gly Asn Arg Leu 545 550 555 560 Leu His Arg Val Glu Gly Val Arg Leu Lys Thr Arg Pro Ala Gln Cys 565 570 575 Thr Asp Phe Val Asn Ile Lys Lys Gln Leu Glu Met Leu Ala Arg Met 580 585 590 Lys Val Thr His Tyr Arg Phe Ala Leu Asp Trp Ala Ser Val Leu Pro 595 600 605 Thr Gly Asn Leu Ser Ala Val Asn Arg Gln Ala Leu Arg Tyr Tyr Arg 610 615 620 Cys Val Val Ser Glu Gly Leu Lys Leu Gly Ile Ser Ala Met Val Thr 625 630 635 640 Leu Tyr Tyr Pro Thr His Ala His Leu Gly Leu Pro Glu Pro Leu Leu 645 650 655 His Ala Asp Gly Trp Leu Asn Pro Ser Thr Ala Glu Ala Phe Gln Ala 660 665 670 Tyr Ala Gly Leu Cys Phe Gln Glu Leu Gly Asp Leu Val Lys Leu Trp 675 680 685 Ile Thr Ile Asn Glu Pro Asn Arg Leu Ser Asp Ile Tyr Asn Arg Ser 690 695 700 Gly Asn Asp Thr Tyr Gly Ala Ala His Asn Leu Leu Val Ala His Ala 705 710 715 720 Leu Ala Trp Arg Leu Tyr Asp Arg Gln Phe Arg Pro Ser Gln Arg Gly 725 730 735 Ala Val Ser Leu Ser Leu His Ala Asp Trp Ala Glu Pro Ala Asn Pro 740 745 750 Tyr Ala Asp Ser His Trp Arg Ala Ala Glu Arg Phe Leu Gln Phe Glu 755 760 765 Ile Ala Trp Phe Ala Glu Pro Leu Phe Lys Thr Gly Asp Tyr Pro Ala 770 775 780 Ala Met Arg Glu Tyr Ile Ala Ser Lys His Arg Arg Gly Leu Ser Ser 785 790 795 800 Ser Ala Leu Pro Arg Leu Thr Glu Ala Glu Arg Arg Leu Leu Lys Gly 805 810 815 Thr Val Asp Phe Cys Ala Leu Asn His Phe Thr Thr Arg Phe Val Met 820 825 830 His Glu Gln Leu Ala Gly Ser Arg Tyr Asp Ser Asp Arg Asp Ile Gln 835 840 845 Phe Leu Gln Asp Ile Thr Arg Leu Ser Ser Pro Thr Arg Leu Ala Val 850 855 860 Ile Pro Trp Gly Val Arg Lys Leu Leu Arg Trp Val Arg Arg Asn Tyr 865 870 875 880 Gly Asp Met Asp Ile Tyr Ile Thr Ala Ser Gly Ile Asp Asp Gln Ala 885 890 895 Leu Glu Asp Asp Arg Leu Arg Lys Tyr Tyr Leu Gly Lys Tyr Leu Gln 900 905 910 Glu Val Leu Lys Ala Tyr Leu Ile Asp Lys Val Arg Ile Lys Gly Tyr 915 920 925 Tyr Ala Phe Lys Leu Ala Glu Glu Lys Ser Lys Pro Arg Phe Gly Phe 930 935 940 Phe Thr Ser Asp Phe Lys Ala Lys Ser Ser Ile Gln Phe Tyr Asn Lys 945 950 955 960 Val Ile Ser Ser Arg Gly Phe Pro Phe Glu Asn Ser Ser Ser Arg Cys 965 970 975 Ser Gln Thr Gln Glu Asn Thr Glu Cys Thr Val Cys Leu Phe Leu Val 980 985 990 Gln Lys Lys Pro Leu Ile Phe Leu Gly Cys Cys Phe Phe Ser Thr Leu 995 1000 1005 Val Leu Leu Leu Ser Ile Ala Ile Phe Gln Arg Gln Lys Arg Arg 1010 1015 1020 Lys Phe Trp Lys Ala Lys Asn Leu Gln His Ile Pro Leu Lys Lys 1025 1030 1035 Gly Lys Arg Val Val Ser 1040 3481043PRTMus musculus 348Met Lys Thr Gly Cys Ala Ala Gly Ser Pro Gly Asn Glu Trp Ile Phe 1 5 10 15 Phe Ser Ser Asp Glu Arg Asn Thr Arg Ser Arg Lys Thr Met Ser Asn 20 25 30 Arg Ala Leu Gln Arg Ser Ala Val Leu Ser Ala Phe Val Leu Leu Arg 35 40 45 Ala Val Thr Gly Phe Ser Gly Asp Gly Lys Ala Ile Trp Asp Lys Lys 50 55 60 Gln Tyr Val Ser Pro Val Asn Pro Ser Gln Leu Phe Leu Tyr Asp Thr 65 70 75 80 Phe Pro Lys Asn Phe Ser Trp Gly Val Gly Thr Gly Ala Phe Gln Val 85 90 95 Glu Gly Ser Trp Lys Thr Asp Gly Arg Gly Pro Ser Ile Trp Asp Arg 100 105 110 Tyr Val Tyr Ser His Leu Arg Gly Val Asn Gly Thr Asp Arg Ser Thr 115 120 125 Asp Ser Tyr Ile Phe Leu Glu Lys Asp Leu Leu Ala Leu Asp Phe Leu 130 135 140 Gly Val Ser Phe Tyr Gln Phe Ser Ile Ser Trp Pro Arg Leu Phe Pro 145 150 155 160 Asn Gly Thr Val Ala Ala Val Asn Ala Gln Gly Leu Arg Tyr Tyr Arg 165 170 175 Ala Leu Leu Asp Ser Leu Val Leu Arg Asn Ile Glu Pro Ile Val Thr 180 185 190 Leu Tyr His Trp Asp Leu Pro Leu Thr Leu Gln Glu Glu Tyr Gly Gly 195 200 205 Trp Lys Asn Ala Thr Met Ile Asp Leu Phe Asn Asp Tyr Ala Thr Tyr 210 215 220 Cys Phe Gln Thr Phe Gly Asp Arg Val Lys Tyr Trp Ile Thr Ile His 225 230 235 240 Asn Pro Tyr Leu Val Ala Trp His Gly Phe Gly Thr Gly Met His Ala 245 250 255 Pro Gly Glu Lys Gly Asn Leu Thr Ala Val Tyr Thr Val Gly His Asn 260 265 270 Leu Ile Lys Ala His Ser Lys Val Trp His Asn Tyr Asp Lys Asn Phe 275 280 285 Arg Pro His Gln Lys Gly Trp Leu Ser Ile Thr Leu Gly Ser His Trp 290 295 300 Ile Glu Pro Asn Arg Thr Asp Asn Met Glu Asp Val Ile Asn Cys Gln 305 310 315 320 His Ser Met Ser Ser Val Leu Gly Trp Phe Ala Asn Pro Ile His Gly 325 330 335 Asp Gly Asp Tyr Pro Glu Phe Met Lys Thr Gly Ala Met Ile Pro Glu 340 345 350 Phe Ser Glu Ala Glu Lys Glu Glu Val Arg Gly Thr Ala Asp Phe Phe 355 360 365 Ala Phe Ser Phe Gly Pro Asn Asn Phe Arg Pro Ser Asn Thr Val Val 370 375 380 Lys Met Gly Gln Asn Val Ser Leu Asn Leu Arg Gln Val Leu Asn Trp 385 390 395 400 Ile Lys Leu Glu Tyr Asp Asp Pro Gln Ile Leu Ile Ser Glu Asn Gly 405 410 415 Trp Phe Thr Asp Ser Tyr Ile Lys Thr Glu Asp Thr Thr Ala Ile Tyr 420 425 430 Met Met Lys Asn Phe Leu Asn Gln Val Leu Gln Ala Ile Lys Phe Asp 435 440 445 Glu Ile Arg Val Phe Gly Tyr Thr Ala Trp Thr Leu Leu Asp Gly Phe 450 455 460 Glu Trp Gln Asp Ala Tyr Thr Thr Arg Arg Gly Leu Phe Tyr Val Asp 465 470 475 480 Phe Asn Ser Glu Gln Lys Glu Arg Lys Pro Lys Ser Ser Ala His Tyr 485 490 495 Tyr Lys Gln Ile Ile Gln Asp Asn Gly Phe Pro Leu Lys Glu Ser Thr 500 505 510 Pro Asp Met Lys Gly Arg Phe Pro Cys Asp Phe Ser Trp Gly Val Thr 515 520 525 Glu Ser Val Leu Lys Pro Glu Phe Thr Val Ser Ser Pro Gln Phe Thr 530 535 540 Asp Pro His Leu Tyr Val Trp Asn Val Thr Gly Asn Arg Leu Leu Tyr 545 550 555 560 Arg Val Glu Gly Val Arg Leu Lys Thr Arg Pro Ser Gln Cys Thr Asp 565 570 575 Tyr Val Ser Ile Lys Lys Arg Val Glu Met Leu Ala Lys Met Lys Val 580 585 590 Thr His Tyr Gln Phe Ala Leu Asp Trp Thr Ser Ile Leu Pro Thr Gly 595 600 605 Asn Leu Ser Lys Val Asn Arg Gln Val Leu Arg Tyr Tyr Arg Cys Val 610 615 620 Val Ser Glu Gly Leu Lys Leu Gly Val Phe Pro Met Val Thr Leu Tyr 625 630 635 640 His Pro Thr His Ser His Leu Gly Leu Pro Leu Pro Leu Leu Ser Ser 645 650 655 Gly Gly Trp Leu Asn Met Asn Thr Ala Lys Ala Phe Gln Asp Tyr Ala 660 665 670 Glu Leu Cys Phe Arg Glu Leu Gly Asp Leu Val Lys Leu Trp Ile Thr 675 680 685 Ile Asn Glu Pro Asn Arg Leu Ser Asp Met Tyr Asn Arg Thr Ser Asn 690 695 700 Asp Thr Tyr Arg Ala Ala His Asn Leu Met Ile Ala His Ala Gln Val 705 710 715 720 Trp His Leu Tyr Asp Arg Gln Tyr Arg Pro Val Gln His Gly Ala Val 725 730 735 Ser Leu Ser Leu His Cys Asp Trp Ala Glu Pro Ala Asn Pro Phe Val 740 745 750 Asp Ser His Trp Lys Ala Ala Glu Arg Phe Leu Gln Phe Glu Ile Ala 755 760 765 Trp Phe Ala Asp Pro Leu Phe Lys Thr Gly Asp Tyr Pro Ser Val Met 770 775 780 Lys Glu Tyr Ile Ala Ser Lys Asn Gln Arg Gly Leu Ser Ser Ser Val 785 790 795 800 Leu Pro Arg Phe Thr Ala Lys Glu Ser Arg Leu Val Lys Gly Thr Val 805 810 815 Asp Phe Tyr Ala Leu Asn His Phe Thr Thr Arg Phe Val Ile His Lys 820 825 830 Gln Leu Asn Thr Asn Arg Ser Val Ala Asp Arg Asp Val Gln Phe Leu 835 840 845 Gln Asp Ile Thr Arg Leu Ser Ser Pro Ser Arg Leu Ala Val Thr Pro 850 855 860 Trp Gly Val Arg Lys Leu Leu Ala Trp Ile Arg Arg Asn Tyr Arg Asp 865 870 875 880 Arg Asp Ile Tyr Ile Thr Ala Asn Gly Ile Asp Asp Leu Ala Leu Glu 885 890 895 Asp Asp Gln Ile Arg Lys Tyr Tyr Leu Glu Lys Tyr Val Gln Glu Ala 900 905 910 Leu Lys Ala Tyr Leu Ile Asp Lys Val Lys Ile Lys Gly Tyr Tyr Ala 915 920 925 Phe Lys Leu Thr Glu Glu Lys Ser Lys Pro Arg Phe Gly Phe Phe Thr 930 935 940 Ser Asp Phe Arg Ala Lys Ser Ser Val Gln Phe Tyr Ser Lys Leu Ile 945 950 955 960 Ser Ser Ser Gly Leu Pro Ala Glu Asn Arg Ser Pro Ala Cys Gly Gln 965 970 975 Pro Ala Glu Asp Thr Asp Cys Thr Ile Cys Ser Phe Leu Val Glu Lys 980 985 990 Lys Pro Leu Ile Phe Phe Gly Cys Cys Phe Ile Ser Thr Leu Ala Val 995 1000 1005 Leu Leu Ser Ile Thr Val Phe His His Gln Lys Arg Arg Lys Phe 1010 1015 1020 Gln Lys Ala Arg Asn Leu Gln Asn Ile Pro Leu Lys Lys Gly His 1025 1030 1035 Ser Arg Val Phe Ser 1040 3493135DNAHomo sapiens 349atgaagccag gctgtgcggc aggatctcca gggaatgaat ggattttctt cagcactgat 60gaaataacca cacgctatag gaatacaatg tccaacgggg gattgcaaag atctgtcatc 120ctgtcagcac ttattctgct acgagctgtt actggattct ctggagatgg aagagctata 180tggtctaaaa atcctaattt tactccggta aatgaaagtc agctgtttct ctatgacact 240ttccctaaaa actttttctg gggtattggg actggagcat tgcaagtgga agggagttgg 300aagaaggatg gaaaaggacc ttctatatgg gatcatttca tccacacaca ccttaaaaat 360gtcagcagca cgaatggttc cagtgacagt tatatttttc tggaaaaaga cttatcagcc 420ctggatttta taggagtttc tttttatcaa ttttcaattt cctggccaag gcttttcccc 480gatggaatag taacagttgc caacgcaaaa ggtctgcagt actacagtac tcttctggac 540gctctagtgc ttagaaacat tgaacctata gttactttat accactggga tttgcctttg 600gcactacaag aaaaatatgg ggggtggaaa aatgatacca taatagatat cttcaatgac 660tatgccacat actgtttcca gatgtttggg gaccgtgtca aatattggat tacaattcac 720aacccatatc tagtggcttg gcatgggtat gggacaggta tgcatgcccc tggagagaag 780ggaaatttag cagctgtcta cactgtggga cacaacttga tcaaggctca ctcgaaagtt 840tggcataact acaacacaca tttccgccca catcagaagg gttggttatc gatcacgttg 900ggatctcatt ggatcgagcc aaaccggtcg gaaaacacga tggatatatt caaatgtcaa 960caatccatgg tttctgtgct tggatggttt gccaacccta tccatgggga tggcgactat 1020ccagagggga tgagaaagaa gttgttctcc gttctaccca ttttctctga agcagagaag 1080catgagatga gaggcacagc tgatttcttt gccttttctt ttggacccaa caacttcaag 1140cccctaaaca ccatggctaa aatgggacaa aatgtttcac ttaatttaag agaagcgctg 1200aactggatta aactggaata caacaaccct cgaatcttga ttgctgagaa tggctggttc 1260acagacagtc gtgtgaaaac agaagacacc acggccatct acatgatgaa gaatttcctc 1320agccaggtgc ttcaagcaat aaggttagat gaaatacgag tgtttggtta tactgcctgg 1380tctctcctgg atggctttga atggcaggat gcttacacca tccgccgagg attattttat 1440gtggatttta acagtaaaca gaaagagcgg aaacctaagt cttcagcaca ctactacaaa 1500cagatcatac gagaaaatgg tttttcttta aaagagtcca cgccagatgt gcagggccag 1560tttccctgtg acttctcctg gggtgtcact gaatctgttc ttaagcccga gtctgtggct 1620tcgtccccac agttcagcga tcctcatctg tacgtgtgga acgccactgg caacagactg 1680ttgcaccgag tggaaggggt gaggctgaaa acacgacccg ctcaatgcac agattttgta 1740aacatcaaaa aacaacttga gatgttggca agaatgaaag tcacccacta ccggtttgct 1800ctggattggg cctcggtcct tcccactggc aacctgtccg cggtgaaccg acaggccctg 1860aggtactaca ggtgcgtggt cagtgagggg ctgaagcttg gcatctccgc gatggtcacc 1920ctgtattatc cgacccacgc ccacctaggc ctccccgagc ctctgttgca tgccgacggg 1980tggctgaacc catcgacggc cgaggccttc caggcctacg ctgggctgtg cttccaggag 2040ctgggggacc tggtgaagct ctggatcacc atcaacgagc ctaaccggct aagtgacatc 2100tacaaccgct

ctggcaacga cacctacggg gcggcgcaca acctgctggt ggcccacgcc 2160ctggcctggc gcctctacga ccggcagttc aggccctcac agcgcggggc cgtgtcgctg 2220tcgctgcacg cggactgggc ggaacccgcc aacccctatg ctgactcgca ctggagggcg 2280gccgagcgct tcctgcagtt cgagatcgcc tggttcgccg agccgctctt caagaccggg 2340gactaccccg cggccatgag ggaatacatt gcctccaagc accgacgggg gctttccagc 2400tcggccctgc cgcgcctcac cgaggccgaa aggaggctgc tcaagggcac ggtcgacttc 2460tgcgcgctca accacttcac cactaggttc gtgatgcacg agcagctggc cggcagccgc 2520tacgactcgg acagggacat ccagtttctg caggacatca cccgcctgag ctcccccacg 2580cgcctggctg tgattccctg gggggtgcgc aagctgctgc ggtgggtccg gaggaactac 2640ggcgacatgg acatttacat caccgccagt ggcatcgacg accaggctct ggaggatgac 2700cggctccgga agtactacct agggaagtac cttcaggagg tgctgaaagc atacctgatt 2760gataaagtca gaatcaaagg ctattatgca ttcaaactgg ctgaagagaa atctaaaccc 2820agatttggat tcttcacatc tgattttaaa gctaaatcct caatacaatt ttacaacaaa 2880gtgatcagca gcaggggctt cccttttgag aacagtagtt ctagatgcag tcagacccaa 2940gaaaatacag agtgcactgt ctgcttattc cttgtgcaga agaaaccact gatattcctg 3000ggttgttgct tcttctccac cctggttcta ctcttatcaa ttgccatttt tcaaaggcag 3060aagagaagaa agttttggaa agcaaaaaac ttacaacaca taccattaaa gaaaggcaag 3120agagttgtta gctaa 31353503132DNAHouse mouse 350atgaagacag gctgtgcagc agggtctccg gggaatgaat ggattttctt cagctctgat 60gaaagaaaca cacgctctag gaaaacaatg tccaacaggg cactgcaaag atctgccgtg 120ctgtctgcgt ttgttctgct gcgagctgtt accggcttct ccggagacgg gaaagcaata 180tgggataaaa aacagtacgt gagtccggta aacccaagtc agctgttcct ctatgacact 240ttccctaaaa acttttcctg gggcgttggg accggagcat ttcaagtgga agggagttgg 300aagacagatg gaagaggacc ctcgatctgg gatcggtacg tctactcaca cctgagaggt 360gtcaacggca cagacagatc cactgacagt tacatctttc tggaaaaaga cttgttggct 420ctggattttt taggagtttc tttttatcag ttctcaatct cctggccacg gttgtttccc 480aatggaacag tagcagcagt gaatgcgcaa ggtctccggt actaccgtgc acttctggac 540tcgctggtac ttaggaatat cgagcccatt gttaccttgt accattggga tttgcctctg 600acgctccagg aagaatatgg gggctggaaa aatgcaacta tgatagatct cttcaacgac 660tatgccacat actgcttcca gacctttgga gaccgtgtca aatattggat tacaattcac 720aacccttacc ttgttgcttg gcatgggttt ggcacaggta tgcatgcacc aggagagaag 780ggaaatttaa cagctgtcta cactgtggga cacaacctga tcaaggcaca ttcgaaagtg 840tggcataact acgacaaaaa cttccgccct catcagaagg gttggctctc catcaccttg 900gggtcccatt ggatagagcc aaacagaaca gacaacatgg aggacgtgat caactgccag 960cactccatgt cctctgtgct tggatggttc gccaacccca tccacgggga cggcgactac 1020cctgagttca tgaagacggg cgccatgatc cccgagttct ctgaggcaga gaaggaggag 1080gtgaggggca cggctgattt ctttgccttt tccttcgggc ccaacaactt caggccctca 1140aacaccgtgg tgaaaatggg acaaaatgta tcactcaact taaggcaggt gctgaactgg 1200attaaactgg aatacgatga ccctcaaatc ttgatttcgg agaacggctg gttcacagat 1260agctatataa agacagagga caccacggcc atctacatga tgaagaattt cctaaaccag 1320gttcttcaag caataaaatt tgatgaaatc cgcgtgtttg gttatacggc ctggactctc 1380ctggatggct ttgagtggca ggatgcctat acgacccgac gagggctgtt ttatgtggac 1440tttaacagtg agcagaaaga gaggaaaccc aagtcctcgg ctcattacta caagcagatc 1500atacaagaca acggcttccc tttgaaagag tccacgccag acatgaaggg tcggttcccc 1560tgtgatttct cttggggagt cactgagtct gttcttaagc ccgagtttac ggtctcctcc 1620ccgcagttta ccgatcctca cctgtatgtg tggaatgtca ctggcaacag attgctctac 1680cgagtggaag gggtaaggct gaaaacaaga ccatcccagt gcacagatta tgtgagcatc 1740aaaaaacgag ttgaaatgtt ggcaaaaatg aaagtcaccc actaccagtt tgctctggac 1800tggacctcta tccttcccac tggcaatctg tccaaagtta acagacaagt gttaaggtac 1860tataggtgtg tggtgagcga aggactgaag ctgggcgtct tccccatggt gacgttgtac 1920cacccaaccc actcccatct cggcctcccc ctgccacttc tgagcagtgg ggggtggcta 1980aacatgaaca cagccaaggc cttccaggac tacgctgagc tgtgcttccg ggagttgggg 2040gacttggtga agctctggat caccatcaat gagcctaaca ggctgagtga catgtacaac 2100cgcacgagta atgacaccta ccgtgcagcc cacaacctga tgatcgccca tgcccaggtc 2160tggcacctct atgataggca gtataggccg gtccagcatg gggctgtgtc gctgtcctta 2220cattgcgact gggcagaacc tgccaacccc tttgtggatt cacactggaa ggcagccgag 2280cgcttcctcc agtttgagat cgcctggttt gcagatccgc tcttcaagac tggcgactat 2340ccatcggtta tgaaggaata catcgcctcc aagaaccagc gagggctgtc tagctcagtc 2400ctgccgcgct tcaccgcgaa ggagagcagg ctggtgaagg gtaccgtcga cttctacgca 2460ctgaaccact tcactacgag gttcgtgata cacaagcagc tgaacaccaa ccgctcagtt 2520gcagacaggg acgtccagtt cctgcaggac atcacccgcc taagctcgcc cagccgcctg 2580gctgtaacac cctggggagt gcgcaagctc cttgcgtgga tccggaggaa ctacagagac 2640agggatatct acatcacagc caatggcatc gatgacctgg ctctagagga tgatcagatc 2700cgaaagtact acttggagaa gtatgtccag gaggctctga aagcatatct cattgacaag 2760gtcaaaatca aaggctacta tgcattcaaa ctgactgaag agaaatctaa gcctagattt 2820ggatttttca cctctgactt cagagctaag tcctctgtcc agttttacag caagctgatc 2880agcagcagtg gcctccccgc tgagaacaga agtcctgcgt gtggtcagcc tgcggaagac 2940acagactgca ccatttgctc atttctcgtg gagaagaaac cactcatctt cttcggttgc 3000tgcttcatct ccactctggc tgtactgcta tccatcaccg tttttcatca tcaaaagaga 3060agaaaattcc agaaagcaag gaacttacaa aatataccat tgaagaaagg ccacagcaga 3120gttttcagct aa 3132351251PRTHomo sapiens 351Met Leu Gly Ala Arg Leu Arg Leu Trp Val Cys Ala Leu Cys Ser Val 1 5 10 15 Cys Ser Met Ser Val Leu Arg Ala Tyr Pro Asn Ala Ser Pro Leu Leu 20 25 30 Gly Ser Ser Trp Gly Gly Leu Ile His Leu Tyr Thr Ala Thr Ala Arg 35 40 45 Asn Ser Tyr His Leu Gln Ile His Lys Asn Gly His Val Asp Gly Ala 50 55 60 Pro His Gln Thr Ile Tyr Ser Ala Leu Met Ile Arg Ser Glu Asp Ala 65 70 75 80 Gly Phe Val Val Ile Thr Gly Val Met Ser Arg Arg Tyr Leu Cys Met 85 90 95 Asp Phe Arg Gly Asn Ile Phe Gly Ser His Tyr Phe Asp Pro Glu Asn 100 105 110 Cys Arg Phe Gln His Gln Thr Leu Glu Asn Gly Tyr Asp Val Tyr His 115 120 125 Ser Pro Gln Tyr His Phe Leu Val Ser Leu Gly Arg Ala Lys Arg Ala 130 135 140 Phe Leu Pro Gly Met Asn Pro Pro Pro Tyr Ser Gln Phe Leu Ser Arg 145 150 155 160 Arg Asn Glu Ile Pro Leu Ile His Phe Asn Thr Pro Ile Pro Arg Arg 165 170 175 His Thr Arg Ser Ala Glu Asp Asp Ser Glu Arg Asp Pro Leu Asn Val 180 185 190 Leu Lys Pro Arg Ala Arg Met Thr Pro Ala Pro Ala Ser Cys Ser Gln 195 200 205 Glu Leu Pro Ser Ala Glu Asp Asn Ser Pro Met Ala Ser Asp Pro Leu 210 215 220 Gly Val Val Arg Gly Gly Arg Val Asn Thr His Ala Gly Gly Thr Gly 225 230 235 240 Pro Glu Gly Cys Arg Pro Phe Ala Lys Phe Ile 245 250 35242PRTArtificialFGF21 variant 352Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro 20 25 30 Ser Gln Gly Arg Ser Pro Ser Tyr Ala Lys 35 40 35342PRTArtificialFGF21 variant 353Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro 20 25 30 Ser Gln Gly Arg Ser Pro Ser Tyr Glu Ser 35 40 35442PRTArtificialFGF21 variant 354Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro 20 25 30 Ser Gln Gly Arg Ser Pro Ser Phe Ala Ser 35 40 35542PRTArtificialFGF21 variant 355Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro 20 25 30 Ser Gln Val Arg Ser Pro Ser Tyr Ala Ser 35 40 35642PRTArtificialFGF21 variant 356Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro 20 25 30 Ser Ala Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 35742PRTArtificialFGF21 variant 357Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro 20 25 30 Glu Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 35842PRTArtificialFGF21 variant 358Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Leu 20 25 30 Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 35943PRTArtificialFGF21 variant 359Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Thr Gly 20 25 30 Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 36042PRTArtificialFGF21 variant 360Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Leu Val Gly Pro 20 25 30 Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 36142PRTArtificialFGF21 variant 361Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Gly Met Val Gly Pro 20 25 30 Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 36242PRTArtificialFGF21 variant 362Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Phe Ser Met Val Gly Pro 20 25 30 Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 36342PRTArtificialFGF21 variant 363Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Met Asp Pro Leu Ser Met Val Gly Pro 20 25 30 Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 36442PRTArtificialFGF21 variant 364Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Asp Ser Ser Asp Pro Leu Ser Met Val Gly Pro 20 25 30 Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 36542PRTArtificialFGF21 variant 365Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Thr Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro 20 25 30 Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 36642PRTArtificialFGF21 variant 366Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Glu Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro 20 25 30 Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 36742PRTArtificialFGF21 variant 367Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Leu Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro 20 25 30 Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 36842PRTArtificialFGF21 variant 368Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Ser Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro 20 25 30 Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 36942PRTArtificialFGF21 variant 369Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Ser 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro 20 25 30 Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 37042PRTArtificialFGF21 variant 370Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Phe Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro 20 25 30 Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 37142PRTArtificialFGF21 variant 371Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Met Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro 20 25 30 Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 37242PRTArtificialFGF21 variant 372Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Asp Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro 20 25 30 Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 37342PRTArtificialFGF21 variant 373Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Ser Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro 20 25 30 Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 37442PRTArtificialFGF21 variant 374Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Glu Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro 20 25 30 Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 37542PRTArtificialFGF21 variant 375Pro Gly Leu Pro Pro Ala Leu Pro Glu Leu Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro 20 25 30 Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 37643PRTArtificialFGF21 variant 376Pro Gly Leu Pro Pro Ala Leu Pro Glu His Pro Pro Gly Ile Leu Ala 1 5 10 15 Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly 20 25 30 Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 37743PRTArtificialFGF21 variant 377Pro Gly Leu Pro Pro Ala Leu Pro Glu Gly Pro Pro Gly Ile Leu Ala 1 5 10 15 Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly 20 25 30 Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 37843PRTArtificialFGF21 variant 378Pro Gly Leu Pro Pro Ala Leu Pro Glu Arg Pro Pro Gly Ile Leu Ala 1 5 10 15 Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly 20 25 30 Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 37943PRTArtificialFGF21 variant 379Pro Gly Leu Pro Pro Ala Leu Pro Glu Leu Pro Pro Gly Ile Leu Ala 1 5 10 15 Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly 20 25 30 Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 38043PRTArtificialFGF21 variant 380Pro Gly Leu Pro Pro Ala Leu Pro Glu Asp Pro Pro Gly Ile Leu Ala 1 5 10 15 Pro Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly 20 25 30 Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 38142PRTArtificialFGF21 variant 381Pro Gly Leu Pro Pro Ala Glu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro 20

25 30 Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 38242PRTArtificialFGF21 variant 382Pro Gly Leu Pro Pro Glu Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro 20 25 30 Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 38342PRTArtificialFGF21 variant 383Pro Gly Leu Val Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro 20 25 30 Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 38442PRTArtificialFGF21 variant 384Pro Gly Met Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro 20 25 30 Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 38542PRTArtificialFGF21 variant 385Pro Pro Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro 20 25 30 Ser Gln Gly Arg Ser Pro Ser Tyr Ala Ser 35 40 38642PRTArtificialFGF21 variant 386Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro 20 25 30 Ser Gln Gly Arg Ser Pro Ser Tyr Glu Lys 35 40 38742PRTArtificialFGF21 variant 387Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro 20 25 30 Ser Gln Gly Arg Ser Pro Ser Phe Glu Lys 35 40 38842PRTArtificialFGF21 variant 388Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro 20 25 30 Ser Gln Val Arg Ser Pro Ser Phe Glu Lys 35 40 38942PRTArtificialFGF21 variant 389Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro 20 25 30 Ser Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 39042PRTArtificialFGF21 variant 390Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Pro 20 25 30 Glu Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 39142PRTArtificialFGF21 variant 391Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Gly Leu 20 25 30 Glu Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 39242PRTArtificialFGF21 variant 392Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Met Val Thr Gly 20 25 30 Leu Glu Ala Val Arg Ser Pro Phe Glu Lys 35 40 39343PRTArtificialFGF21 variant 393Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Ser Leu Val Thr Gly 20 25 30 Leu Glu Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 39443PRTArtificialFGF21 variant 394Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Leu Gly Leu Val Thr Gly 20 25 30 Leu Glu Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 39543PRTArtificialFGF21 variant 395Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Ser Asp Pro Phe Gly Leu Val Thr Gly 20 25 30 Leu Glu Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 39643PRTArtificialFGF21 variant 396Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Gly Ser Met Asp Pro Phe Gly Leu Val Thr Gly 20 25 30 Leu Glu Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 39743PRTArtificialFGF21 variant 397Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Val Asp Ser Met Asp Pro Phe Gly Leu Val Thr Gly 20 25 30 Leu Glu Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 39843PRTArtificialFGF21 variant 398Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Asp Thr Asp Ser Met Asp Pro Phe Gly Leu Val Thr Gly 20 25 30 Leu Glu Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 39943PRTArtificialFGF21 variant 399Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Pro Glu Thr Asp Ser Met Asp Pro Phe Gly Leu Val Thr Gly 20 25 30 Leu Glu Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 40043PRTArtificialFGF21 variant 400Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Gln Pro Leu Glu Thr Asp Ser Met Asp Pro Phe Gly Leu Val Thr Gly 20 25 30 Leu Glu Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 40143PRTArtificialFGF21 variant 401Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Pro 1 5 10 15 Ser Pro Leu Glu Thr Asp Ser Met Asp Pro Phe Gly Leu Val Thr Gly 20 25 30 Leu Glu Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 40243PRTArtificialFGF21 variant 402Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Ala Ser 1 5 10 15 Ser Pro Leu Glu Thr Asp Ser Met Asp Pro Phe Gly Leu Val Thr Gly 20 25 30 Leu Glu Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 40343PRTArtificialFGF21 variant 403Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Leu Phe Ser 1 5 10 15 Ser Pro Leu Glu Thr Asp Ser Met Asp Pro Phe Gly Leu Val Thr Gly 20 25 30 Leu Glu Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 40443PRTArtificialFGF21 variant 404Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Ile Met Phe Ser 1 5 10 15 Ser Pro Leu Glu Thr Asp Ser Met Asp Pro Phe Gly Leu Val Thr Gly 20 25 30 Leu Glu Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 40543PRTArtificialFGF21 variant 405Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Gly Asp Met Phe Ser 1 5 10 15 Ser Pro Leu Glu Thr Asp Ser Met Asp Pro Phe Gly Leu Val Thr Gly 20 25 30 Leu Glu Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 40643PRTArtificialFGF21 variant 406Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Pro Ser Asp Met Phe Ser 1 5 10 15 Ser Pro Leu Glu Thr Asp Ser Met Asp Pro Phe Gly Leu Val Thr Gly 20 25 30 Leu Glu Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 40743PRTArtificialFGF21 variant 407Pro Gly Leu Pro Pro Ala Leu Pro Glu Pro Glu Ser Asp Met Phe Ser 1 5 10 15 Ser Pro Leu Glu Thr Asp Ser Met Asp Pro Phe Gly Leu Val Thr Gly 20 25 30 Leu Glu Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 40843PRTArtificialFGF21 variant 408Pro Gly Leu Pro Pro Ala Leu Pro Glu Leu Glu Ser Asp Met Phe Ser 1 5 10 15 Ser Pro Leu Glu Thr Asp Ser Met Asp Pro Phe Gly Leu Val Thr Gly 20 25 30 Leu Glu Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 40944PRTArtificialFGF21 variant 409Pro Gly Leu Pro Pro Ala Leu Pro Glu His Leu Glu Ser Asp Met Phe 1 5 10 15 Ser Ser Pro Leu Glu Thr Asp Ser Met Asp Pro Phe Gly Leu Val Thr 20 25 30 Gly Leu Glu Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 41045PRTArtificialFGF21 variant 410Pro Gly Leu Pro Pro Ala Leu Pro Glu Gly His Leu Glu Ser Asp Met 1 5 10 15 Phe Ser Ser Pro Leu Glu Thr Asp Ser Met Asp Pro Phe Gly Leu Val 20 25 30 Thr Gly Leu Glu Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 45 41146PRTArtificialFGF21 variant 411Pro Gly Leu Pro Pro Ala Leu Pro Glu Arg Gly His Leu Glu Ser Asp 1 5 10 15 Met Phe Ser Ser Pro Leu Glu Thr Asp Ser Met Asp Pro Phe Gly Leu 20 25 30 Val Thr Gly Leu Glu Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 45 41247PRTArtificialFGF21 variant 412Pro Gly Leu Pro Pro Ala Leu Pro Glu Leu Arg Gly His Leu Glu Ser 1 5 10 15 Asp Met Phe Ser Ser Pro Leu Glu Thr Asp Ser Met Asp Pro Phe Gly 20 25 30 Leu Val Thr Gly Leu Glu Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 45 41348PRTArtificialFGF21 variant 413Pro Gly Leu Pro Pro Ala Leu Pro Glu Asp Leu Arg Gly His Leu Glu 1 5 10 15 Ser Asp Met Phe Ser Ser Pro Leu Glu Thr Asp Ser Met Asp Pro Phe 20 25 30 Gly Leu Val Thr Gly Leu Glu Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 45 41448PRTArtificialFGF21 variant 414Pro Gly Leu Pro Pro Ala Glu Pro Glu Asp Leu Arg Gly His Leu Glu 1 5 10 15 Ser Asp Met Phe Ser Ser Pro Leu Glu Thr Asp Ser Met Asp Pro Phe 20 25 30 Gly Leu Val Thr Gly Leu Glu Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 45 41548PRTArtificialFGF21 variant 415Pro Gly Leu Pro Pro Glu Glu Pro Glu Asp Leu Arg Gly His Leu Glu 1 5 10 15 Ser Asp Met Phe Ser Ser Pro Leu Glu Thr Asp Ser Met Asp Pro Phe 20 25 30 Gly Leu Val Thr Gly Leu Glu Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 45 41648PRTArtificialFGF21 variant 416Pro Gly Leu Val Pro Glu Glu Pro Glu Asp Leu Arg Gly His Leu Glu 1 5 10 15 Ser Asp Met Phe Ser Ser Pro Leu Glu Thr Asp Ser Met Asp Pro Phe 20 25 30 Gly Leu Val Thr Gly Leu Glu Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 45 41748PRTArtificialFGF21 variant 417Pro Gly Met Val Pro Glu Glu Pro Glu Asp Leu Arg Gly His Leu Glu 1 5 10 15 Ser Asp Met Phe Ser Ser Pro Leu Glu Thr Asp Ser Met Asp Pro Phe 20 25 30 Gly Leu Val Thr Gly Leu Glu Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 45 41848PRTArtificialFGF21 variant 418Pro Pro Met Val Pro Glu Glu Pro Glu Asp Leu Arg Gly His Leu Glu 1 5 10 15 Ser Asp Met Phe Ser Ser Pro Leu Glu Thr Asp Ser Met Asp Pro Phe 20 25 30 Gly Leu Val Thr Gly Leu Glu Ala Val Arg Ser Pro Ser Phe Glu Lys 35 40 45