Our goals are to use the mammalian growth hormone (GH) and its receptor (GHR) as a model system to study the process and mechanisms of molecular coevolution and to understand the molecular basis of GH-GHR interaction. Mammalian GHs and GHRs exhibit large diversity and species specificity. For example, human GH and GHR have peculiar features: (1) Human GH differ greatly in sequence from nonprimate GHs. (2) Human GH stimulates growth in nonprimates, whereas nonprimate GHs are inactive in humans (known as the species specificity of human GHR). (3) Nonprimate mammals have only one GH gene, whereas humans have 5 GH-like genes. Peculiar features of GH and GHR are also found in other mammals such as rat, mouse, and cow. In particular, guinea pig GHR does not bind to human (or bovine) GH, and guinea pigs grow well even in the absence of GH. To understand these and other features, we need to study the molecular basis of the GH-GHR interaction. We propose to pursue the following work, using a combination of molecular, biochemical, evolutionary, and statistical approaches: 1. Determine the numbers of GH and GH-like genes in the galago, tarsier, squirrel monkey, and guinea pig. Sequence the GH and GH-like genes in these species and the GH gene in several primates and the guinea pig. 2. Sequence the GHR gene in the galago, tarsier, squirrel monkey (and, partially, other higher primates), the rabbit, and guinea pig. 3. Express GH and GH binding protein (GHBP) cDNAs from various species. 4. Identify sites in GH and GHR that are potentially functionally important and perform specific mutagenesis to generate mutants. 5. Use the variant GHs and GHBPs in competitive binding assays to determine the effect of each change. For amino acid differences with observed significant effects on binding, determine their collective effect in combinations. 6. Conduct statistical analyses of data to characterize evolution of GH and GHR.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD038287-04
Application #
6521257
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Grave, Gilman D
Project Start
1999-03-15
Project End
2003-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
4
Fiscal Year
2002
Total Cost
$179,335
Indirect Cost
Name
University of Chicago
Department
Biology
Type
Schools of Medicine
DUNS #
225410919
City
Chicago
State
IL
Country
United States
Zip Code
60637
Cavalcanti, Andre R O; Ferreira, Ricardo; Gu, Zhenglong et al. (2003) Patterns of gene duplication in Saccharomyces cerevisiae and Caenorhabditis elegans. J Mol Evol 56:28-37
Jensen-Seaman, Michael I; Li, Wen-Hsiung (2003) Evolution of the hominoid semenogelin genes, the major proteins of ejaculated semen. J Mol Evol 57:261-70
Li, Wen-Hsiung; Gu, Zhenglong; Cavalcanti, Andre R O et al. (2003) Detection of gene duplications and block duplications in eukaryotic genomes. J Struct Funct Genomics 3:27-34
Nekrutenko, Anton; Chung, Wen-Yu; Li, Wen-Hsiung (2003) ETOPE: Evolutionary test of predicted exons. Nucleic Acids Res 31:3564-7
Nekrutenko, Anton; Makova, Kateryna D; Li, Wen-Hsiung (2002) The K(A)/K(S) ratio test for assessing the protein-coding potential of genomic regions: an empirical and simulation study. Genome Res 12:198-202
Yi, Soojin; Ellsworth, Darrell L; Li, Wen-Hsiung (2002) Slow molecular clocks in Old World monkeys, apes, and humans. Mol Biol Evol 19:2191-8
Yi, Soojin; Bernat, Bryan; Pal, Gabor et al. (2002) Functional promiscuity of squirrel monkey growth hormone receptor toward both primate and nonprimate growth hormones. Mol Biol Evol 19:1083-92
Gu, Zhenglong; Cavalcanti, Andre; Chen, Feng-Chi et al. (2002) Extent of gene duplication in the genomes of Drosophila, nematode, and yeast. Mol Biol Evol 19:256-62
Yu, Ning; Chen, Feng-Chi; Ota, Satoshi et al. (2002) Larger genetic differences within africans than between Africans and Eurasians. Genetics 161:269-74
Liu, J C; Makova, K D; Adkins, R M et al. (2001) Episodic evolution of growth hormone in primates and emergence of the species specificity of human growth hormone receptor. Mol Biol Evol 18:945-53

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