The long-term goal of this project is to understand the genomic mechanisms that generate phenotypic diversity in vertebrates. Rapid progress in genomics has provided nearly complete sequences for several organisms. Comparative analysis suggests many fundamental pathways and gene networks are conserved between organisms. And yet, the morphology, physiology, and behavior of different species are obviously and profoundly different. What are the mechanisms that generate these key differences? Are unique traits controlled by few or many genetic changes? What kinds of changes? Are there particular genes and mechanisms that are used repeatedly when organisms adapt to new environments? Can better understanding of these mechanisms help explain dramatic differences in disease susceptibility that also exist between groups? The Stanford CEGS will use an innovative combination of approaches in fish, mice, and humans to identify the molecular basis of major phenotypic change in natural populations of vertebrates.
Specific aims i nclude: 1) cross stickleback fish and develop a genome wide map of the chromosomes, genes, and mutations that control a broad range of new morphological, physiological, and behavioral traits in natural environments;2) test which population genetic measures provide the most reliable """"""""signatures of selection"""""""" surrounding genes that are known to have served as the basis of parallel adaptive change in many different natural populations around the world;3) assemble the stickleback proto Y chromosome and test whether either sex or autosomal rearrangements play an important role in generating phenotypic diversity, or are enriched in genomic regions that control phenotypic change;4) test whether particular genes and mechanisms are used repeatedly to control phenotypic change in many different vertebrates. Preliminary data suggests that mechanisms identified as the basis of adaptive change in natural fish populations may be broadly predictive of adaptive mechanisms across a surprisingly large range of animals, including humans. Genetic regions hypothesized to be under selection in humans will be compared to genetic regions under selection in fish. Regions predicted to play an important role in natural human variation and disease susceptibility will be modeled in mice, generating new model systems for confirming functional variants predicted from human population genetics and comparative genomics.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Specialized Center (P50)
Project #
5P50HG002568-10
Application #
8141446
Study Section
Ethical, Legal, Social Implications Review Committee (GNOM)
Program Officer
Felsenfeld, Adam
Project Start
2002-04-19
Project End
2014-05-31
Budget Start
2011-06-01
Budget End
2014-05-31
Support Year
10
Fiscal Year
2011
Total Cost
$2,676,390
Indirect Cost
Name
Stanford University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Indjeian, Vahan B; Kingman, Garrett A; Jones, Felicity C et al. (2016) Evolving New Skeletal Traits by cis-Regulatory Changes in Bone Morphogenetic Proteins. Cell 164:45-56
O'Brown, Natasha M; Summers, Brian R; Jones, Felicity C et al. (2015) A recurrent regulatory change underlying altered expression and Wnt response of the stickleback armor plates gene EDA. Elife 4:e05290
Conte, Gina L; Arnegard, Matthew E; Best, Jacob et al. (2015) Extent of QTL Reuse During Repeated Phenotypic Divergence of Sympatric Threespine Stickleback. Genetics 201:1189-200
Mills, Margaret G; Greenwood, Anna K; Peichel, Catherine L (2014) Pleiotropic effects of a single gene on skeletal development and sensory system patterning in sticklebacks. Evodevo 5:5
Cleves, Phillip A; Ellis, Nicholas A; Jimenez, Monica T et al. (2014) Evolved tooth gain in sticklebacks is associated with a cis-regulatory allele of Bmp6. Proc Natl Acad Sci U S A 111:13912-7
Kumar, Maya E; Bogard, Patrick E; Espinoza, F HernĂ¡n et al. (2014) Mesenchymal cells. Defining a mesenchymal progenitor niche at single-cell resolution. Science 346:1258810
Wilson, Benjamin A; Petrov, Dmitri A; Messer, Philipp W (2014) Soft selective sweeps in complex demographic scenarios. Genetics 198:669-84
Guenther, Catherine A; Tasic, Bosiljka; Luo, Liqun et al. (2014) A molecular basis for classic blond hair color in Europeans. Nat Genet 46:748-52
Arnegard, Matthew E; McGee, Matthew D; Matthews, Blake et al. (2014) Genetics of ecological divergence during speciation. Nature 511:307-11

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