Mapping deep evolutionary divergences in cellular models of stress response

绘制应激反应细胞模型的深层进化差异

• 批准号: 10464610
• 负责人: Rachel Beth Brem
• 金额: $ 43.66万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10464610
• 关键词: Age; Aging; Alleles; Amino Acids; Architecture; Behavior; Biological Assay; Biological Models; Biology of Aging; Candidate Disease Gene; Case Study; Cell Aging; Cell model; Cells; Chromosome Mapping; Complex; Data; Dissection; Evolution; Funding; Genes; Genetic; Genetic Epistasis; Genetic Population Study; Genetic Variation; Genome; Goals; Hybrids; Individual; Inflammation; Inflammatory; Invertebrates; Laboratories; Light; Literature; Mammals; Maps; Metabolism; Methods; Modeling; Molecular; Mus; Nature; Nematoda; Organism; Partner in relationship; Pathology; Phenotype; Polygenic Traits; Proteins; Recombinants; Recording of previous events; Saccharomyces cerevisiae; Sister; Sterility; Stress; Surveys; System; Testing; Time; Variant; Work; Yeast Model System; Yeasts; biological adaptation to stress; experimental study; genetic architecture; genome-wide; innovation; interest; method development; molecular phenotype; mouse model; programs; reproductive; screening; senescence; tool; trait

SUMMARY Understanding how nature builds new traits is a fundamental goal of evolutionary genetics. Unbiased experimental dissection of trait variation from the wild has to date used linkage or association mapping, which are suitable only for crosses between compatible individuals of a given species. In the first funding period of this methods-development R01, PI Brem developed RH-seq, an approach for the unbiased mapping of natural trait variation that can be applied to reproductively isolated species. Our RH-seq projects in invertebrate test cases have put the complex genetics of ancient traits within reach for the first time in the experimental literature. We now want to advance strategies that investigate deeper themes in complex genetics between species—namely whether evolution uses concerted molecular mechanisms across the loci underlying a polygenic adaptation, and how these loci work together to drive phenotype. To test-drive these approaches, in our first Aim we will use an ecologically relevant model system, a thermotolerance divergence between yeast species that last shared an ancestor five million years ago. In our second Aim, we will port our ideas and tools for interspecies genetics to mouse primary cells. The latter will use as a testbed a cell-autonomous, pro- inflammatory aging program called cellular senescence, which we have found to diverge between between sister species of mice. We will develop RH-seq for unbiased genetic mapping of senescence traits, and we will pursue epistatic and molecular mechanisms of the underlying loci as a parallel to our yeast model. Together, our yeast and mouse projects will advance methods for the analysis of polygenic traits as they differ between species, and accelerate the dissection of such ancient characters in systems across Eukarya.

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