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: 10618340
• 负责人: Rachel Beth Brem
• 金额: $ 37.66万
• 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/10618340
• 关键词: Acceleration; 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; 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.

摘要 了解大自然如何创造新的特征是进化遗传学的一个基本目标。不偏不倚 到目前为止，对野生性状变异的实验解剖一直使用连锁或关联作图，这 仅适用于给定物种的相容个体之间的杂交。年的第一个资助期 这种方法-发展了R01，PiBrem发展了RH-seq，一种用于自然地图无偏映射的方法 可应用于繁殖隔离物种的性状变异。我们的RH-SEQ项目用于无脊椎动物测试 在实验中，案例首次将古老特征的复杂遗传学放在了可触及的范围内 文学。我们现在想要推进研究复杂遗传学中更深层次主题的策略 物种--即进化是否在一个基因座上使用协同的分子机制 多基因适应，以及这些基因如何共同作用来驱动表型。要测试这些方法，请在 我们的第一个目标是使用一个与生态相关的模型系统，酵母之间的耐热性差异 最后一次共享祖先的物种是500万年前。在我们的第二个目标中，我们将把我们的想法和工具 用于小鼠原代细胞的种间遗传学。后者将使用一种细胞自主的、亲 炎症性衰老程序称为细胞衰老，我们发现它在 姊妹种的老鼠。我们将开发RH-SEQ用于衰老性状的无偏遗传作图，我们将 与我们的酵母模型类似，追求潜在基因座的上位性和分子机制。一起， 我们的酵母和小鼠项目将改进多基因性状的分析方法，因为它们在 物种，并加速在欧亚各地的系统中解剖这些古老的字符。