Mapping deep evolutionary divergences in cellular models of stress response

总结 了解自然如何建立新的特征是进化遗传学的一个基本目标。无偏 迄今为止，对野生性状变异的实验解剖使用了连锁或关联作图， 仅适用于给定物种的相容个体之间的杂交。在第一个供资期， 这种方法开发R 01，PI Brem开发了RH-seq，这是一种无偏映射自然 可以应用于生殖隔离物种的性状变异。我们在无脊椎动物测试中的RH-seq项目 这些案例首次将复杂的古代特征遗传学置于实验研究的范围之内。 文学我们现在希望推进研究复杂遗传学中更深层次主题的策略， 物种-即进化是否使用协调一致的分子机制在基因座的基础上， 多基因适应，以及这些基因座如何共同作用以驱动表型。为了测试这些方法， 我们的第一个目标，我们将使用一个生态相关的模型系统，酵母之间的耐热性分歧 最后一个共同祖先是在五百万年前。在我们的第二个目标中，我们将把我们的想法和工具 用于种间遗传学的小鼠原代细胞。后者将作为一个试验平台，细胞自主，亲， 炎症性衰老程序称为细胞衰老，我们已经发现， 老鼠的姊妹种我们将开发RH-seq用于衰老性状的无偏遗传作图，我们将 追求上位性和潜在基因座的分子机制，作为我们的酵母模型的平行。在一起， 我们的酵母和小鼠项目将推进多基因性状的分析方法，因为它们在不同的 物种，并加速在整个真核生物系统中对这些古老字符的解剖。

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.