Mapping deep evolutionary divergences in cellular models of stress response

总结(家长奖励不变) 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，一种用于无偏映射的方法 可应用于繁殖隔离物种的自然性状变异。我们的RH-SEQ项目在 无脊椎动物测试案例首次将古老特征的复杂遗传学置于 实验文学。我们现在想要推进战略，调查复杂的更深层次的主题 物种间的遗传学--即进化是否使用跨基因的协同分子机制 潜在的多基因适应，以及这些基因如何共同作用来驱动表型。来试驾这些 方法，在我们的第一个目标中，我们将使用一个与生态相关的模型系统，即耐热发散 在500万年前最后共享祖先的酵母物种之间。在我们的第二个目标中，我们将把我们的 小鼠原代细胞种间遗传学的思路和工具。后者将使用一种细胞作为试验床- 自主的、促炎的衰老程序被称为细胞衰老，我们发现它存在分歧 在姐妹种小鼠之间。我们将开发RH-SEQ用于无偏遗传作图 衰老特征，我们将探索下位基因的上位性和分子机制作为平行的 我们的酵母模型。我们的酵母和鼠标项目将共同推动分析方法的发展 多基因特征，因为它们在物种之间存在差异，并加速了对这些古老特征的剖析 整个尤卡里亚地区的系统。

SUMMARY (No Changes from Parent Award) 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.