The evolution of human specific regulatory pathways

描述(申请人提供)：进化生物学的一个中心目标是阐明适应的遗传结构。对于人类来说，这个问题既是因为它将揭示我们物种特有的特征，也是因为适应和疾病易感性之间正在出现的联系。然而，到目前为止，人类监管适应的例子屈指可数，以至于许多悬而未决的问题仍然悬而未决。其中包括：哪些路径在人类进化中被重塑了？整个通路调节的适应性变化是涉及到许多基因的变化，还是涉及几个基因的变化？顺式(例如启动子区域)与反式(例如转录因子)调控元件的变化的相对重要性是什么？调节途径中的补偿性变化有多普遍？作为回答这些问题的第一步，我们建议识别在人类中已经适应性重塑的转录途径，并检查它们在三个灵长类物种中的进化。具体地说，我们计划将重点放在五个转录因子上，这些转录因子以前已经(在我们的工作中和其他人)被证明是人类谱系中积极选择的目标。通过siRNA敲除、基因表达谱、芯片序列和报告基因实验的组合，我们将确定这些转录因子直接调控的基因，不仅在人类中，而且在两个进化上的近亲黑猩猩和猕猴中也是如此。拟议的方法组合将导致对三个物种中五个转录因子的直接调控靶标进行可靠的注释，并有助于识别奠定人类特异性适应基础的转录途径。对这三个物种的调控网络进行比较，将揭示人类和密切相关物种之间存在大量调控差异的遗传基础，使我们能够解决上述许多问题。据我们所知，这项研究代表了第一次在全基因组范围内探索不同物种之间调控途径的差异。除了识别在人类谱系中被适应性重塑的途径外，它还将在转录水平上对调控变化的遗传基础产生前所未有的见解。

DESCRIPTION (provided by applicant): A central goal of evolutionary biology is to elucidate the genetic architecture of adaptation. In humans, this question is of interest both for what it will reveal about our species-specific traits and because of the emerging links between adaptation and disease susceptibility. To date, however, there are only a handful of examples of human regulatory adaptations, such that many outstanding questions remain open. Among these: Which pathways have been remodeled in human evolution? Do adaptive changes in the regulation of entire pathways involve changes to many genes, or to few? What is the relative importance of changes in cis (e.g., promoter regions) vs. trans (e.g., transcription factors) regulatory elements? How prevalent are compensatory changes in regulatory pathways? As a first step towards answering these questions, we propose to identify transcriptional pathways that have been adaptively remodeled in humans and to examine their evolution across three primate species. Specifically, we plan to focus on five transcription factors that have been shown previously (in our work and by others) to be the target of positive selection in the human lineage. Through a combination of siRNA knockdowns, gene expression profiles, ChIP-seq, and reporter gene experiments, we will identify the genes that are directly regulated by these transcription factors, not only in humans but also in two close evolutionary relatives, chimpanzees and rhesus macaques. The proposed combination of approaches will lead to the reliable annotation of direct regulatory targets of five transcription factors in three species and facilitate the identification of transcriptional pathways that underlie human-specific adaptation. Comparison of regulatory networks in the three species will reveal the genetic basis for a large set of regulatory differences between humans and closely related species, enabling us to address many of the above questions. To our knowledge, this research represents the first genome-wide exploration of differences in regulatory pathways across species. In addition to identifying pathways that have been adaptively remodeled in the human lineage, it will yield unprecedented insights into the genetic basis of regulatory change at the transcription level.