The evolution of human specific regulatory pathways

描述（由申请人提供）：进化生物学的一个中心目标是阐明适应的遗传结构。在人类中，这个问题很有趣，因为它将揭示我们的物种特异性特征，也因为适应和疾病易感性之间的联系。然而，到目前为止，只有少数人类调节适应的例子，因此许多悬而未决的问题仍然悬而未决。其中包括：哪些途径在人类进化中被重塑？调节整个通路的适应性变化是否涉及到许多基因的变化，还是少数？顺式变化的相对重要性是什么（例如，启动子区）与反式（例如，转录因子）调控元件？调节途径的代偿性变化有多普遍？作为回答这些问题的第一步，我们建议确定已适应性改造的转录途径，在人类和研究他们的进化跨越三个灵长类动物物种。具体来说，我们计划专注于五个转录因子，这些转录因子以前（在我们的工作中和其他人）已经被证明是人类谱系中正选择的目标。通过siRNA敲除，基因表达谱，ChIP-seq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，而且在两个密切的进化亲属，黑猩猩和恒河猴。建议的方法相结合，将导致可靠的注释的直接调控目标的五个转录因子在三个物种和促进识别的转录途径，人类特异性适应的基础。比较这三个物种的调控网络将揭示人类与密切相关物种之间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全基因组探索跨物种调控途径的差异。除了识别在人类谱系中已经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。 公共卫生相关性：这项研究的目的是确定第一组在人类中重塑的调控途径，并了解灵长类动物基因调控变化的遗传基础。

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. PUBLIC HEALTH RELEVANCE: The goal of the proposed study is to identify a first set of regulatory pathways that have been remodeled in humans, and learn about the genetic basis of gene regulatory changes in primates.