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The evolution of human specific regulatory pathways

人类特定调控途径的进化

基本信息

批准号：
8433392
负责人：
Yoav Gilad
金额：
$ 33.36万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8433392
关键词：
Address Affect Antibodies Architecture Binding Binding Sites Biological Biological Assay Biology Candidate Disease Gene Cells ChIP-seq Chromatin DNA Microarray Chip Data Disease Disease susceptibility Epitopes Evolution Gene Expression Genes Genetic Genetic Transcription Genome Scan Genomics Goals Human Human Genome Immunoglobulin G Individual Lead Learning Link Luciferases Lymphocyte Macaca mulatta Messenger RNA Modeling Molecular Evolution Molecular Profiling Mutation Orthologous Gene Pan Genus Pathway interactions Play Primary Cell Cultures Primates Promoter Regions Proteins Regulation Regulator Genes Regulatory Element Regulatory Pathway Relative (related person)Reporter Genes Research Role Sampling Site-Directed Mutagenesis Small Interfering RNA Technology Transfection Western Blotting Work base chromatin immunoprecipitation comparative genomics genome-wide insight interest lymphoblast promoter public health relevance reproductive research study species difference theories trait transcription factor

项目摘要

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.

描述（由申请人提供）：进化生物学的中心目标是阐明适应的遗传结构。对人类来说，这个问题很有趣，因为它揭示了我们物种特有的特征，也因为适应和疾病易感性之间出现了联系。然而，迄今为止，人类调节适应的例子屈指可数，因此许多悬而未决的问题仍未解决。其中包括：哪些途径在人类进化中被重塑？整个通路调节中的适应性变化是否涉及到许多基因的变化，还是少数基因的变化？顺式（如启动子区）与反式（如转录因子）调控元件变化的相对重要性是什么？调节途径中的代偿性变化有多普遍？作为回答这些问题的第一步，我们建议确定在人类中适应性重塑的转录途径，并研究它们在三种灵长类动物中的进化。具体来说，我们计划将重点放在五种转录因子上，这些转录因子之前（在我们的工作和其他人的工作中）已被证明是人类谱系中积极选择的目标。通过siRNA敲低、基因表达谱、ChIP-seq和报告基因实验的结合，我们将确定由这些转录因子直接调节的基因，不仅在人类中，而且在两个进化近亲黑猩猩和恒河猴中。所提出的方法组合将导致对三种物种中五种转录因子的直接调控靶点的可靠注释，并有助于确定人类特异性适应的转录途径。对这三个物种的调控网络进行比较，将揭示人类和近亲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，这项研究代表了跨物种调控途径差异的第一次全基因组探索。除了确定在人类谱系中适应性重塑的途径外，它还将对转录水平上调控变化的遗传基础产生前所未有的见解。