Identifying human adaptations: theory and applications

人类遗传学的一个中心挑战是确定基因组的哪些区域具有功能性 重要性，特别是哪个子集影响疾病风险。这项研究通常包括 连锁分析或关联研究。一种互补的、基于群体遗传的方法是 通过检查核苷酸变异模式来确定人类谱系中可能的适应靶点 在人类内部以及人类与其进化近亲之间。涉及到的基因变化 人类特有的适应体系结构对它们本身非常感兴趣，并代表着 很有希望成为复杂疾病易感性的候选对象。 我们建议在各种人口统计环境中建立积极选择的模型，这些环境对 人类。在此基础上，我们将制定可靠的统计方法来评估对 最近适应的多态数据，并估计其时间和基因组位置。这个 新方法的可靠性将在一系列假设下模拟的数据上进行测试。用户友好型 实施这些计划的计划将通过网络公开提供。 我们将把我们的新方法应用于人类特有表达基因的多态数据 由顺监管区域的变化产生的模式。这些基因将从一种 我们之前的工作表明，在人脑中相对于其他基因的表达存在差异 类人猿。一旦RT-PCR确认了表达模式，我们将通过报告基因测试进行测试 人类和黑猩猩之间在-1.5kb区域的序列差异是否 转录起始位置影响表达。如果他们这样做，我们将收集以5‘’为中心的多态数据 该地区的30名约鲁巴人，并应用我们的新方法来评估最近适应的证据。 因此，拟议的研究将产生新的统计工具，用于检测 功能重要性，并将确定第一组人类特有的适应 基因表达调控。

A central challenge of human genetics is to determine which regions of the genome are of functional importance and, in particular, which subset influences the risk of disease. This research usually includes linkage analyses or association studies. A complementary, population-genetic based approach is to identify likely targets of adaptation in the human lineage by examining patterns of nucleotide variation within humans and between humans and their close evolutionary relatives. Genetic changes involved in the architecture of human-specific adaptations are of great interest in their own right and represent promising candidates for complex disease susceptibility. We propose to model positive selection in a variety of demographic settings that are plausible for humans. On this basis, we will develop robust statistical methods to assess the support in polymorphism data for a recent adaptation and to estimate its timing and genomic location. The reliability of the new methods will be tested on data simulated under a range of assumptions. User-friendly programs to implement them will be made publicly available via the web. We will apply our new methods to polymorphism data from genes with human-specific expression patterns that result from changes in the cis-regulatory regions. These genes will be identified from a set that our previous work has shown to be differentially expressed in the human brain relative to other apes. Once the expression patterns have been confirmed by RT-PCR, we will test by a reporter gene assay whether sequence differences between humans and chimpanzees in a -1.5kb region around the transcription start site affect expression. If they do, we will collect polymorphism data centered on the 5' region in 30 Yoruba individuals and apply our new methods to gauge the evidence for a recent adaptation. Thus, the proposed research will generate new statistical tools for the detection of regions of functional importance and will identify the first set of candidates for human-specific adaptations in gene expression regulation.