Identifying human adaptations: theory and applications

描述（由申请人提供）：人类遗传学的一个核心挑战是确定基因组的哪些区域具有功能重要性，特别是哪个子集影响疾病风险。这种研究通常包括连锁分析或关联研究。一个互补的，基于群体遗传学的方法是通过检查人类内部以及人类与其进化近亲之间的核苷酸变异模式来确定人类谱系中可能的适应目标。涉及人类特定适应结构的遗传变化本身就具有极大的意义，并代表了复杂疾病易感性的有希望的候选者。我们建议在各种人口统计学环境中模拟正向选择，这些环境对人类来说是合理的。在此基础上，我们将开发强大的统计方法来评估最近适应的多态性数据的支持，并估计其时间和基因组位置。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。将通过网络公开提供便于用户使用的执行这些建议的方案。我们将应用我们的新方法，从基因的多态性数据与人类特异性的表达模式，导致顺式调控区的变化。这些基因将从我们先前的工作已经表明在人类大脑中相对于其他猿类差异表达的一组基因中鉴定出来。一旦通过RT-PCR证实了表达模式，我们将通过报告基因测定来测试人类和黑猩猩之间在转录起始位点周围约1.5kb区域的序列差异是否影响表达。如果他们这样做了，我们将收集30个约鲁巴人5'区域的多态性数据，并应用我们的新方法来衡量最近适应的证据。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区域，并将确定基因表达调控中人类特异性适应的第一组候选者。

DESCRIPTION (provided by applicant): 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 approximately 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.