Human-Specific Gain and Loss of Function

描述(由申请人提供)：拟议的研究将寻求利用群体遗传数据来区分经历纯化选择的人类基因组区域和不受限制的基因组区域。由于受选择性限制的基因组序列执行对生物体有益的功能，这项工作将揭示人类基因组以前未知的功能区域。特别是，由于这种方法不依赖于人类和密切相关物种之间的比较，它可以揭示人类从其他类人猿分裂后获得或失去选择性约束的区域。在这段时间内获得功能的区域将代表最近人类适应的一类重要类别，并可能揭示导致人类独特表型的分子变化。除了进化上的重要性，这项工作还将改进人类基因组的功能注释，揭示如果被破坏可能导致有害影响的功能区域，这些功能区域无法从比较基因组技术中检测到。除了揭示人类特有的功能收益外，拟议的项目还将允许检测自人类-黑猩猩分化以来发生的功能损失。这些事件也可能是最近人类进化中重要的表型变化的基础，因为几种已知的人类特有的功能丧失是适应性的。即使是健康中性的功能丧失也是有用的，因为它们可能揭示出选择压力的差异，允许某些功能在人类身上丧失，但需要在我们的亲属身上保持这些功能。最后，这里提出的工作将结合种群遗传和系统发育数据，以比单独检查这两种类型的数据更准确的方式揭示受限制的区域。这将导致人类基因组功能注释的进一步改进，特别是对于从头算技术无法可靠地检测到的非蛋白质编码功能区域。进行这项研究将提高申请人对群体遗传学和计算方法的知识，这些方法可以利用多态来推断不同基因组座位的选择和功能重要性。来自在这两个领域都有专业知识的赞助商和共同赞助商的指导，以及与赞助商所在机构的其他教职员工和博士后的互动，对提高申请者的技能将是非常宝贵的。这一经历将极大地提高申请人实现其作为一名独立科学家在研究型大学管理实验室的目标的机会。

DESCRIPTION (provided by applicant): The proposed research will seek to utilize population genetic data to distinguish regions of the human genome experiencing purifying selection from unconstrained genomic regions. Because genomic sequences subject to selective constraint perform functions beneficial to the organism, this work will reveal previously unknown functional regions of the human genome. In particular, since this approach does not rely on comparisons between humans and closely related species, it can uncover regions acquiring or losing selective constraint after humans split from other great apes. Regions acquiring function during this time period would represent an important class of recent human adaptations, and could reveal molecular changes responsible for uniquely human phenotypes. Beyond its evolutionary importance, this work would improve the functional annotation of the human genome, revealing functional regions that could result in harmful effects if disrupted, and that cannot be detected from comparative genomic techniques. In addition to revealing human-specific gains-of- function, the proposed project would allow for detection of losses-of-function occurring since the human- chimpanzee divergence. These events could also underlie important phenotypic changes in recent human evolution, as several known human-specific losses-of-function were adaptive. Even fitness-neutral losses of function are informative, as they may reveal differences in selective pressures allowing certain functions to be lost in humans but requiring them to be maintained in our relatives. Finally, the work proposed here will combine population genetic and phylogenetic data to reveal constrained regions with better accuracy than can be achieved by examining either of these types of data alone. This will result in further improvements to the functional annotation of the human genome, especially with respect to non-protein-coding functional regions that cannot be reliably detected by ab initio techniques. Performing this research will improve the applicant's knowledge of population genetics and computational methods that can leverage polymorphism to draw inferences about the selective and functional importance of different genomic loci. Instruction from a sponsor and co-sponsor with expertise in both of these areas, as well as interaction with other faculty members and postdocs at the sponsor's institution, will be invaluable for improving the applicant's skills. This experience wil greatly enhance the applicant's chances of achieving his goal of succeeding as an independent scientist running a lab at a research university.