What Made Us Human?

描述（由申请人提供）：比较基因组学有望揭示那些导致现代人类物种的遗传变化。越来越多的证据表明，人类和黑猩猩基因组之间的绝大多数功能差异都在不编码蛋白质的区域。重点放在这些非编码区，我们将研究人类基因组中的谱系特异性进化。我们的方法包括开发似然比检验，用于确定单个谱系中核苷酸取代的速率或模式的变化。这些新方法将在开源软件中实现，可用于扫描整个基因组。我们将把这种进化分析应用于人类和其他脊椎动物的多个序列比对，包括几个密切相关的物种（猕猴，黑猩猩，尼安德特人），使我们能够识别人类基因组的最新变化。为了专注于功能相关的变化，进化测试将限于具有特定已知或预测功能的候选区域（例如调控区域，RNA基因）。将使用机器学习分类技术识别预测的功能区域。这些分类器将采用序列保守措施以及人类基因组实验和生物信息学注释的快速扩展集合，包括ENCODE项目和其他功能基因组研究的结果。在确定了人类谱系中最显著改变的区域之后，我们将使用这些功能信息来开发关于所观察到的变化的影响的可验证的假设。对这些基因组区域的实验研究将导致对人类生物学和健康进化的新理解。 项目简介：该项目将极大地扩展人类基因组生物相关特征的知识，这些特征是我们物种所独有的。鉴定和描述导致现代人类的基因变化具有根本意义。这些研究还有望有助于我们了解人类疾病背后的因果机制，从而制定有针对性的治疗和预防战略。

DESCRIPTION (provided by applicant): Comparative genomics promises to shed light on those genetic changes that gave rise to the modern human species. Mounting evidence suggests that the vast majority of functional differences between the human and chimpanzee genomes are in regions that do not code for proteins. Focusing on these non-coding regions, we will investigate lineage-specific evolution in the human genome. Our approach includes developing likelihood ratio tests for identifying changes in either the rate or the pattern of nucleotide substitution in a single lineage. These novel methods will be implemented in open source software that can be used to scan an entire genome. We will apply this evolutionary analysis to multiple sequence alignments of human and other vertebrates, including several closely related species (macaque, chimpanzee, Neanderthal), allowing us to identify recent changes in the human genome. In order to concentrate on functionally relevant changes, evolutionary testing will be limited to sets of candidate regions with specific known or predicted functions (e.g. regulatory regions, RNA genes). Predicted functional regions will be identified using machine learning classification techniques. These classifiers will employ measures of sequence conservation as well as the rapidly expanding collection of experimental and bioinformatic annotations of the human genome, including results of the ENCODE Project and other functional genomic studies. After identifying those regions that were most significantly altered in the human lineage, we will use this functional information to develop testable hypotheses about the effects of the observed changes. Experimental investigations of these genomic regions will lead to new understanding of the evolution of human biology and health. PROJECT NARRATIVE: This project will vastly expand knowledge of biologically relevant features of the human genome that are unique to our species. Identification and characterization of the genetic changes leading to modern humans is of fundamental interest. These investigations also promise to contribute to our understanding of the causal mechanisms behind human diseases, leading to directed treatment and prevention strategies.