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产生的基因变化。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存在于不编码蛋白质的区域。以这些非编码区为重点，我们将研究人类基因组的谱系特异性进化。我们的方法包括发展似然比测试，以确定单一谱系中核苷酸替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最近的变化。为了专注于功能相关的变化，进化测试将仅限于具有特定已知或预测功能的候选区域集（例如调控区域，RNA基因）。预测的功能区域将使用机器学习分类技术进行识别。这些分类器将采用序列保护措施，以及快速扩展的人类基因组实验和生物信息学注释集合，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变化最显著的区域之后，我们将使用这些功能信息来开发关于观察到的变化影响的可测试假设。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认识。

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.