Genome-Wide Analysis of Adaptive Evolution in Humans

人类适应性进化的全基因组分析

• 批准号: 7145675
• 负责人: Joshua Michael Akey
• 金额: $ 27.04万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7145675
• 关键词: DNA footprinting; Primates; alleles; animal tissue; functional /structural genomics; genetic regulation; genetic screening; genome; geographic difference; human; human genetic material tag; human tissue; linkage disequilibriums; molecular biology information system; natural selections; nucleic acid sequence; population genetics; single nucleotide polymorphism

DESCRIPTION (provided by applicant): Positive selection, or adaptive evolution, is the driving force of Darwinian evolution and acts to increase the frequency of advantageous alleles in a population. Despite intense interest and study a detailed understanding of the adaptive landscape of the human genome has remained elusive. Identifying regions of the genome that have been targets of adaptive evolution will provide important insights into human evolutionary history and facilitate the identification of complex disease genes. The long-term goal of this project is to further our knowledge of how positive selection has contributed to extant patterns of human genetic variation by identifying genes that have been subject to adaptive evolution. To this end, in specific aim 1, we will use dense catalogs of publicly available SIMP data to perform genome-wide scans for positive selection and identify candidate selection genes. In contrast to the traditional paradigm of studying a small number of loci that one hypothesizes a priori to be influenced by selection, a population genomics approach allows global and unbiased inferences about selection to be made. In specific aim 2, we will confirm the signature of positive selection in 30 candidate selection genes by resequencing them in 88 individuals (22 each from African, Chinese, European, and Japanese populations) and 7 non-human primates. High resolution DNA sequence data will allow detailed evolutionary hypotheses to be tested. Specifically, statistical tests of neutrality based on levels of intraspecific polymorphism and interspecific divergence will be performed, and the magnitude and ages of selective events will be estimated. Finally, in specific aim 3, we will genotype SNPs in confirmed genes subject to adaptive evolution in a geographically diverse panel of 1,064 individuals. These data will provide important insights into the geographic distribution of genetic variation subject to adaptive evolution and allow us to test the hypothesis that selected allele and haplotype frequencies are correlated with environmental attributes such as latitude, altitude, or climate. The data generated in this project will have a significant impact on public health. One of the most difficult challenges confronting human genetics is to find genes that contribute to common complex diseases such as diabetes, cancer, and hypertension. Research that increases our understanding of the evolutionary forces that shape patterns of human genetic variation will facilitate disease gene mapping studies.

描述（由申请人提供）：正选择或适应性进化是达尔文进化的驱动力，其作用是增加群体中有利等位基因的频率。尽管人们对此产生了浓厚的兴趣并进行了研究，但对人类基因组适应性景观的详细了解仍然难以捉摸。识别作为适应性进化目标的基因组区域将为了解人类进化史提供重要见解，并有助于识别复杂的疾病基因。该项目的长期目标是通过识别经过适应性进化的基因，进一步了解正选择如何促进人类遗传变异的现有模式。为此，在具体目标 1 中，我们将使用公开可用的 SIMP 数据的密集目录来执行全基因组扫描以进行正选择并识别候选选择基因。与研究少量基因座（假设先验地受到选择影响）的传统范式相反，群体基因组学方法允许对选择进行全局且无偏见的推论。在具体目标 2 中，我们将通过对 88 个个体（非洲、中国、欧洲和日本种群各 22 个）和 7 个非人类灵长类动物进行重新测序来确认 30 个候选选择基因的正选择特征。高分辨率 DNA 序列数据将允许测试详细的进化假设。具体来说，将进行基于种内多态性和种间差异水平的中性统计检验，并估计选择性事件的程度和年龄。最后，在具体目标 3 中，我们将对 1,064 名来自不同地理位置的个体进行适应性进化，确认基因中的 S​​NP 进行基因分型。这些数据将为了解适应进化的遗传变异的地理分布提供重要的见解，并使我们能够检验所选等位基因和单倍型频率与纬度、海拔或气候等环境属性相关的假设。该项目产生的数据将对公众健康产生重大影响。人类遗传学面临的最困难的挑战之一是寻找导致糖尿病、癌症和高血压等常见复杂疾病的基因。增加我们对塑造人类遗传变异模式的进化力量的理解的研究将促进疾病基因图谱研究。