LINKAGE DISEQUILIBRIUM IN THE HUMAN GENOME

描述(摘自《研究人员摘要》)：这项建议的主要目的是阐明人口统计学和自然选择如何在人类基因组和人类群体中形成序列变异和连锁不平衡(LD)的组织。这样的理解将为设计旨在剖析复杂表型遗传基础的研究提供所需的关键背景信息。为了推进这些目标，研究人员提出了以下具体目标：1.在多达10对紧密但不完全连锁的基因座上调查三个不同种族群体的序列变异和LD，以：a)评估不同人口情景对变异和LD模式的影响；b)估计推断的人类群体人口模型的参数；以及c)通过计算机模拟在全基因组水平上对序列变异和LD的数量和位置间变异性进行预期。对于每个1-2kb的序列，将调查来自代表主要民族的三大群体的30-50条染色体样本的变异：喀麦隆(非洲)、汉人(亚洲)和意大利人(欧洲)。研究人员已经通过计算机模拟表明，这是一种在全基因组水平上发展对变异模式和LD的预期的高效和信息丰富的方法。此外，他们还将能够描述主要种族群体的遗传变异和LD的组织方式。2.研究人员将调查两个常见变异体G6PDdef和Duffy O血型(FY)的序列变异并重建单倍型。众所周知，这些基因是在非洲人口的正向选择下进化而来的。特别是，他们将估计被选择位点两侧区域的核苷酸多样性和LD，并在中性进化区域比较这些数量。这一分析的目的是表征LD模式上的选择特征和与所研究的变体相关联的序列变异。

DESCRIPTION (Adapted from the Investigator's Abstract): The main goal of this proposal is to elucidate how demography and natural selection have shaped the organization of sequence variation and linkage disequilibrium (LD) in the human genome and across human populations. Such an understanding will provide critical background information needed to design studies aimed at dissecting the genetic bases of complex phenotypes. To advance these goals, the investigators propose the following specific aims: 1. To survey sequence variation and LD in three ethnically diverse populations at up to ten pairs of tightly, but not completely linked loci to: a) evaluate the effect of different demographic scenarios on patterns of variation and LD; b) estimate the parameters of the inferred demographic model for human populations; and c) develop expectations for the amount and inter-locus variability of sequence variation and LD at the genome-wide level by computer simulations. For each locus 1-2 kb of sequence will be surveyed for variation in samples of 30-50 chromosomes from three large populations representative of the major ethnic groups: Cameroon (Africa), Han Chinese (Asia) and Italians (Europe). The investigators have already shown by computer simulations that this is a highly efficient and informative approach to develop expectations for the pattern of variation and LD at the genome-wide level. In addition they will be able to characterize how genetic variation and LD is organized across major ethnic groups. 2. The investigators will survey sequence variation and reconstruct haplotypes around two common variants: G6PDdef and Duffy O blood group (FY). These are known to have evolved under positive selection in African populations. In particular, they will estimate nucleotide diversity and LD in the regions flanking the site under selection and compare these quantities in neutrally evolving regions. This analysis is aimed at characterizing the signature of selection on the pattern of LD and sequence variation linked to the variants examined.