LINKAGE DISEQUILIBRIUM IN THE HUMAN GENOME

描述（改编自研究者摘要）：本提案的主要目标是阐明人口统计学和自然选择如何塑造人类基因组和人类种群中序列变异和连锁不平衡（LD）的组织。这样的理解将提供设计旨在解剖复杂表型的遗传基础的研究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。在三个不同种族的人群中，在多达10对紧密连锁但不完全连锁的基因座上调查序列变异和LD，以：a）评估不同人口统计学情景对变异模式和LD的影响; B）估计人群推断的人口统计学模型的参数;和c）通过计算机模拟在全基因组水平上对序列变异和LD的数量和基因座间变异性进行预测。对于每个基因座，将调查1- 2kb序列在来自代表主要种族群体的三个大群体的30-50条染色体的样品中的变异：喀麦隆人（非洲）、中国汉族人（亚洲）和意大利人（欧洲）。研究人员已经通过计算机模拟表明，这是一种高效和信息丰富的方法，可以在全基因组水平上对变异模式和LD进行预测。此外，他们将能够描述遗传变异和LD如何在主要种族群体中组织起来。2.研究人员将调查序列变异，并围绕两种常见的变体重建单倍型：G6 PDdef和达菲O血型（FY）。已知这些是在非洲种群的积极选择下进化而来的。特别是，他们将估计选择位点侧翼区域的核苷酸多样性和LD，并在中性进化区域中比较这些数量。该分析旨在表征LD模式上的选择特征和与所检查的变体相关的序列变异。

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.