Genomic Patterns of Polymorphism in Primates

描述（由申请人提供）：随着HapMap项目的完成和1000基因组项目的持续努力，一个近乎全面的DNA序列变异目录将很快为人类提供。这些数据将为阐明形成随时间变化模式的历史力量提供非常丰富的信息。为了更好地理解这些信息，本研究建议从8种灵长类动物中收集大规模的序列多态性数据。重要的是，该小组包括对生物医学研究具有基本兴趣的物种，以及已经完成或正在进行的基因组测序项目。一个主要目标是推断对X染色体和常染色体有不同影响的若干种群遗传过程的相对影响，例如种群规模的变化和性别偏倚迁移、自然选择（例如背景和正向方向选择）和性选择（即男性与女性生殖成功率的较大差异）。为了建立一个比较框架，所选的8种灵长类动物代表了广泛的不同交配策略和分散模式，包括一夫一妻制（如长臂猿）、单雄性多雌性群体（大猩猩、猩猩、狒狒）和多雄性多雌性群体（黑猩猩、狒狒、猕猴）。为了解开人口统计学和选择力的相对影响，本研究针对X染色体和常染色体上300个基因和非基因区域的组合。实验设计采用DNA捕获阵列，从每个物种的10个个体中富集1.8 Mb的目标DNA。然后通过大规模平行测序技术对目标DNA进行40-80倍深度的测序。下一代序列数据的质量将通过与传统Sanger方法测序的100 Kb pcr扩增DNA进行比较来评估。这项研究将有助于确定行为观察和形态测量在多大程度上预测变异的基因组模式，以及自然选择在形成遗传变异的精细模式中起什么作用。这些信息也将作为人类变异的群体遗传学模型。此外，它对于阐明作为人类主要生物医学模型的物种中影响遗传变异的因素至关重要。在这些物种中建立中性多态性和连锁不平衡的基线水平将有助于候选基因研究和全基因组关联研究的适当设计和分析，以确定复杂性状的遗传决定因素。

DESCRIPTION (provided by applicant): With the completion of the HapMap project and the ongoing efforts of the 1000 genomes project, a nearly comprehensive catalog of DNA sequence variants will soon become available for human populations. These data will be very informative for elucidating the historical forces that have shaped patterns of variation over time. To help put this information in perspective, this study proposes to gather large-scale sequence polymorphism data from a broad panel of eight primate species. Importantly, this panel includes species that are of fundamental interest to biomedical research and have genome sequencing projects that are completed or underway. A major goal is to infer the relative influence of a number of population genetic processes that differentially affect the X chromosome versus autosomes, such as changes in population size and sex-biased migration, natural selection (e.g., background and positive directional selection), and sexual selection (i.e., higher variance in male versus female reproductive success). To develop a comparative framework, the chosen set of 8 primate species represents a wide range of different mating strategies and dispersal patterns, including monogamous pairs (e.g., gibbons), single male multi-female groups (gorillas, orangutans, baboons), and multi-male multi-female groups (chimps, baboons, macaques). To disentangle the relative influence of demographic and selective forces, this study targets a combination of 300 genic and non-genic regions on the X chromosome and autosomes. The experimental design employs DNA capture arrays to enrich for 1.8 Mb of target DNA from 10 individuals from each species. The target DNA will then be sequenced to a depth of 40-80-fold coverage through massively parallel sequencing technology. The quality of the next generation sequence data will be assessed through comparison with 100 Kb of PCR-amplified DNA sequenced by conventional Sanger methodology. This study will help determine to what extent behavioral observations and morphological measurements are predictive of genomic patterns of variation, and what role natural selection plays in shaping fine-scale patterns of genetic variability. This information will also serve as a model for the population genetics of human variation. Moreover, it is essential for elucidating the factors that have affected genetic variation in species that serve as major biomedical models for humans. Establishing baseline levels of neutral polymorphism and linkage disequilibrium in these species will facilitate the proper design and analysis of both candidate gene studies and genome-wide association studies to identify the genetic determinants of complex traits. PUBLIC HEALTH RELEVANCE: This research on large-scale patterns of DNA sequence variation within eight species of primates promises to contribute to our understanding of the population genetic processes that affect the genomes of our closest living non-human relatives, and to provide a context and statistical tools for interpreting the rapidly growing database of human DNA sequence polymorphism. Several of the selected species serve as animal models for a broad range of human diseases and disease-related biological processes. A more complete understanding of the factors that have shaped genetic variation in these species is important for the proper design and analysis of both candidate-gene studies and genome-wide association studies for identifying the genetic determinants of complex traits, such as disease susceptibility or drug toxicity.