Genomic Origins and Admixture in Latinos (GOAL)

描述(由申请人提供)： 项目摘要/摘要种群结构和混合物是全基因组关联和医学重新测序研究中的关键混杂因素。特别是，考虑到病例和对照在基因组和地理位置上的祖先差异，对于正确分析和解释多种族和跨种族样本的研究至关重要。对拉美裔/拉丁裔的基因组研究表明，他们是一个高度遗传异质性的混合群体，在非洲、欧洲和美洲原住民祖先的个体和群体中存在巨大差异。拉美裔/拉丁裔是美国规模最大、增长最快的少数群体。此外，虽然墨西哥人口在某种程度上具有基因组特征，但对加勒比和南美洲人口的遗传研究在很大程度上没有得到充分的代表。因此，了解美国拉美裔/拉丁裔和加勒比人群的潜在复杂遗传结构，对于确保美国和整个美洲不同人群的基因-表型关联的稳健性和了解相关变异的医学相关性至关重要。此外，由于对过去500年来非洲和欧洲移民进入美洲的了解很多，拉美裔/拉丁裔的人口遗传学研究是开发新的算法和方法的一个极好的模式，一般而言，这些算法和方法描述混合种群的精细遗传结构。该项目将扩展目前对美国拉美裔/拉丁裔群体遗传结构的研究，通过对180个亲代-后代三联体进行密集基因分型，并对来自六个加勒比裔美国人口的30个三联体的基因组进行排序：波多黎各、古巴、多米尼加共和国、海地、洪都拉斯和哥伦比亚。我们将把SNP、CNV和全基因组序列(WGS)数据与其他公开可用的基因组资源结合起来，包括国际HapMap项目和1000基因组项目，以了解美国拉美裔/拉丁裔人口的复杂遗传结构。我们将通过以下具体目标来实现这一目标：1)使用Affymetrix 6.0全基因组SNP芯片(~100万个SNP和CNV)在我们的180个三联体样本中生成密集的SNP基因型数据；2)生成高覆盖率的WGS数据，并构建30个三联体的完整基因组(6个种群中的每个5个)到至少20倍的覆盖率；3)基于SNP基因型和WGS数据描述美国拉美裔/拉丁裔三联体的种群结构和混合，包括与HapMap和1000G数据的比较，以及目的4)评估和说明亚结构对疾病关联测试的影响，以改进下一代跨种族和多种族的医学基因组研究。我们的项目意义重大，因为它将提供即时的见解和新的统计方法，以改进拉美裔/拉丁裔、其他复杂混合群体以及多种族和跨种族研究的医学基因组研究的研究设计和遗传分析。 公共卫生相关性： 项目简介拟议的研究与公共卫生相关，因为我们开发了新的方法，利用美国拉美裔/拉丁裔人口内部和之间的遗传多样性，以提高在这一美国人口日益增长的部分中进行医学遗传学研究的成功。我们将使用拉美裔/拉丁裔作为模型系统，开发可用于从基因数据推断大陆和次大陆祖先的下一代方法。这项研究承诺开发关键知识，这将改变我们在具有复杂混合物的人群中进行基因研究的方式，使我们能够确定遗传原因，并最终诊断和治疗美国的遗传病，特别是在非洲裔美国人和拉美裔/拉美裔美国人等代表性和严重不足的群体中。

DESCRIPTION (provided by applicant): Project Summary/Abstract Population structure and admixture are key confounders in genome-wide association and medical resequencing studies. In particular, accounting for difference in ancestry among cases and controls, both in terms of genomic and geographic location, is critical for proper analysis and interpretation of studies with multi- and trans-ethnic samples. Genomic studies of Hispanics/Latinos, the largest and fastest growing minority group in the US, reveal that they are a highly genetically heterogeneous admixed group with immense variation among individuals and populations in the proportions of African, European, and Native American ancestry. Furthermore, while Mexican populations have been characterized genomically to some extent, genetic studies of populations from the Caribbean and South America have been largely underrepresented. Knowledge of the underlying complex genetic structure of US Hispanic/Latino and Caribbean populations is, therefore, essential to ensuring robustness of genotype-phenotype associations and understanding the medical relevance of associated variants across diverse populations in the US and throughout the Americas. Furthermore, since much is known about the African and European migrations into the Americas over the past 500 years, population genetic studies of Hispanics/Latinos serve as an excellent model for developing novel algorithms and approaches for characterizing fine-scale genetic structure of admixed populations, in general. This project will extend current studies of population genetic structure in US Hispanics/Latinos by densely genotyping 180 parent-offspring triads and sequencing the genomes of 30 triads from six U.S. populations of Caribbean- descent: Puerto Rico, Cuba, Dominican Republic, Haiti, Honduras and Colombia. We will combine the SNP, CNV, and whole genome sequence (WGS) data with other publically available genomic resources including the International HapMap project and the 1000 Genomes project to understand the complex genetic architecture of Hispanic/Latino populations in the US. We will accomplish this goal through the following specific aims: 1) Generate dense SNP genotype data across our sample of 180 triads using the Affymetrix 6.0 whole genome SNP chip (~1 million SNPs and CNVs), 2) Generate high coverage WGS data and build the complete genomes of 30 triads (5 from each of 6 populations) to at least 20X coverage, 3) Characterize population structure and admixture in our US Hispanic/Latino triads based on SNP genotype and WGS data including comparison to HapMap and 1000G data, and Aim 4) Assess and account for the impact of substructure on disease-association tests in order to improve the next generation of trans and multi-ethnic medical genomic studies. Our project is highly significant because it will provide immediate insights and new statistical methods to improve study design and genetic analysis for medical genomic studies in Hispanics/Latinos, other complex admixed groups, and multi- and trans-ethnic studies. PUBLIC HEALTH RELEVANCE: Project Narrative The proposed research is relevant to public health because we develop novel approaches for using genetic diversity within and among US Hispanic/Latino populations to improve the success of medical genetic studies in this growing segment of the US population. We will use Hispanic/Latinos as a model system to develop next-generation methods that can be used to infer continental and subcontinental ancestry from genetic data. This study promises to develop critical knowledge that will transform the way we conduct genetic studies in populations with complex admixture allowing us to identify genetic causes and ultimately diagnose and treat genetic disease in the US, particularly in underrepresented and critically underserved groups such as African- Americans and Hispanics/Latinos.