Genomic Origins and Admixture in Latinos (GOAL)

描述（由申请人提供）： 群体结构和混合是全基因组关联和医学重测序研究中的关键混杂因素。特别是，考虑到病例和对照之间在基因组和地理位置方面的祖先差异，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。西班牙裔/拉丁美洲人，在美国最大和增长最快的少数民族群体的基因组研究表明，他们是一个高度遗传异质性的混合群体，在非洲，欧洲和美洲原住民血统的比例在个人和人口之间的巨大变化。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代表性不足。因此，了解美国西班牙裔/拉丁美洲裔和加勒比地区人群的潜在复杂遗传结构对于确保基因型-表型关联的稳健性以及了解美国和整个美洲不同人群中相关变异的医学相关性至关重要。此外，由于在过去的500年里，非洲和欧洲移民到美洲的情况已经有了很多了解，西班牙裔/拉丁裔的人口遗传学研究是一个很好的模型，可以用来开发新的算法和方法来表征混合人口的精细遗传结构。该项目将通过对180个父母-后代三联体进行密集的基因分型，并对来自六个加勒比裔美国人口（波多黎各、古巴、多米尼加共和国、海地、洪都拉斯和哥伦比亚）的30个三联体的基因组进行测序，来扩展目前对美国西班牙裔/拉丁裔人口遗传结构的研究。我们将结合联合收割机的SNP，CNV，和全基因组序列（WGS）数据与其他医学上可用的基因组资源，包括国际HapMap项目和1000个基因组项目，以了解复杂的遗传结构的西班牙裔/拉丁美洲人在美国的人口。我们将通过以下具体目标实现这一目标：1）使用Affytechnology 6.0全基因组SNP芯片在我们的180个三联体的样品中生成密集的SNP基因型数据（~100万个SNP和CNV），2）生成高覆盖率WGS数据并构建30个三合会的完整基因组3）基于SNP基因型和WGS数据（包括与HapMap和1000G数据的比较）表征我们的美国西班牙裔/拉丁裔三联体中的群体结构和混合物，和目的4）评估和解释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医学基因组研究。我们的项目是非常重要的，因为它将提供即时的见解和新的统计方法，以改善研究设计和遗传分析的医学基因组研究在西班牙裔/拉丁美洲人，其他复杂的混合群体，以及多种族和跨种族的研究。 公共卫生相关性： 项目叙述拟议的研究与公共卫生有关，因为我们开发了新的方法，用于使用美国西班牙裔/拉丁裔人口内部和之间的遗传多样性，以提高医学遗传学研究在美国人口这一不断增长的部分的成功。我们将使用西班牙裔/拉丁美洲人作为模型系统来开发下一代方法，这些方法可用于从遗传数据中推断大陆和次大陆血统。这项研究有望发展关键知识，这将改变我们在复杂混合人群中进行遗传研究的方式，使我们能够识别遗传原因，并最终诊断和治疗美国的遗传疾病，特别是在代表性不足和服务严重不足的群体中，如非洲裔美国人和西班牙裔/拉丁美洲人。

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.