An ethnically diverse genomic reference resource for the human heavy and light chain immunoglobulin loci

人类重链和轻链免疫球蛋白基因座的种族多样化基因组参考资源

• 批准号: 10202394
• 负责人: Melissa Laird Smith
• 金额: $ 38.18万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-23 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202394
• 关键词: African; Alleles; Antibodies; Antibody Repertoire; Antibody Response; Asians; Autoimmunity; B-Lymphocytes; Biological Assay; Catalogs; Clinical; Communities; Complex; Copy Number Polymorphism; Data; Data Analyses; Data Set; Databases; Deposition; Development; Diploidy; Disease; Ensure; European; Evaluation; Foundations; Future; Genbank; Genes; Genetic; Genetic Diseases; Genetic Polymorphism; Genetic Research; Genetic Variation; Genome; Genomics; Genotype; Haplotypes; Health; Human; Human Resources; IGL@ gene cluster; Immune; Immune System Diseases; Immunogenetics; Immunoglobulins; Immunology; Individual; Infection; Information Systems; International; Knowledge; Libraries; Light; Link; Malignant Neoplasms; Methods; Nucleic Acid Regulatory Sequences; Nucleotides; Outcome; Population; Positioning Attribute; Resolution; Resources; Role; Sampling; Single Nucleotide Polymorphism; Structure; Update; Variant; Work; adaptive immunity; analysis pipeline; cohort; dbSNP; design; direct application; ethnic diversity; genetic association; high standard; human reference genome; immunoglobulin light chain locus; improved; insight; inter-individual variation; novel; novel strategies; personalized medicine; population survey; precision medicine; reference genome; tool; vaccine response

Project Summary/Abstract There is a fundamental gap in our understanding of how germline variation in immunoglobulin (IG) heavy (IGH) and light chain (IGK; IGL) loci in the human population impacts the development of the functional antibody (Ab) response in health and disease. However, there is a growing appreciation that IG polymorphism contributes to variability in the Ab repertoire, indicating that the integration of IG genetic data has the potential to inform our understanding of Ab function in various clinical contexts. A critical barrier to progress has been that existing genomic resources for IG loci are lacking and poorly represent diversity found across human populations. IG regions are structurally complex, consisting of large segmental duplications, and are among the most polymorphic in the genome, with large copy number variants (CNVs), elevated nucleotide diversity, and population-specific haplotype variants. These complexities have long made IG loci difficult to study at the genomic and population level using standard high-throughput methods, with direct negative impacts on genetic disease association studies and more recently the analysis of expressed Ab repertoire data. As a result, our knowledge of human IG germline diversity (particularly in non-Caucasians) and its contribution to disease lags far behind that of other well studied immune loci. This highlights a direct need for publically available well- characterized IG haplotype references and accurate variant catalogues from diverse ethnic backgrounds to facilitate the design and integration of more accurate genotyping tools, analysis pipelines, and their interpretation. To meet this need, we have developed several robust approaches, which we will utilize here to establish critical community resources for the IG loci. We will first enumerate up to 16 novel IGH/K/L haplotype reference assemblies from an existing set of 8 fosmid libraries from individuals of African, Asian, and European descent. We will also use a novel multi-haplotype informed genotyping pipeline to profile IGH/K/L genetic variation in a cohort of 180 familial and unrelated individuals from these same three populations. This will represent the most comprehensive population survey of IG germline diversity, including descriptions of variable, diversity, joining, and constant gene variation, and locus-wide single nucleotide polymorphisms (SNPs) and CNVs, allowing for fine-scale assessment of variant imputation panels for disease association studies. Finally, to facilitate the utility of these data as long-term resources, all sequences, tools/methods, and analysis pipelines will be made publically available. We will work with established databases to ensure all sequences are deposited in both raw and annotated form. This will include the integration of assemblies into future releases of the human genome reference for use by the genomics community, as well as updates to existing germline gene/allele databases critical to expressed Ab repertoire analysis. This project establishes desperately needed genomic resources for the human IG loci, which will better serve the immunology community for years to come. These will stand as a foundation for future efforts to define the role of IG germline variation in Ab function, health, and disease.

项目概要/摘要 我们对免疫球蛋白（IG）重链（IGH）种系变异的理解存在根本性差距 人群中的轻链（IGK；IGL）位点影响功能性抗体（Ab）的发育 健康和疾病的反应。然而，人们越来越认识到 IG 多态性有助于 Ab 库的变异性，表明 IG 遗传数据的整合有可能为我们提供信息 了解抗体在各种临床情况下的功能。进步的一个关键障碍是现有的 IG 位点的基因组资源缺乏，并且不能很好地代表人类群体中发现的多样性。免疫组化 这些区域结构复杂，由大片段重复组成，并且是最复杂的区域之一 基因组多态性，具有大拷贝数变异（CNV）、核苷酸多样性升高以及 人群特异性单倍型变异。这些复杂性长期以来使得 IG 基因座难以在实验室进行研究。 使用标准高通量方法进行基因组和群体水平的分析，对遗传有直接的负面影响 疾病关联研究以及最近表达的抗体库数据的分析。结果，我们的 了解人类 IG 种系多样性（尤其是非白种人）及其对疾病滞后的影响 远远落后于其他经过充分研究的免疫位点。这凸显了对公开可用的直接需求 描述了来自不同种族背景的 IG 单倍型参考和准确的变异目录 促进更准确的基因分型工具、分析流程及其解释的设计和集成。 为了满足这一需求，我们开发了几种强大的方法，我们将在这里利用这些方法来建立关键的 IG 位点的社区资源。我们将首先列举多达 16 个新颖的 IGH/K/L 单倍型参考 来自非洲、亚洲和欧洲血统的现有 8 个 fosmid 文库的组件。 我们还将使用一种新颖的多单倍型基因分型流程来分析 IGH/K/L 遗传变异 来自这三个人群的 180 名家族和无关个体组成的队列。这将代表最 IG 种系多样性的全面群体调查，包括变量、多样性、连接、 和恒定的基因变异，以及全基因座单核苷酸多态性 (SNP) 和 CNV，从而允许 用于疾病关联研究的变异插补小组的精细评估。最后，为了方便 将这些数据作为长期资源，所有序列、工具/方法和分析管道都将被利用 公开可用。我们将与已建立的数据库合作，确保所有序列都存储在原始数据库中 和注释形式。这将包括将组件集成到人类基因组的未来版本中 供基因组学界使用的参考，以及现有种系基因/等位基因数据库的更新 对于表达的抗体库分析至关重要。该项目建立了急需的基因组资源 人类 IG 基因座，这将在未来几年更好地为免疫学界服务。这些将作为 为未来确定 IG 种系变异在 Ab 功能、健康和疾病中的作用奠定了基础。