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.

项目摘要/摘要 我们了解免疫球蛋白（IG）重（IG）的种系变化的理解存在根本的差距 人口中的轻链（IGK; IgL）基因座影响功能抗体的发展（AB） 健康和疾病的反应。但是，越来越多的理解Ig多态性有助于 AB曲目中的可变性，表明IG遗传数据的整合有可能告知我们 在各种临床环境中了解AB功能。进步的关键障碍是现有 缺乏针对IG基因座的基因组资源，并且在人类人群中发现了不良的多样性。 IG 区域在结构上很复杂，包括大量的分段重复，是最多的 基因组中的多态性，具有较大的拷贝数变体（CNV），核苷酸多样性升高和 人群特定的单倍型变体。这些复杂性长期使IG基因座难以研究 使用标准高通量方法的基因组和种群水平，对遗传产生直接负面影响 疾病协会的研究以及最近对表达的AB曲目数据的分析。结果，我们的 了解人类Ig种系多样性（尤其是在非高加索人）及其对疾病滞后的贡献 远远落后于其他经过良好研究的免疫位点。这凸显了直接需要公开可用的 从不同种族背景到的IG单倍型引用和准确的变体目录 促进更准确的基因分型工具，分析管道及其解释的设计和集成。 为了满足这种需求，我们已经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 IG基因座的社区资源。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，亚洲和欧洲血统的个人的现有8个福斯米德图书馆的集会。 我们还将使用一种新型的多人型知情基因分型管道来介绍A中的IGH/K/L遗传变异 来自这三个人群的180个家族和无关的个体组成的队列。这将代表最大的 Ig系多样性的全面人口调查，包括可变，多样性，加入的描述， 和恒定的基因变异以及范围范围的单核苷酸多态性（SNP）和CNV，从而允许 疾病关联研究变体归合面板研究的精细评估。最后，促进 这些数据作为长期资源，所有序列，工具/方法和分析管道的实用性将被制成 公开可用。我们将使用已建立的数据库，以确保所有序列都沉积在两个RAW中 和注释的形式。这将包括将集会集成到人类基因组的未来释放中 基因组学界使用的参考，以及对现有种系基因/等位基因数据库的更新 对表达的AB曲目分析至关重要。该项目建立了迫切需要的基因组资源 人类IG基因座，将在未来几年内更好地为免疫学界服务。这些将成为 未来努力定义Ig系在AB功能，健康和疾病中的作用的努力的基础。