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

基本信息

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
项目类别：
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

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

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项目摘要

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.