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：
10693395
负责人：
Melissa Laird Smith
金额：
$ 78.24万
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 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10693395
关键词：
2019-nCoV Adaptive Immune System Adult Antibodies Antibody Repertoire Antibody Response Antibody-mediated protection Area Autoimmunity Award B-Lymphocytes Basic Science Biomedical Research Brazil Catalogs Clinical Collaborations Collection Communities Complex Data Data Set Databases Deposition Development Disease Ensure European Genbank Gene Expression Regulation General Practitioners Genes Genetic Genetic Diseases Genetic Polymorphism Genetic Variation Genome Genomics Genotype Genotype-Tissue Expression Project Germ-Line Mutation HIV Haplotypes Health Human Human Genome Human Resources IGL@ gene cluster Immune Immunogenetics Immunogenomics Immunoglobulin A Immunoglobulin G Immunoglobulin Genes Immunoglobulin M Immunoglobulins Immunologic Receptors Immunology Individual Infection International Investigation Knowledge Light Link Malignant Neoplasms Methods Modeling Nucleotides Oceania Outcome Population Population Heterogeneity Positioning Attribute Quantitative Trait Loci Research Resources Rheumatic Heart Disease Role Sampling Single Nucleotide Polymorphism South African Summary Reports Uganda Underrepresented Populations V(D)J Recombination Variant analysis pipeline cohort data access database of Genotypes and Phenotypes dbSNP design ethnic diversity frontier genetic association genome browser genome resource genomic data high standard immunoglobulin light chain locus improved novel precision medicine reference genome response tool vaccine response

项目摘要

PROJECT SUMMARY There is a fundamental gap in our understanding of how germline variation in the immunoglobulin (IG) heavy (IGH) and light chain (kappa, IGK; lambda, IGL) loci in the human population impacts the development of the functional antibody (Ab) response in health and disease. However, there is growing appreciation for the fact that IG polymorphism contributes to variability in the Ab repertoire, indicating that the integration of IG genetic data in basic and biomedical research can inform our understanding of how IG gene regulation, as well as Ab repertoire dynamics, function in various clinical contexts. A critical barrier to progress has been that existing genomic resources for the IG loci are incomplete and poorly represent diversity across human populations, particularly those from non-European ancestries. Evidence continues to accumulate in support of the notion that the IG regions are among the most structurally complex and polymorphic regions of the human genome, enriched for large structural variants (SVs) and single nucleotide variants (SNVs), resulting in extreme interindividual haplotype variation. These complexities have long made the IG loci difficult to study using standard high- throughput methods, with direct negative impacts on genetic disease association studies and, more recently, the analysis of adaptive immune receptor repertoire sequencing (AIRR-seq) data. As a result, knowledge of human IG germline diversity, particularly in populations underrepresented in genomics databases, and its contribution to disease lags far behind that of other well-studied immune loci. This highlights a direct need for publicly 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 these needs, we have developed this renewal proposal, which will build the most comprehensive IG genomic dataset to date, with transformative potential impact for the fields of B cell immunology and immunogenetics. The resource generated will: (i) shed light on the extent of IG diversity worldwide; (ii) establish a framework for linking genetic data to expressed antibody repertoire variation to inform our understanding of V(D)J recombination and seed models of antibody repertoire dynamics; and (iii) substantially augment key databases and research initiatives pushing the frontiers of genomics and immunology research. This renewal project will seamlessly build and expand upon the foundational IG genomics data generated in our initial proposal and continue to establish desperately needed genomic resources for the human IG loci, particularly in underrepresented populations and cohorts of immediate biomedical relevance, which will serve the immunology and larger genomics communities for years to come.

项目摘要我们对免疫球蛋白（IG）沉重的种系变化的理解有根本的差距（IGH）和轻链（Kappa，IGK； Lambda，Igl）基因座的人口中的基因座影响健康和疾病中的功能抗体（AB）反应。但是，人们越来越感谢 IG多态性有助于AB曲目的变异性，表明Ig遗传数据的整合在基础和生物医学研究中，可以告知我们对IG基因调节以及AB的理解曲目动力学，在各种临床环境中的功能。进步的关键障碍是现有 IG基因座的基因组资源不完整，并且代表人类种群的多样性不足，特别是那些来自非欧洲裔的人。证据继续积累，以支持 IG区域是人类基因组的结构最复杂和多态性区域之一，富含用于大型结构变体（SVS）和单核苷酸变体（SNV），导致极端个体单倍型变化。这些复杂性长期使Ig基因座难以使用标准高级研究吞吐量方法，对遗传疾病关联研究产生直接负面影响，最近分析自适应免疫受体曲目测序（AIRR-SEQ）数据。结果，对人的知识 IG种系多样性，特别是在基因组学数据库中代表性不足及其贡献的人群中疾病落后于其他良好的免疫基因座的疾病。这突出了公开的直接需求可用，特征良好的IG单倍型参考和来自不同种族的准确变体目录促进更准确的基因分型工具，分析管道和整合的背景他们的解释。为了满足这些需求，我们已经制定了这项续签建议，这将建立最多迄今为止，全面的IG基因组数据集对B细胞领域具有变革性的潜在影响免疫学和免疫遗传学。产生的资源将：（i）阐明IG多样性的程度全世界; （ii）建立一个将遗传数据与表达的抗体库差异联系起来的框架，以告知我们对抗体曲目动力学的V（d）J重组和种子模型的理解；（iii）实质上增加了关键数据库和研究计划，以推动基因组学和免疫学的前沿研究。这个更新项目将无缝地建立和扩展基础IG基因组数据数据在我们的最初提案中产生，并继续为人类建立迫切需要的基因组资源 IG基因座，特别是在代表性不足的人群和直接生物医学相关性中的人群中在未来几年内为免疫学和较大的基因组学社区服务。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A Novel Framework for Characterizing Genomic Haplotype Diversity in the Human Immunoglobulin Heavy Chain Locus.

DOI：
10.3389/fimmu.2020.02136
发表时间：
2020
期刊：
Frontiers in immunology
影响因子：
7.3
作者：
Rodriguez OL;Gibson WS;Parks T;Emery M;Powell J;Strahl M;Deikus G;Auckland K;Eichler EE;Marasco WA;Sebra R;Sharp AJ;Smith ML;Bashir A;Watson CT
通讯作者：
Watson CT

Targeted long-read sequencing facilitates phased diploid assembly and genotyping of the human T cell receptor alpha, delta, and beta loci.

DOI：
10.1016/j.xgen.2022.100228
发表时间：
2022-12-14
期刊：
CELL GENOMICS
影响因子：
0
作者：
Rodriguez, Oscar L.;Silver, Catherine A.;Shields, Kaitlyn;Smith, Melissa L.;Watson, Corey T.
通讯作者：
Watson, Corey T.

Germline immunoglobulin genes: disease susceptibility genes hidden in plain sight?

DOI：
10.1016/j.coisb.2020.10.011
发表时间：
2020-12
期刊：
Current opinion in systems biology
影响因子：
3.7
作者：
通讯作者：

T cell receptor beta germline variability is revealed by inference from repertoire data.

DOI：
10.1186/s13073-021-01008-4
发表时间：
2022-01-07
期刊：
Genome medicine
影响因子：
12.3
作者：
Omer A;Peres A;Rodriguez OL;Watson CT;Lees W;Polak P;Collins AM;Yaari G
通讯作者：
Yaari G

Looking to the future of antibody genetics: resolving the roles of immunoglobulin diversity in gene regulation, function, and immunity.

展望抗体遗传学的未来：解决免疫球蛋白多样性在基因调控、功能和免疫中的作用。

DOI：
10.1038/s41435-023-00238-3
发表时间：
2024
期刊：
Genes and immunity
影响因子：
5
作者：
Watson,CoreyT;Rodriguez,OscarL;Engelbrecht,Eric;Safonova,Yana;Marasco,WayneA;Smith,MelissaL
通讯作者：
Smith,MelissaL