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: 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
• 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

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.

项目总结

项目成果

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
• 作者: Rodriguez, Oscar L.;Silver, Catherine A.;Shields, Kaitlyn;Smith, Melissa L.;Watson, Corey T.
• 通讯作者: Watson, Corey T.

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

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

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