Basic Science Session - May 18th, 2022
Antibody repertoire heavy chain gene usage is explained by common genetic variants in the immunoglobulin heavy chain locus
Oscar Rodriguez. Postdoctoral Fellow. University of Louisville School of Medicine
Introduction by Steven Kleinstein (Yale University)

Antibodies (Abs) are critical components of the adaptive immune system. The heavy chains of Abs are encoded by genes at the immunoglobulin heavy chain (IGH) locus. The IGH locus harbors over 100 variable (V), diversity (D), and joining (J) gene segments, and is among the most structurally complex regions of the human genome, containing extensive haplotype diversity, with an increased amount of single nucleotide variants (SNVs) and large gene-containing structural variants (SVs). Mounting evidence shows that genetic variants within IGH influences inter-individual variation in the expressed Ab repertoire, with potential downstream consequences on Ab function in human health. However, genetic variants contributing to Ab repertoire differences between healthy adults have not been comprehensively characterized. To address this, we conducted the first genetic association study to identify IGH variants that contribute to expressed Ab repertoire signatures. Utilizing our novel targeted genomic long read sequencing approach, we generated paired IGH haplotype and expressed Ab repertoire sequencing data in 154 healthy adults, the largest dataset of its kind. Our analysis revealed IGH genetic variants strongly influence the composition of the expressed repertoire, principally through impacts on V and D gene usage. Associations revealed effects of both coding and non-coding SNPs, and large SVs. Variants were associated with gene usage for single genes or multiple genes demonstrating signatures of coordinated gene regulation, and were enriched in regulatory regions annotated by the ENCODE project, including co-localization within CTCF binding sites, a transcription factor involved in V(D)J recombination. These data provide the first robust links between IGH polymorphism and the Ab repertoire. Extending this dataset will allow for the discovery of novel genomic factors and molecular mechanisms influencing Ab repertoire development and diversity, and facilitate better characterization of the Ab response in disease and clinical phenotypes.


AIRR Community Meeting VI “Exploring New Frontiers”. La Jolla, CA. May 17-19, 2022.
[ Ссылка ]

свернуть