Human genetic variation shapes the antibody repertoire across B cell development

Abstract

The peripheral antibody repertoire is shaped by inherited genetic variation and selection during B cell development. However, how the repertoire changes across developmental stages--and the relative impact of genetics and selection in establishing the antibody repertoire--remain largely unknown. To dissect the individual and combined effects of these factors, we integrated antibody repertoire transcriptomics across pro-B, pre-B, immature, and naive B cells with single-molecule real-time long-read DNA sequencing of the immunoglobulin heavy (IGH), kappa (IGK), and lambda (IGL) chain loci. We find that IGH genetic variants establish gene usage biases at the pro-B stage that persist throughout development. In contrast, IGK and IGL repertoires are extensively remodeled during maturation, consistent with receptor editing. Surprisingly, IGH variants also exert trans effects on light chain gene usage, suggesting coordinated constraints on heavy-light chain pairing. Principal component and allele-specific analyses reveal that genetics primarily shapes the heavy chain repertoire, while selection more strongly influences light chain diversity. These findings define distinct dynamics of antibody repertoire development and underscore the importance of personal immunogenomics in understanding individual immune responses.