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- Title
Genetic variation in the immunoglobulin heavy chain locus shapes the human antibody repertoire.
- Authors
Rodriguez, Oscar L.; Safonova, Yana; Silver, Catherine A.; Shields, Kaitlyn; Gibson, William S.; Kos, Justin T.; Tieri, David; Ke, Hanzhong; Jackson, Katherine J. L.; Boyd, Scott D.; Smith, Melissa L.; Marasco, Wayne A.; Watson, Corey T.
- Abstract
Variation in the antibody response has been linked to differential outcomes in disease, and suboptimal vaccine and therapeutic responsiveness, the determinants of which have not been fully elucidated. Countering models that presume antibodies are generated largely by stochastic processes, we demonstrate that polymorphisms within the immunoglobulin heavy chain locus (IGH) impact the naive and antigen-experienced antibody repertoire, indicating that genetics predisposes individuals to mount qualitatively and quantitatively different antibody responses. We pair recently developed long-read genomic sequencing methods with antibody repertoire profiling to comprehensively resolve IGH genetic variation, including novel structural variants, single nucleotide variants, and genes and alleles. We show that IGH germline variants determine the presence and frequency of antibody genes in the expressed repertoire, including those enriched in functional elements linked to V(D)J recombination, and overlapping disease-associated variants. These results illuminate the power of leveraging IGH genetics to better understand the regulation, function, and dynamics of the antibody response in disease. Haplotype diversity in the human immunoglobulin heavy chain (IGH) locus is poorly characterized. Here, the authors use long-read sequencing to discover extensive IGH diversity and link germline variants to variation in the antibody repertoire.
- Subjects
IMMUNOGLOBULIN heavy chains; GENETIC variation; SINGLE nucleotide polymorphisms; ANTIBODY diversity; IMMUNOGLOBULINS; ANTIBODY formation; MONOCLONAL antibodies; T cell receptors
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-40070-x