Genetic variation in the immunoglobulin heavy chain locus shapes the human antibody repertoire

Oscar L. Rodriguez, Yana Safonova, Catherine A. Silver, Kaitlyn Shields, William S. Gibson, Justin T. Kos, David Tieri, Hanzhong Ke, Katherine J. L. Jackson, Scott D. Boyd, Melissa L. Smith (), Wayne A. Marasco () and Corey T. Watson ()
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Oscar L. Rodriguez: University of Louisville School of Medicine
Yana Safonova: Johns Hopkins University
Catherine A. Silver: University of Louisville School of Medicine
Kaitlyn Shields: University of Louisville School of Medicine
William S. Gibson: University of Louisville School of Medicine
Justin T. Kos: University of Louisville School of Medicine
David Tieri: University of Louisville School of Medicine
Hanzhong Ke: Harvard Medical School
Katherine J. L. Jackson: The Garvan Institute of Medical Research
Scott D. Boyd: Stanford University School of Medicine
Melissa L. Smith: University of Louisville School of Medicine
Wayne A. Marasco: Harvard Medical School
Corey T. Watson: University of Louisville School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40070-x

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