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Looking to the future of antibody genetics: resolving the roles of immunoglobulin diversity in gene regulation, function, and immunity

Genes & Immunity volume 25, pages 92–94 (2024)Cite this article

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In our recent article [1], we combined targeted long-read single-molecule real-time (SMRT) sequencing of the human immunoglobulin heavy chain (IGH) locus with expressed adaptive immune receptor repertoire sequencing (AIRR-seq) from blood cells in a cohort of healthy donors of diverse genetic ancestry. With these data, we uncovered direct links between IGH germline variation and variability in the circulating antibody (Ab) repertoire, establishing a fundamental role for heritable factors in setting the baseline for an individual’s Ab response.

Leveraging the strengths of highly accurate, long-read sequencing, we conducted the most comprehensive survey of IGH haplotype diversity to date and overcame technical hurdles that have historically challenged genetic investigations in this region. We extensively cataloged novel IGH polymorphisms, including single nucleotide variants (SNVs), small insertion-deletions (indels), and large structural variants (SVs), that are associated with the frequency at which IGH variable (IGHV), diversity (IGHD), and joining (IGHJ) genes are observed among expressed rearranged heavy chain transcripts (“gene usage”). We termed these variants gene usage quantitative trait loci (guQTLs) and revealed that they were inclusive of all forms of IG germline variation, in some cases, explaining up to ~70% of variation in usage of a given gene across the population. This includes examples in which genes were completely absent from individual repertoires due to inherited gene deletions. Critically, we showed that these effects could be observed across both naive (IgM) and antigen-stimulated (IgG) repertoires, indicating the potential for broad effects of germline polymorphism on circulating receptors that are available for engagement during an immune response.

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Fig. 1: Key research focus areas for expanding our understanding of IG haplotype diversity and its impact on Ab repertoire variation, Ab function, and Ab-mediated immunity.

References

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, USA

    Corey T. Watson, Oscar L. Rodriguez, Eric Engelbrecht & Melissa L. Smith

  2. Computer Science and Engineering Department, Huck Institutes of the Life Sciences, Penn State University, State College, PA, USA

    Yana Safonova

  3. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    Wayne A. Marasco

  4. Department of Medicine, Harvard Medical School, Boston, MA, USA

    Wayne A. Marasco

Authors
  1. Corey T. Watson
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  2. Oscar L. Rodriguez
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  3. Eric Engelbrecht
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  4. Yana Safonova
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  5. Wayne A. Marasco
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  6. Melissa L. Smith
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Contributions

CTW, OLR, EE, YS, WAM, and MLS contributed to conceptual outline and writing of the manuscript.

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Correspondence to Corey T. Watson.

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Watson, C.T., Rodriguez, O.L., Engelbrecht, E. et al. Looking to the future of antibody genetics: resolving the roles of immunoglobulin diversity in gene regulation, function, and immunity. Genes Immun 25, 92–94 (2024). https://doi.org/10.1038/s41435-023-00238-3

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