An ethnically diverse genomic reference resource for the human heavy and light chain immunoglobulin loci

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PROJECT SUMMARY There is a fundamental gap in our understanding of how germline variation in the immunoglobulin (IG) heavy (IGH) and light chain (kappa, IGK; lambda, IGL) loci in the human population impacts the development of the functional antibody (Ab) response in health and disease. However, there is growing appreciation for the fact that IG polymorphism contributes to variability in the Ab repertoire, indicating that the integration of IG genetic data in basic and biomedical research can inform our understanding of how IG gene regulation, as well as Ab repertoire dynamics, function in various clinical contexts. A critical barrier to progress has been that existing genomic resources for the IG loci are incomplete and poorly represent diversity across human populations, particularly those from non-European ancestries. Evidence continues to accumulate in support of the notion that the IG regions are among the most structurally complex and polymorphic regions of the human genome, enriched for large structural variants (SVs) and single nucleotide variants (SNVs), resulting in extreme interindividual haplotype variation. These complexities have long made the IG loci difficult to study using standard high- throughput methods, with direct negative impacts on genetic disease association studies and, more recently, the analysis of adaptive immune receptor repertoire sequencing (AIRR-seq) data. As a result, knowledge of human IG germline diversity, particularly in populations underrepresented in genomics databases, and its contribution to disease lags far behind that of other well-studied immune loci. This highlights a direct need for publicly available, well-characterized IG haplotype references and accurate variant catalogues from diverse ethnic backgrounds to facilitate the design and integration of more accurate genotyping tools, analysis pipelines, and their interpretation. To meet these needs, we have developed this renewal proposal, which will build the most comprehensive IG genomic dataset to date, with transformative potential impact for the fields of B cell immunology and immunogenetics. The resource generated will: (i) shed light on the extent of IG diversity worldwide; (ii) establish a framework for linking genetic data to expressed antibody repertoire variation to inform our understanding of V(D)J recombination and seed models of antibody repertoire dynamics; and (iii) substantially augment key databases and research initiatives pushing the frontiers of genomics and immunology research. This renewal project will seamlessly build and expand upon the foundational IG genomics data generated in our initial proposal and continue to establish desperately needed genomic resources for the human IG loci, particularly in underrepresented populations and cohorts of immediate biomedical relevance, which will serve the immunology and larger genomics communities for years to come.