Genetic variation in the immunoglobulin heavy chain locus shapes CDR3 amino acid composition 4123

Abstract Description The complementarity-determining region 3 (CDR3) of immunoglobulin heavy chains (IGH) is essential for antigen recognition. It is formed through recombination of variable (V), diversity (D), and joining (J) genes, with added non-templated (N-) and palindromic (P-) nucleotides increasing its diversity. Previously seen as stochastic, our prior research highlighted genetic influences on V, D, and J gene selection. Expanding on this, we investigated how genetic factors shape CDR3 amino acid composition using a cohort of 154 individuals of diverse ethnic backgrounds, combining IgM antibody repertoire sequencing from peripheral blood mononuclear cells (PBMC) with long-read genomic sequencing of the IGH locus. Focusing on CDR3 regions of 15 amino acids, we identified 376 single-nucleotide polymorphisms (SNPs) that statistically explained amino acid composition in 12 of the 15 CDR3 positions. Among these, a subset of SNPs was also associated with V and D gene usage, suggesting a shared genetic mechanism. For instance, non-coding SNP rs2516992 was linked to the frequency of IGHD1-1 usage and the frequency of Gly amino acid at CDR3 position 12. These results reveal how IGH locus variants shape CDR3 sequences and influence immune function. This research advances our understanding of the genetic determinants of antibody repertoire diversity, with implications for predicting immune responsiveness and improving vaccine design for diverse populations. Topic Categories Computational and Systems Immunology (COMP)