Bovine immunoglobulin genetics: Novel phylogenetic perspective

Abstract

Limited germline sequence divergence and combinatorial diversity in cattle, unlike rodents and humans, has resulted in unconventional antibody diversification strategies that involve: (a) generation of exceptionally long CDR3H (>50 codons) by using single long IGHD2 gene (potentially capable of coding for 49 codons) and insertion of conserved short nucleotide sequence (CSNS) specifically at IGHV-IGHD junction; (b) somatic hypermutations without exposure to external antigen during B cell ontogeny. The presence of atypical CDR3H (up to 66 amino acids) in cattle antibodies is yet to be seen in any other species. The antibodies with exceptionally long CDR3H show restricted V?+VH pairings where ? light chain provides only structural support. The ?-light chain is predominantly expressed in bovine antibody repertoire mostly encoded by restricted IGLV1-IGLJ3-IGLC3 recombinations. Despite significant complexity at IGK locus, ?-light chains are expressed al low levels in the antibody repertoire predominantly coded by IGVK2-IGKJ1-IGKC recombination. Three IgM allotypes are defined where some allelic variants may arise via alternate splicing. Of four IgG1 allotypes described, unique presence of Pro-Ala-Ser-Ser in C?1 domain of IgG1c allotype may have a role in cell adhesion and migration function. Overall, generation of exceptionally long CDR3H, with or without CSNS insertions, and somatic hypermutations without prior antigen exposure compensate for limited germline divergence and contribute to antibody diversification in cattle. Such an atypical CDR3H with multiple cystienes generates minidomains by intra-CDR3H disulfide bridges creating novel configurational diversity in the antigen-binding site.