Germline murine immunoglobulin IGHV genes in wild-derived and classical inbred strains: a comparison

ABSTRACT To better understand the subspecies origin of antibody genes in classical inbred mouse strains, the IGH gene loci of four wild-derived mouse strains were explored by analysis of VDJ gene rearrangements. A total of 341 unique IGHV gene sequences were inferred in the wild-derived strains, including 247 sequences that have not previously been reported. The genes of the Non-Obese Diabetic (NOD) strain were also documented, and all but one of the 84 inferred NOD IGHV genes have previously been observed in C57BL/6 mice. This is surprising because the Swiss mouse-derived NOD strain and the C57BL/6 strain have no known shared ancestry. The relationships between the genes of the wild-derived inbred strains and of the C57BL/6, NOD and BALB/c classical inbred strain were then explored. The IGH loci of the C57BL/6 and the MSM/MsJ strains share many sequences, but analysis showed that few sequences are shared with wild-derived strains representing the three major subspecies of the house mouse. There were also few IGHV sequences that were shared by the BALB/c strain and any of the four wild-derived strains. The origins of IGHV genes in the C57BL/6, MSM/MsJ and BALB/c strains therefore remain unclear. These unexpected similarities and differences highlight our lack of understanding of the antibody gene loci of the laboratory mouse, with implications for the interpretation of strain-specific differences in models of antibody-mediated diseases, and of Adaptive Immune Receptor Repertoire sequencing (AIRR-seq) data. These results also suggest that a position-based immunoglobulin gene nomenclature may be unworkable in the mouse.