A comparison of immunoglobulin IGHV, IGHD and IGHJ genes in wild‐derived and classical inbred mouse strains

Abstract

The genomes of classical inbred mouse strains include genes derived from all three major subspecies of the house mouse, Mus musculus. We recently posited that genetic diversity in the immunoglobulin heavy chain (IGH) gene loci of C57BL/6 and BALB/c mice reflects differences in subspecies origin. To investigate this hypothesis, we conducted high‐throughput sequencing of IGH gene rearrangements to document IGH variable (IGHV), joining (IGHJ) and diversity (IGHD) genes in four inbred wild‐derived mouse strains (CAST/EiJ, LEWES/EiJ, MSM/MsJ and PWD/PhJ) and a single disease model strain (NOD/ShiLtJ), collectively representing genetic backgrounds of several major mouse subspecies. A total of 341 germline IGHV sequences were inferred in the wild‐derived strains, including 247 not curated in the international ImMunoGeneTics information system. By contrast, 83/84 inferred NOD IGHV genes had previously been observed in C57BL/6 mice. Variability among the strains examined was observed for only a single IGHJ gene, involving a description of a novel allele. By contrast, unexpected variation was found in the IGHD gene loci, with four previously unreported IGHD gene sequences being documented. Very few IGHV sequences of C57BL/6 and BALB/c mice were shared with strains representing major subspecies, suggesting that their IGH loci may be complex mosaics of genes of disparate origins. This suggests a similar level of diversity is likely present in the IGH loci of other classical inbred strains. This must now be documented if we are to properly understand interstrain variation in models of antibody‐mediated disease.

Immunology & Cell Biology’s Top 10 original research articles 2019–2020

“…BAFF, IL‐4 and IL‐21 separably program germinal centre‐like phenotype acquisition, BCL6 expression, proliferation and survival of CD40L‐activated B cells in vitro Jeong et al 2 . Over‐expression of p190RhoGEF enhances B‐cell activation and germinal center formation in T‐cell‐dependent humoral immune responses Watson et al 3 . A comparison of immunoglobulin IGHV, IGHD and IGHJ genes in wild‐derived and classical inbred mouse strains Sood et al 4 .…”

“…Talking about B cells leads us naturally to antibodies and antibody diversity, the topic of the article by Watson et al 3 . By comparing the diversity of the IgH gene loci of wild‐derived and inbred strains of mice, the investigators find an unexpected level of genetic variation and propose that these loci may represent a mosaic of genes derived from a variety of different origins 3 .…”

Editorial: Nomenclature - Avoiding Babylonian Speech Confusion in Present Day Immunology

“…Busse et al address the nomenclature challenges that arise from structural variation in the IGH loci of laboratory mice. The IMGT positional-within-families mouse IGH nomenclature is based upon annotations of the IGH locus of the C57BL/6 mouse genome reference sequence, but this sequence is remarkably different to the IGH loci of other inbred strains (15,16). Busse and colleagues outline the principles that should guide the development of a new nomenclature to deal with this challenge.…”

A Proposed New Nomenclature for the Immunoglobulin Genes of Mus musculus

“…It has been proposed that the differences between the genes of the BALB/c and C57BL/6 strains could have resulted from their loci having originated in different subspecies of the house mouse (22). However, investigations of Ighv genes in wild-derived strains now suggest this is not the case (23). Instead, the Ighv loci of classical inbred strains appear to be mosaics, made up of many relatively short haplotype blocks that may have their origins in disparate subspecies of the house mouse, and even in other Mus species.…”

“…The discovery of variation in BALB/c and wild-derived strains was made using inferential techniques. These techniques are widely used in human and other species to identify allelic variants (24)(25)(26), but it is already clear that it will not be possible to unequivocally associate most inferred variants in the mouse to any particular gene in the C57BL/6 genome reference sequence (22,23). For example, amongst the set of inferred BALB/c Ighv sequences, there are instances in which three or more sequences are most closely aligned with a single C57BL/6 Ighv gene.…”