Characterization of extensive diversity in immunoglobulin light chain variable germline genes across biomedically important mouse strains.

Abstract

The light chain immunoglobulin (IG) genes of inbred mouse strains are poorly documented in current gene databases. We previously showed that IG heavy chain (IGH) loci of wild-derived mouse strains, representing the major mouse subspecies, contained 247 IGH variable (V) sequences not curated in the International ImMunoGeneTics (IMGT) information system database, commonly used for adaptive immune receptor repertoire sequencing (AIRR-seq) analysis. Despite containing levels of polymorphism similar to the IGH locus, the germline gene content and diversity of the light chain loci (kappa, IGK; lambda, IGL) have not been comprehensively cataloged. To explore the extent of germline light chain repertoire diversity across mouse strains commonly used in the biomedical sciences, we performed AIRR-seq analysis and germline gene inference for 18 inbred mouse strains, including 4 wild-derived strains with diverse sub-species origins. We inferred 1582 IGKV and 63 IGLV sequences, representing 459 and 22 unique IGKV and IGLV germline alleles. Of the unique germline IGKV and IGLV sequences, 67.8% and 59%, respectively, were undocumented in IMGT. Across strains we observed germline IGKV sequences shared by three distinct IGK haplotypes and a more conserved IGLV germline repertoire. In addition, joining (J) gene inference indicated a novel IGKJ2 allele shared between PWD/PhJ and MSM/MsJ, a novel IGLJ1 allele for LEWES/EiJ, and a novel IGLJ2 allele for MSM/MsJ. Finally, combined IGHV, IGKV, and IGLV phylogenetic analysis of wild-derived germline sets revealed reduced diversity for light chain sequences compared to the heavy chain, suggesting potential evolutionary differences between heavy and light chain loci.