Novel genes and polymorphisms in human immunoglobulin light chains across diverse populations

Abstract The human immunoglobulin light chain loci, kappa (IGK) and lambda (IGL), are structurally complex genomic regions with germline gene content that is not yet fully characterized. These loci are marked by extensive gene duplication, allelic diversity, and segmental duplications, features that contribute critically to the adaptive immune response. In this study, we present a comprehensive IMGT annotation of IGK and IGL using two high-quality human reference assemblies (GRCh38 and T2T-CHM13) along with 142 and 125 additional chromosomal-level haploid assemblies, respectively for each locus, from individuals representing all major human superpopulations. Detailed gene and allele annotation of the reference assemblies led to the identification of 5 novel IGKV genes and 8 new IGKV alleles, 16 new IGLV genes, and 22 novel IGLV alleles. These were confirmed through assembly read validation, presence in whole genome sequencing datasets, and recurrence in multiple assemblies. Gene-level identification across the broader dataset enabled assessment of structural variation (SV) at both loci. IGL displayed high conservation, with recurrent absence observed for only one gene. In contrast, IGK exhibited greater variability, including complete loss of the distal region in certain assemblies. This structural diversity was analyzed across superpopulations, allowing us to map potential patterns of gene presence and absence across different ancestral groups. All newly identified genes were consistently observed across individuals and genomic backgrounds. This work enhances the structural resolution of the IGK and IGL loci and expands the IMGT reference directory with newly described germline genes and alleles. The results provide a more complete view of light chain genomic diversity and serve as a valuable resource for studies of antibody gene repertoires, immunogenetic variation, monoclonal antibody development and population-level diversity.