Base by Base explores advances in genetics and genomics, with a focus on gene-disease associations, variant interpretation, protein structure, and insights from exome and genome sequencing. Each episode breaks down key studies and their clinical relevance—one base at a time.
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Base by Base explores advances in genetics and genomics, with a focus on gene-disease associations, variant interpretation, protein structure, and insights from exome and genome sequencing. Each episode breaks down key studies and their clinical relevance—one base at a time.
Powered by AI, Base by Base offers a new way to learn on the go. Special thanks to authors who publish under CC BY 4.0, making open-access science faster to share and easier to explore.
️ Episode 238: Germline polymorphisms shape antibody light chain repertoires
In this episode of PaperCast Base by Base, we explore Long-read sequencing of IGK and IGL paired with AIRR-seq shows that common germline SNVs, SVs, and alleles drive inter-individual differences in light chain gene usage and CDR3 properties
Study Highlights:The authors combined targeted long-read genomic sequencing of IGK and IGL in 177 donors with matched AIRR-seq (IGK n=164, IGL n=168) to generate phased SNV, SV, and allele callsets and personalized germline databases. Cis guQTL analysis identified 2,352 variants in the unmutated IGK repertoire linked to usage changes in 21 IGKV and 3 IGKJ genes, and 911 variants in IGL linked to 22 IGLV and 3 IGLJ genes, indicating germline variation affects >70% of light chain genes. Lead variants mapped to intergenic regions, RSSs, coding exons and structural variants, with examples including a premature stop in IGKV2-29, a K50D missense in IGKV1-5, RSS spacer changes in IGLV3-16, and copy-number SVs that alter gene usage. Genetic effects were stronger in the antigen-naïve repertoire, associated with shifts in encoded V/J alleles and CDR3 physicochemical properties, and IGK exhibited larger LD blocks and coordinated multi-gene usage compared with IGL.
Conclusion:Germline polymorphisms across IGK and IGL establish reproducible baseline differences in light chain gene availability and amino acid composition that likely influence antibody-mediated responses.
Music:Enjoy the music based on this article at the end of the episode.
Reference:Engelbrecht E, Rodriguez OL, Lees W, Vanwinkle Z, Shields K, Schultze S, Gibson WS, Smith DR, Jana U, Saha S, Peres A, Yaari G, Smith ML, Watson CT. Germline polymorphisms in the immunoglobulin kappa and lambda loci underpinning antibody light chain repertoire variability. Nat Commun. 2025. https://doi.org/10.1038/s41467-025-66759-9
License:This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/
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On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics.
Episode link: https://basebybase.castos.com/episodes/ig-light-chain-variation
Episode Slug: ig-light-chain-variation
Keywords: immunoglobulin-kappa, immunoglobulin-lambda, germline-variation, antibody-repertoire, long-read-sequencing
Base by Base
Base by Base explores advances in genetics and genomics, with a focus on gene-disease associations, variant interpretation, protein structure, and insights from exome and genome sequencing. Each episode breaks down key studies and their clinical relevance—one base at a time.
Powered by AI, Base by Base offers a new way to learn on the go. Special thanks to authors who publish under CC BY 4.0, making open-access science faster to share and easier to explore.
