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Different classes of genomic inserts contribute to human antibody diversity

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Item Type:Article
Title:Different classes of genomic inserts contribute to human antibody diversity
Creators Name:Lebedin, M. and Foglierini, M. and Khorkova, S. and Vázquez García, C. and Ratswohl, C. and Davydov, A.N. and Turchaninova, M.A. and Daubenberger, C. and Chudakov, D.M. and Lanzavecchia, A. and de la Rosa, K.
Abstract:Recombination of antibody genes in B cells can involve distant genomic loci and contribute a foreign antigen-binding element to form hybrid antibodies with broad reactivity for Plasmodium falciparum. So far, antibodies containing the extracellular domain of the LAIR1 and LILRB1 receptors represent unique examples of cross-chromosomal antibody diversification. Here, we devise a technique to profile non-VDJ elements from distant genes in antibody transcripts. Independent of the preexposure of donors to malaria parasites, non-VDJ inserts were detected in 80% of individuals at frequencies of 1 in 10(4) to 10(5) B cells. We detected insertions in heavy, but not in light chain or T cell receptor transcripts. We classify the insertions into four types depending on the insert origin and destination: 1) mitochondrial and 2) nuclear DNA inserts integrated at VDJ junctions; 3) inserts originating from telomere proximal genes; and 4) fragile sites incorporated between J-to-constant junctions. The latter class of inserts was exclusively found in memory and in in vitro activated B cells, while all other classes were already detected in naïve B cells. More than 10% of inserts preserved the reading frame, including transcripts with signs of antigen-driven affinity maturation. Collectively, our study unravels a mechanism of antibody diversification that is layered on the classical V(D)J and switch recombination.
Keywords:B Cell Diversity, Antibody Repertoire, Insert
Source:Proceedings of the National Academy of Sciences of the United States of America
Publisher:National Academy of Sciences
Page Range:e2205470119
Date:6 September 2022
Official Publication:https://doi.org/10.1073/pnas.2205470119
PubMed:View item in PubMed

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