Different classes of genomic inserts contribute to human antibody diversity

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.. (2022) Different classes of genomic inserts contribute to human antibody diversity. Proc Natl Acad Sci U S A, 119 (36). e2205470119.

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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 naive 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.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Clinical Immunology (Daubenberger)
UniBasel Contributors:Daubenberger, Claudia
Item Type:Article, refereed
Article Subtype:Research Article
ISSN:1091-6490 (Electronic)0027-8424 (Linking)
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:27 Dec 2022 11:06
Deposited On:27 Dec 2022 11:06

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