Different classes of genomic inserts contribute to human antibody diversity

• DOI: 10.1073/pnas.2205470119
• Publication Date: 2022-08-29T19:13:40Z
• Authors: Mikhail Lebedin; Mathilde Foglierini; Svetlana Khorkova; Clara Vázquez García; Christoph Ratswohl; Alexey N. Davydov; Maria A. Turchani...; Claudia Daubenberger; Dmitriy M. Chudakov; Antonio Lanzavecchia; Kathrin de la Rosa
• Keywords: Antibody Repertoire; V(D)J recombination; Affinity maturation

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, containing the extracellular domain LAIR1 LILRB1 receptors represent unique examples cross-chromosomal diversification. Here, we devise technique profile non-VDJ elements from transcripts. Independent preexposure donors malaria parasites, inserts were detected 80% individuals at frequencies 1 104 105 cells. We insertions heavy, but not light chain or T cell receptor classify into four types depending on insert origin destination: 1) mitochondrial 2) nuclear DNA integrated VDJ junctions; 3) originating telomere proximal genes; 4) fragile sites incorporated between J-to-constant junctions. The latter class was exclusively found memory vitro activated cells, while all other classes already naïve More than 10% preserved reading frame, including transcripts signs antigen-driven affinity maturation. Collectively, our study unravels mechanism diversification that is layered classical V(D)J switch recombination.