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V(DD)J recombination is an important and evolutionarily conserved mechanism for generating antibodies with unusually long CDR3s

The V(DD)J recombination is currently viewed as an aberrant and inconsequential variant of the canonical V(D)J recombination. Moreover, since the classical 12/23 rule for the V(D)J recombination fails to explain the V(DD)J recombination, the molecular mechanism of tandem D-D fusions has remained unk...

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Autores principales: Safonova, Yana, Pevzner, Pavel A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605257/
https://www.ncbi.nlm.nih.gov/pubmed/32948615
http://dx.doi.org/10.1101/gr.259598.119
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author Safonova, Yana
Pevzner, Pavel A.
author_facet Safonova, Yana
Pevzner, Pavel A.
author_sort Safonova, Yana
collection PubMed
description The V(DD)J recombination is currently viewed as an aberrant and inconsequential variant of the canonical V(D)J recombination. Moreover, since the classical 12/23 rule for the V(D)J recombination fails to explain the V(DD)J recombination, the molecular mechanism of tandem D-D fusions has remained unknown since they were discovered three decades ago. Revealing this mechanism is a biomedically important goal since tandem fusions contribute to broadly neutralizing antibodies with ultralong CDR3s. We reveal previously overlooked cryptic nonamers in the recombination signal sequences of human IGHD genes and demonstrate that these nonamers explain the vast majority of tandem fusions in human repertoires. We further reveal large clonal lineages formed by tandem fusions in antigen-stimulated immunosequencing data sets, suggesting that such data sets contain many more tandem fusions than previously thought and that about a quarter of large clonal lineages with unusually long CDR3s are generated through tandem fusions. Finally, we developed the SEARCH-D algorithm for identifying D genes in mammalian genomes and applied it to the recently completed Vertebrate Genomes Project assemblies, nearly doubling the number of mammalian species with known D genes. Our analysis revealed cryptic nonamers in RSSs of many mammalian genomes, thus demonstrating that the V(DD)J recombination is not a “bug” but an important feature preserved throughout mammalian evolution.
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spelling pubmed-76052572021-05-01 V(DD)J recombination is an important and evolutionarily conserved mechanism for generating antibodies with unusually long CDR3s Safonova, Yana Pevzner, Pavel A. Genome Res Research The V(DD)J recombination is currently viewed as an aberrant and inconsequential variant of the canonical V(D)J recombination. Moreover, since the classical 12/23 rule for the V(D)J recombination fails to explain the V(DD)J recombination, the molecular mechanism of tandem D-D fusions has remained unknown since they were discovered three decades ago. Revealing this mechanism is a biomedically important goal since tandem fusions contribute to broadly neutralizing antibodies with ultralong CDR3s. We reveal previously overlooked cryptic nonamers in the recombination signal sequences of human IGHD genes and demonstrate that these nonamers explain the vast majority of tandem fusions in human repertoires. We further reveal large clonal lineages formed by tandem fusions in antigen-stimulated immunosequencing data sets, suggesting that such data sets contain many more tandem fusions than previously thought and that about a quarter of large clonal lineages with unusually long CDR3s are generated through tandem fusions. Finally, we developed the SEARCH-D algorithm for identifying D genes in mammalian genomes and applied it to the recently completed Vertebrate Genomes Project assemblies, nearly doubling the number of mammalian species with known D genes. Our analysis revealed cryptic nonamers in RSSs of many mammalian genomes, thus demonstrating that the V(DD)J recombination is not a “bug” but an important feature preserved throughout mammalian evolution. Cold Spring Harbor Laboratory Press 2020-11 /pmc/articles/PMC7605257/ /pubmed/32948615 http://dx.doi.org/10.1101/gr.259598.119 Text en © 2020 Safonova and Pevzner; Published by Cold Spring Harbor Laboratory Press http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Research
Safonova, Yana
Pevzner, Pavel A.
V(DD)J recombination is an important and evolutionarily conserved mechanism for generating antibodies with unusually long CDR3s
title V(DD)J recombination is an important and evolutionarily conserved mechanism for generating antibodies with unusually long CDR3s
title_full V(DD)J recombination is an important and evolutionarily conserved mechanism for generating antibodies with unusually long CDR3s
title_fullStr V(DD)J recombination is an important and evolutionarily conserved mechanism for generating antibodies with unusually long CDR3s
title_full_unstemmed V(DD)J recombination is an important and evolutionarily conserved mechanism for generating antibodies with unusually long CDR3s
title_short V(DD)J recombination is an important and evolutionarily conserved mechanism for generating antibodies with unusually long CDR3s
title_sort v(dd)j recombination is an important and evolutionarily conserved mechanism for generating antibodies with unusually long cdr3s
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605257/
https://www.ncbi.nlm.nih.gov/pubmed/32948615
http://dx.doi.org/10.1101/gr.259598.119
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