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Somatic hypermutation spectra are independent of the local transcriptional and epigenetic landscape

Ursula E. Schoeberl, Johanna Fitz, Kimon Froussios, Renan Valieris, Marina Makharova, Iordanis Ourailidis, Bernd Bauer, Tobias Neumann, Eva-Maria Wiedemann, Monika Steininger, Adriana Cantoran Garcia, Marialaura Mastrovito, Hugo Mouquet, View ORCID ProfileIsrael Tojal Da Silva, View ORCID ProfileRushad Pavri
doi: https://doi.org/10.1101/2022.05.21.492925
Ursula E. Schoeberl
1Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, 1030 Vienna, Austria
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Johanna Fitz
1Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, 1030 Vienna, Austria
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Kimon Froussios
1Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, 1030 Vienna, Austria
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Renan Valieris
2Laboratory of Bioinformatics and Computational Biology, A. C. Camargo Cancer Center, São Paulo, SP, Brazil
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Marina Makharova
1Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, 1030 Vienna, Austria
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Iordanis Ourailidis
1Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, 1030 Vienna, Austria
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Bernd Bauer
1Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, 1030 Vienna, Austria
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Tobias Neumann
1Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, 1030 Vienna, Austria
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Eva-Maria Wiedemann
1Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, 1030 Vienna, Austria
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Monika Steininger
1Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, 1030 Vienna, Austria
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Adriana Cantoran Garcia
1Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, 1030 Vienna, Austria
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Marialaura Mastrovito
1Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, 1030 Vienna, Austria
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Hugo Mouquet
3Laboratory of Humoral Immunology, Institut Pasteur, INSERM U1222, Université Paris Cité, 75015 Paris, France
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Israel Tojal Da Silva
2Laboratory of Bioinformatics and Computational Biology, A. C. Camargo Cancer Center, São Paulo, SP, Brazil
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  • ORCID record for Israel Tojal Da Silva
Rushad Pavri
1Research Institute of Molecular Pathology (IMP), Campus-Vienna-Biocenter 1, 1030 Vienna, Austria
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  • For correspondence: rushad.pavri@imp.ac.at
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Abstract

Somatic hypermutation (SHM) of immunoglobulin variable regions in B cells modulates antibody-antigen affinity and is indispensable for adaptive immunity. Mutations are introduced by activation-induced cytidine deaminase (AID) in a co-transcriptional manner resulting in discrete mutation spectra. Current models propose that activating epigenetic marks, transcriptional pausing and convergent transcription are necessary for optimal AID recruitment. However, whether these or other transcriptional features can explain the discrete mutation spectra is unknown. To address this, we compared mutation and nascent transcription at single nucleotide resolution. Surprisingly, with this precision, SHM spectra do not correlate with any transcriptional feature at human and mouse variable regions and non-immunoglobulin AID targets. Moreover, SHM is resistant to up to four-fold reduction of both activating epigenetic marks and transcription. We propose that, following AID recruitment to its target genes, the DNA sequence flanking an AID target motif is the key determinant of mutability rather than the local transcriptional and chromatin landscape.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • ↵* equal contribution

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted May 21, 2022.
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Somatic hypermutation spectra are independent of the local transcriptional and epigenetic landscape
Ursula E. Schoeberl, Johanna Fitz, Kimon Froussios, Renan Valieris, Marina Makharova, Iordanis Ourailidis, Bernd Bauer, Tobias Neumann, Eva-Maria Wiedemann, Monika Steininger, Adriana Cantoran Garcia, Marialaura Mastrovito, Hugo Mouquet, Israel Tojal Da Silva, Rushad Pavri
bioRxiv 2022.05.21.492925; doi: https://doi.org/10.1101/2022.05.21.492925
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Somatic hypermutation spectra are independent of the local transcriptional and epigenetic landscape
Ursula E. Schoeberl, Johanna Fitz, Kimon Froussios, Renan Valieris, Marina Makharova, Iordanis Ourailidis, Bernd Bauer, Tobias Neumann, Eva-Maria Wiedemann, Monika Steininger, Adriana Cantoran Garcia, Marialaura Mastrovito, Hugo Mouquet, Israel Tojal Da Silva, Rushad Pavri
bioRxiv 2022.05.21.492925; doi: https://doi.org/10.1101/2022.05.21.492925

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