RT Journal Article
SR Electronic
T1 Somatic hypermutation spectra are independent of the local transcriptional and epigenetic landscape
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.05.21.492925
DO 10.1101/2022.05.21.492925
A1 Ursula E. Schoeberl
A1 Johanna Fitz
A1 Kimon Froussios
A1 Renan Valieris
A1 Marina Makharova
A1 Iordanis Ourailidis
A1 Bernd Bauer
A1 Tobias Neumann
A1 Eva-Maria Wiedemann
A1 Monika Steininger
A1 Adriana Cantoran Garcia
A1 Marialaura Mastrovito
A1 Hugo Mouquet
A1 Israel Tojal Da Silva
A1 Rushad Pavri
YR 2022
UL http://biorxiv.org/content/early/2022/05/21/2022.05.21.492925.abstract
AB 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 StatementThe authors have declared no competing interest.