TY - JOUR T1 - Somatic hypermutation spectra are independent of the local transcriptional and epigenetic landscape JF - bioRxiv DO - 10.1101/2022.05.21.492925 SP - 2022.05.21.492925 AU - Ursula E. Schoeberl AU - Johanna Fitz AU - Kimon Froussios AU - Renan Valieris AU - Marina Makharova AU - Iordanis Ourailidis AU - Bernd Bauer AU - Tobias Neumann AU - Eva-Maria Wiedemann AU - Monika Steininger AU - Adriana Cantoran Garcia AU - Marialaura Mastrovito AU - Hugo Mouquet AU - Israel Tojal Da Silva AU - Rushad Pavri Y1 - 2022/01/01 UR - http://biorxiv.org/content/early/2022/05/21/2022.05.21.492925.abstract N2 - 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. ER -