Noncanonical secondary structures arising from non-B DNA motifs are determinants of mutagenesis.
Authors
Georgakopoulos-Soares, Ilias
Morganella, Sandro
Jain, Naman
Hemberg, Martin
Publication Date
2018-09Journal Title
Genome Res
ISSN
1088-9051
Publisher
Cold Spring Harbor Laboratory
Volume
28
Issue
9
Pages
1264-1271
Language
eng
Type
Article
Physical Medium
Print-Electronic
Metadata
Show full item recordCitation
Georgakopoulos-Soares, I., Morganella, S., Jain, N., Hemberg, M., & Nik-Zainal, S. (2018). Noncanonical secondary structures arising from non-B DNA motifs are determinants of mutagenesis.. Genome Res, 28 (9), 1264-1271. https://doi.org/10.1101/gr.231688.117
Abstract
Somatic mutations show variation in density across cancer genomes. Previous studies have shown that chromatin organization and replication time domains are correlated with, and thus predictive of, this variation. Here, we analyze 1809 whole-genome sequences from 10 cancer types to show that a subset of repetitive DNA sequences, called non-B motifs that predict noncanonical secondary structure formation can independently account for variation in mutation density. Combined with epigenetic factors and replication timing, the variance explained can be improved to 43%-76%. Approximately twofold mutation enrichment is observed directly within non-B motifs, is focused on exposed structural components, and is dependent on physical properties that are optimal for secondary structure formation. Therefore, there is mounting evidence that secondary structures arising from non-B motifs are not simply associated with increased mutation density-they are possibly causally implicated. Our results suggest that they are determinants of mutagenesis and increase the likelihood of recurrent mutations in the genome. This analysis calls for caution in the interpretation of recurrent mutations and highlights the importance of taking non-B motifs that can simply be inferred from the reference sequence into consideration in background models of mutability henceforth.
Keywords
Humans, Neoplasms, Mutagenesis, DNA, B-Form, Nucleotide Motifs
Sponsorship
Wellcome-Beit Award
Wellcome Trust Intermediate Clinical Fellowship (WT100183MA)
CRUK Advanced Clinician Scientist Award (C60100/A23916)
Funder references
Cancer Research UK (23916)
European Commission (242006)
Identifiers
External DOI: https://doi.org/10.1101/gr.231688.117
This record's URL: https://www.repository.cam.ac.uk/handle/1810/282954
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