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Noncanonical secondary structures arising from non-B DNA motifs are determinants of mutagenesis.

Accepted version
Peer-reviewed

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Authors

Georgakopoulos-Soares, Ilias 
Morganella, Sandro 
Jain, Naman 
Hemberg, Martin 

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.

Description

Keywords

DNA, B-Form, Humans, Mutagenesis, Neoplasms, Nucleotide Motifs

Journal Title

Genome Res

Conference Name

Journal ISSN

1088-9051
1549-5469

Volume Title

28

Publisher

Cold Spring Harbor Laboratory
Sponsorship
Cancer Research UK (23916)
European Commission (242006)
Wellcome-Beit Award Wellcome Trust Intermediate Clinical Fellowship (WT100183MA) CRUK Advanced Clinician Scientist Award (C60100/A23916)