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Cited by 146Cancer Genomics and DiagnosticsDNA and Nucleic Acid ChemistryDNA Repair Mechanisms

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

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Georgakopoulos-Soares, Ilias, Morganella, Sandro, Jain, Naman, Hemberg, Martin, Nik-Zainal, Serena·2018·Genome Research
DOI 10.1101/gr.231688.117PMC PMC6120622

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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.

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  • G4s have emerged as drivers of genomic plasticity, both through small- and large-scale genomic variations.

    “Recently, G4s have emerged as drivers of genomic plasticity, both through small- and large-scale genomic variations (4,77).”

    From G-quadruplex-mediated genomic instability drives SNVs in cancer (2024) · cites this paper as [77]

    The Results section reports increased mutagenesis at G4 motifs, including enrichment near indels, supporting the small-scale variation part of the claim. The paper does not establish that G4s drive large-scale genomic variations; its Methods describe analyses of substitutions and indels, not large-scale rearrangements. Page numbers were not available in our copy. (LLM, conf=0.83)

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References 58 · Cited by 146

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Authors
Georgakopoulos-Soares, I., Morganella, S., Jain, N., Hemberg, M., & Nik-Zainal, S.
Affiliations
  • Wellcome Sanger Institute (GB)
  • Imperial College London (GB)
ORCID
Venue
Genome Research
Publisher
Cold Spring Harbor Laboratory
Published
2018-08-13
Volume
28
Issue
9
Pages
1264-1271
ISSN
  • 1088-9051 (ISSN-L)
  • 1549-5469
DOI
10.1101/gr.231688.117
PMC
PMC6120622
OpenAlex
W2949071111
Cited by
146
References
58
Citations by year
2026: 9 · 2025: 21 · 2024: 21 · 2023: 20 · 2022: 29 · 2021: 19 · 2020: 13 · 2019: 14
Type
posted content
Language
en
Open access
Locations
  • Genome Research (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • Wellcome Trust Sanger Institute
  • Wellcome Trust Intermediate Clinical Research (WT100183MA)
  • CRUK (C60100/A23916)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Keywords
recurrent mutations, repetitive DNA, DNA replication timing, chromatin organization, epigenetic factors, cancer genome
MeSH terms
Humans, Neoplasms, Mutagenesis, DNA, B-Form, Nucleotide Motifs

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