TY - JOUR
T1 - Noncanonical secondary structures arising from non-B DNA motifs are determinants of mutagenesis
AU - Georgakopoulos-Soares, Ilias
AU - Morganella, Sandro
AU - Jain, Naman
AU - Hemberg, Martin
AU - Nik-Zainal, Serena
N1 - Publisher Copyright:
© 2018 Georgakopoulos-Soares et al.
PY - 2018/9
Y1 - 2018/9
N2 - 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.
AB - 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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U2 - 10.1101/gr.231688.117
DO - 10.1101/gr.231688.117
M3 - Article
C2 - 30104284
AN - SCOPUS:85052743712
SN - 1088-9051
VL - 28
SP - 1264
EP - 1271
JO - Genome research
JF - Genome research
IS - 9
ER -