RT Journal
A1 Georgakopoulos-Soares, Ilias
A1 Morganella, Sandro
A1 Jain, Naman
A1 Hemberg, Martin
A1 Nik-Zainal, Serena
T1 Noncanonical secondary structures arising from non-B DNA motifs are determinants of mutagenesis
JF Genome Research 
JO Genome Research 
YR 2018 
FD September 01 
VO 28 
IS 9 
SP 1264 
OP 1271 
DO 10.1101/gr.231688.117 
UL http://genome.cshlp.org/content/28/9/1264.abstract 
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.