intermediates during the repair of double-stranded breaks36,37 or transcription-associated mutagenesis, with increased damage on the non-transcribed strand38. Our results are compatible with both these mechanisms: component 2 singletons are enriched near regions of H3K4 trimethylation, a mark associated with double-stranded break response39, and depleted in exon-dense regions (Supplementary Fig. 21). Component 3 singletons (occurring approximately 30–50 kilobases (kb) apart) accounted for around 43–49% of all singletons, and component 4 singletons (occurring approximately 125–170 kb apart) accounted for around 31–37% of all singletons. These latter components have nearly identical mutational spectra (Extended Data Fig. 3a) and are distributed about uniformly in the genome.
