Component 1 represents singletons that occurred an average of around 2–8 bp apart and accounted for approximately 1.5% of singletons in each sample. These singletons are substantially enriched for A>T and C>A transversions (Extended Data Fig. 3a), consistent with the signatures of trans-lesion synthesis that causes multiple non-independent point mutations within very short spans35. The density of component 1 singletons is also associated with CpG island density (Supplementary Fig. 21). Component 2 represents singletons occurring 500–5,000 bp apart, accounting for around 12–24% of singletons. These singletons are enriched for C>G transversions and show prominent subtelomeric concentrations on chromosomes 8p, 9p, 16p and 16q36,37 (Extended Data Fig. 3 and Supplementary Fig. 22), consistent with the recently described maternally derived C>G mutation clusters36,37. The exact mechanism that underlies this distinctive clustering pattern is unknown, but may involve either hypermutability of single-stranded DNA 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
