Fig. 1: Apparent replication-associated mutational asymmetry can be explained by transcription coupled repair.
a, Schematic of DNA lesion segregation2. Mutagen exposure induces lesions (red triangles) on both DNA strands (forward in blue; reverse in gold). Lesions that persist until replication serve as a reduced fidelity template. The two sister chromatids segregate into distinct daughter cells, so new mutations are not shared between daughter cells of the first division. Lesions that persist for multiple cell generations can generate multiallelic variation through repeated replication over the lesion (in italic). b, Summary of tumour generation and mutations called from whole-genome sequencing (WGS; Methods). c, Lesion strand resolved mutation spectra of all tumours (n = 237), representing the relative frequency of strand-specific single-base substitutions and their sequence context (192 categories). d, During the first DNA replication after DNA damage, template lesions (red triangles) are encountered by both the extending leading and the lagging strands. e, The relative enrichment (RE) of liver-expressed genes in the plus versus minus orientation (RE = (plus − minus)/(plus + minus)) across 21 quantile bins of replication fork directionality (RFD) bias (x axis). f, Mutation rates (y axis) for the whole genome (gold) stratified into 21 quantile bins of replication strand bias (RSB; x axis) show a higher mutation rate for the lagging strand than the leading strand replication on a lesion-containing template. This effect is enhanced in expressed genes (tan) and negligible in non-genic regions (orange). Whiskers show 95% bootstrap confidence intervals.
