Hotspot propensity across mutational processes

The ability to study mutation rate variability at nucleotide resolution is impaired by the sparsity of observed mutational events across the genome. To circumvent this problem, here we investigated the propensity of 14 different mutational processes to form recurrently mutated sites across tumour samples (hotspots). We found that mutational signatures 1 (SBS1) and 17 (SBS17a and SBS17b) have the highest propensity to form hotspots, generating 5-78 times more than other common somatic mutational processes. After accounting for trinucleotide mutational probabilities, sequence composition and heterogeneity of mutation rates at 10 Kbp, the majority (89-95%) of SBS17a and b hotspots remain unexplained. This suggests that local genomic features play a significant role in SBS17a and b hotspot propensity, among which we identify CTCF binding as a minor contributor. In the case of SBS1, we demonstrate that including genome-wide distribution of methylated CpGs sites into our models can explain most (80-100%) of its hotspot propensity. We also observe an increased hotspot propensity of SBS1 in normal tissues from mammals, as well as in de novo germline mutations. We demonstrate that hotspot propensity is a useful readout to assess the accuracy of mutation rate models at nucleotide resolution. This new approach and the findings derived from it open up new avenues for a range of somatic and germline studies investigating and modelling mutagenesis.