Extended Data Fig. 7: Characterisation of replication strand bias and extended sequence context of mutational signatures associated with germline DNA polymerase mutations.

(a) Extended sequence context of mutations assigned to signatures SBS10a, SBS10b, SBS10c and SBS10d displayed with pyrimidine annotation. Plots show extended sequence context of C > A and C > T mutations in SBS10a and SBS10b respectively and C > A mutations in SBS10c and SBS10d. (b) Replication strand biases of SBS mutations indicated by excess mutations (annotated by pyrimidine base) on either the leading or lagging DNA strand. Biases are displayed according to mutations assigned to known signatures SBS10a and SBS10b and new signatures SBS10c and SBS10d. Only SBS mutations with an assignment probability >0.7 were included (Supplementary Methods). Strong replicative strand asymmetries are seen in known (SBS10a & SBS10b) signatures as well as new signatures; SBS10c and SBS10d. P-values were calculated using two-sided Poisson tests and corrected for multiple testing using the Benjamini-Hochberg method. Mutation types with statistically significant replication strand bias (adjusted p < 0.0001) are annotated with ‘****’. (c) ID replication strand asymmetries are displayed for single base insertions and deletions according to the affected polymerase gene; POLE (left) POLD1 (right). Replication strand bias is indicated by excess mutations with single base insertions on the leading strand in POLE mutant cells and on the lagging strand in POLD1 mutant cells. (d) Frequency of somatic SBS mutations assigned to each mutational signature SBS10a-d in replication timing bins. (e) Distribution of SBS mutations across different genomic regions; exonic, intronic and intergenic.