All five signatures previously associated with MMR and the novel MSI-linked signature N4 exhibit a clear trend of replication strand asymmetry (significant in signature (sig.) 6 and N4 in MSI), generally with enrichment of C > T mutations on the leading strand template and C > A and T > C mutations on the lagging strand template (Fig. 4 , Additional file 2 : Figure S13), in line with the previously suggested role of MMR to balance mutational asymmetries generated by DNA polymerases during replication [ 9 , 11 ].
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Mutational signature distribution varies with DNA replication timing and strand asymmetry.
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