Replication asymmetry in bMMRD samples with mutations in replicative polymerases. (A) A schematic representation of estimation of the ratio of the mutation rates for complementary mutations. In the example shown, the frequency of the C-dT mismatch, resulting in the C → A mutation, is 1.5 times higher than the rate of the complementary G → T mutation when Pol epsilon is mutated and four times higher when Pol delta is mutated. Leftmost and rightmost bins together correspond to the 20% of the genome for which we can identify with the highest confidence that the reference strand is replicated primarily as lagging or leading, respectively. (B) The ratio of the mutation rates for complementary mutations (vertical axis) as a function of the propensity of the replication fork to replicate the reference strand as lagging or leading (horizontal axis). x-axis bins correspond to the percentiles of the replication timing derivative. Vertical bars represent 95% confidence intervals. Asterisks indicate significance of the deviation from one at the rightmost (or leftmost) bin. (*) P < 0.05; (**) P < 0.01; (***) P < 0.001. D corresponds to nucleotides A, G, or T. H corresponds to nucleotides A, C, or T. Note the logarithmic vertical axis.
