Mutations that compromise mismatch repair (MMR) or DNA polymerase exonuclease domains produce mutator phenotypes capable of fueling cancer evolution. Tandem defects in these pathways dramatically increase mutation rate. Here, we model how mutator phenotypes expand genetic heterogeneity in budding yeast cells using a single-cell resolution approach that tallies all replication errors arising from individual divisions. The distribution of count data from cells lacking MMR and polymerase proofreading was broader than expected for a single rate, consistent with volatility of the mutator phenotype. The number of mismatches that segregated to the mother and daughter cells after the initial round of replication co-varied, suggesting that mutagenesis in each division is governed by a different underlying rate. The distribution of “fixed” mutation counts that cells inherit is further broadened by an unequal sharing of mutations due to semiconservative replication and Mendelian segregation. Modeling suggests that this asymmetric segregation may diversify mutation burden in mutator-driven tumors.

Rate volatility and asymmetric segregation diversify mutation burden in mutator cells