Rate volatility and asymmetric segregation diversify mutation burden in mutator cells

Abstract

Mutations that compromise mismatch repair (MMR) or DNA polymerase exonuclease 11domains produce mutator phenotypes capable of fueling cancer evolution. Tandem 12 defects in these pathways dramatically increase mutation rate. Here, we model how 13 mutator phenotypes expand genetic heterogeneity in budding yeast cells using a single-14 cell resolution approach that tallies all replication errors arising from individual 15divisions. The distribution of count data from cells lacking MMR and polymerase 16 proofreading was broader than expected for a single rate, consistent with volatility of the 17 mutator phenotype. The number of mismatches that segregated to the mother and 18 daughter cells after the initial round of replication co-varied, suggesting that 19 mutagenesis in each division is governed by a different underlying rate. The distribution 20 of "fixed" mutation counts that cells inherit is further broadened by an unequal sharing 21 of mutations due to semiconservative replication and Mendelian segregation. Modeling 22suggests that this asymmetric segregation may diversify mutation burden in mutator-23 driven tumors. 24 25