title: Volatility of Mutator Phenotypes at Single Cell Resolution.
abstract: Mutator phenotypes accelerate the evolutionary process of neoplastic transformation. Historically, the measurement of mutation rates has relied on scoring the occurrence of rare mutations in target genes in large populations of cells. Averaging mutation rates over large cell populations assumes that new mutations arise at a constant rate during each cell division. If the mutation rate is not constant, an expanding mutator population may contain subclones with widely divergent rates of evolution. Here, we report mutation rate measurements of individual cell divisions of mutator yeast deficient in DNA polymerase ε proofreading and base-base mismatch repair. Our data are best fit by a model in which cells can assume one of two distinct mutator states, with mutation rates that differ by an order of magnitude. In error-prone cell divisions, mutations occurred on the same chromosome more frequently than expected by chance, often in DNA with similar predicted replication timing, consistent with a spatiotemporal dimension to the hypermutator state. Mapping of mutations onto predicted replicons revealed that mutations were enriched in the first half of the replicon as well as near termination zones. Taken together, our findings show that individual genome replication events exhibit an unexpected volatility that may deepen our understanding of the evolution of mutator-driven malignancies.
authors: Department of Pathology, University of Washington, Seattle, Washington, United States of America.
authors: Scott R
authors: SR
authors: Kennedy
authors: Department of Pathology, University of Washington, Seattle, Washington, United States of America.
authors: Eric M
authors: EM
authors: Schultz
authors: Department of Entomology, North Carolina State University, Raleigh, North Carolina, United States of America.
authors: Thomas M
authors: TM
authors: Chappell
authors: Department of Pathology, University of Washington, Seattle, Washington, United States of America.
authors: Brendan
authors: B
authors: Kohrn
authors: Department of Pathology, University of Washington, Seattle, Washington, United States of America.
authors: Gary M
authors: GM
authors: Knowels
authors: Department of Pathology, University of Washington, Seattle, Washington, United States of America.
authors: Alan J
authors: AJ
authors: Herr
mesh_terms: D000483:Alleles; D020137:Base Pair Mismatch; D002455:Cell Division; D053843:DNA Mismatch Repair; D004257:DNA Polymerase II / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication; D004271:DNA, Fungal / Q000235:genetics; D016681:Genome, Fungal; D059645:Mutation Rate; D010641:Phenotype; D012093:Replicon; D017422:Sequence Analysis, DNA; D015003:Yeasts / Q000235:genetics* / Q000378:metabolism
chemical_list: D004271:DNA, Fungal; D004257:DNA Polymerase II