title: Heterogeneous polymerase fidelity and mismatch repair bias genome variation and composition.
abstract: Mutational heterogeneity must be taken into account when reconstructing evolutionary histories, calibrating molecular clocks, and predicting links between genes and disease. Selective pressures and various DNA transactions have been invoked to explain the heterogeneous distribution of genetic variation between species, within populations, and in tissue-specific tumors. To examine relationships between such heterogeneity and variations in leading- and lagging-strand replication fidelity and mismatch repair, we accumulated 40,000 spontaneous mutations in eight diploid yeast strains in the absence of selective pressure. We found that replicase error rates vary by fork direction, coding state, nucleosome proximity, and sequence context. Further, error rates and DNA mismatch repair efficiency both vary by mismatch type, responsible polymerase, replication time, and replication origin proximity. Mutation patterns implicate replication infidelity as one driver of variation in somatic and germline evolution, suggest mechanisms of mutual modulation of genome stability and composition, and predict future observations in specific cancers.
authors.affiliation: Laboratory of Molecular Genetics, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA; Laboratory of Structural Biology, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA;
authors.forename: Scott A
authors.initials: SA
authors.lastname: Lujan
authors.affiliation: Laboratory of Molecular Genetics, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA; Laboratory of Structural Biology, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA;
authors.forename: Anders R
authors.initials: AR
authors.lastname: Clausen
authors.affiliation: Laboratory of Molecular Genetics, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA; Laboratory of Structural Biology, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA;
authors.forename: Alan B
authors.initials: AB
authors.lastname: Clark
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA;
authors.forename: Heather K
authors.initials: HK
authors.lastname: MacAlpine
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA;
authors.forename: David M
authors.initials: DM
authors.lastname: MacAlpine
authors.affiliation: Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA;
authors.forename: Ewa P
authors.initials: EP
authors.lastname: Malc
authors.affiliation: Department of Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA;
authors.forename: Piotr A
authors.initials: PA
authors.lastname: Mieczkowski
authors.affiliation: Integrative Bioinformatics, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA.
authors.forename: Adam B
authors.initials: AB
authors.lastname: Burkholder
authors.affiliation: Integrative Bioinformatics, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA.
authors.forename: David C
authors.initials: DC
authors.lastname: Fargo
authors.affiliation: Laboratory of Molecular Genetics, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA;
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Gordenin
authors.affiliation: Laboratory of Molecular Genetics, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA; Laboratory of Structural Biology, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, North Carolina 27709, USA; kunkel@niehs.nih.gov.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Kunkel
mesh_terms: D000465:Algorithms; D053843:DNA Mismatch Repair; D004256:DNA Polymerase I / Q000235:genetics* / Q000378:metabolism; D004257:DNA Polymerase II / Q000235:genetics* / Q000378:metabolism; D004258:DNA Polymerase III / Q000235:genetics* / Q000378:metabolism; D004261:DNA Replication; D019143:Evolution, Molecular; D014644:Genetic Variation; D016681:Genome, Fungal / Q000235:genetics*; D008957:Models, Genetic; D059645:Mutation Rate; D009707:Nucleosomes / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA
chemical_list: D009707:Nucleosomes; D029701:Saccharomyces cerevisiae Proteins; D004256:DNA Polymerase I; D004257:DNA Polymerase II; D004258:DNA Polymerase III