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Heterogeneous polymerase fidelity and mismatch repair bias genome variation and composition.

Journal article
Authors Anders R Clausen
Scott A Lujan
Alan B Clark
Heather K MacAlpine
David M MacAlpine
Ewa P Malc
Piotr A Mieczkowski
Adam B Burkholder
David C Fargo
Dmitry A Gordenin
Thomas A Kunkel
Published in Genome research
Volume 24
Issue 11
Pages 1751-64
ISSN 1549-5469
Publication year 2014
Published at
Pages 1751-64
Language en
Links dx.doi.org/10.1101/gr.178335.114
www.ncbi.nlm.nih.gov/entrez/query.f...
Keywords Algorithms, DNA Mismatch Repair, DNA Polymerase I, genetics, metabolism, DNA Polymerase II, genetics, metabolism, DNA Polymerase III, genetics, metabolism, DNA Replication, Evolution, Molecular, Genetic Variation, Genome, Fungal, genetics, Models, Genetic, Mutation Rate, Nucleosomes, genetics, metabolism, Saccharomyces cerevisiae, enzymology, genetics, metabolism, Saccharomyces cerevisiae Proteins, genetics, metabolism, Sequence Analysis, DNA
Subject categories Molecular biology, Genetics

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.

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