Heterogeneous polymerase fidelity and mismatch repair bias genome variation and composition.
Genome Res
; 24(11): 1751-64, 2014 Nov.
Article
em En
| MEDLINE
| ID: mdl-25217194
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Genoma Fúngico
/
Proteínas de Saccharomyces cerevisiae
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DNA Polimerase I
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DNA Polimerase II
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DNA Polimerase III
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Reparo de Erro de Pareamento de DNA
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Genome Res
Assunto da revista:
BIOLOGIA MOLECULAR
/
GENETICA
Ano de publicação:
2014
Tipo de documento:
Article