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Nucleosomes Suppress Spontaneous Mutations Base-Specifically in Eukaryotes

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Science  09 Mar 2012:
Vol. 335, Issue 6073, pp. 1235-1238
DOI: 10.1126/science.1217580

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Nucleosome Maps and Mutation

Understanding the processes governing the accumulation of mutations impacts many facets of evolutionary biology. Combining data from a mutation accumulation experiment in a DNA repair-deficient yeast strain with genome-wide substitution, Chen et al. (p. 1235) demonstrate that C/G to T/A changes are more likely to affect regions that are nucleosome-free. Furthermore, a similar pattern was seen when comparative analyses were performed among yeast species and in lines of Medaka fish and nematodes. The results are consistent with a model in which DNA bound by nucleosomes is protected against mutations caused by DNA damage.

Abstract

It is unknown how the composition and structure of DNA within the cell affect spontaneous mutations. Theory suggests that in eukaryotic genomes, nucleosomal DNA undergoes fewer C→T mutations because of suppressed cytosine hydrolytic deamination relative to nucleosome-depleted DNA. Comparative genomic analyses and a mutation accumulation experiment showed that nucleosome occupancy nearly eliminated cytosine deamination, resulting in an ~50% decrease of the C→T mutation rate in nucleosomal DNA. Furthermore, the rates of G→T and A→T mutations were also about twofold suppressed by nucleosomes. On the basis of these results, we conclude that nucleosome-dependent mutation spectra affect eukaryotic genome structure and evolution and may have implications for understanding the origin of mutations in cancers and in induced pluripotent stem cells.

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