Reduced intrinsic DNA curvature leads to increased mutation rate

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• dc.contributor.author Duan, Chaorui
• dc.contributor.author Huan, Qing
• dc.contributor.author Chen, Xiaoshu
• dc.contributor.author Wu, Shaohuan
• dc.contributor.author Carey, Lucas, 1980-
• dc.contributor.author He, Xionglei
• dc.contributor.author Qian, Wenfeng
• dc.date.accessioned 2018-12-11T15:50:54Z
• dc.date.available 2018-12-11T15:50:54Z
• dc.date.issued 2018
• dc.description.abstract Background: Mutation rates vary across the genome. Many trans factors that influence mutation rates have been identified, as have specific sequence motifs at the 1–7-bp scale, but cis elements remain poorly characterized. The lack of understanding regarding why different sequences have different mutation rates hampers our ability to identify positive selection in evolution and to identify driver mutations in tumorigenesis. Results: Here, we use a combination of synthetic genes and sequences of thousands of isolated yeast colonies to show that intrinsic DNA curvature is a major cis determinant of mutation rate. Mutation rate negatively correlates with DNA curvature within genes, and a 10% decrease in curvature results in a 70% increase in mutation rate. Consistently, both yeast and humans accumulate mutations in regions with small curvature. We further show that this effect is due to differences in the intrinsic mutation rate, likely due to differences in mutagen sensitivity and not due to differences in the local activity of DNA repair. Conclusions: Our study establishes a framework for understanding the cis properties of DNA sequence in modulating the local mutation rate and identifies a novel causal source of non-uniform mutation rates across the genome.
• dc.format.mimetype application/pdf
• dc.identifier.citation Duan C, Huan Q, Chen X, Wu S, Carey LB, He X et al. Reduced intrinsic DNA curvature leads to increased mutation rate. Genome Biol. 2018;19(1):132. DOI: 10.1186/s13059-018-1525-y
• dc.identifier.doi http://dx.doi.org/10.1186/s13059-018-1525-y
• dc.identifier.issn 1474-7596
• dc.identifier.uri http://hdl.handle.net/10230/36028
• dc.language.iso eng
• dc.publisher BioMed Central
• dc.relation.ispartof Genome Biology. 2018;19(1):132
• dc.rights © The Author(s). 2018 Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword DNA shape
• dc.subject.keyword Intrinsic DNA curvature
• dc.subject.keyword Mutation rate
• dc.subject.keyword Mutational landscape
• dc.subject.keyword Mutagen sensitivity
• dc.title Reduced intrinsic DNA curvature leads to increased mutation rate
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion