Reduced intrinsic DNA curvature leads to increased mutation rate
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 diffe...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-09-01
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| Series: | Genome Biology |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13059-018-1525-y |
| _version_ | 1819239622682607616 |
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| author | Chaorui Duan Qing Huan Xiaoshu Chen Shaohuan Wu Lucas B. Carey Xionglei He Wenfeng Qian |
| author_facet | Chaorui Duan Qing Huan Xiaoshu Chen Shaohuan Wu Lucas B. Carey Xionglei He Wenfeng Qian |
| author_sort | Chaorui Duan |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-12-23T13:55:03Z |
| format | Article |
| id | doaj.art-91e4d101fe1c4c1eb23526b6d8a39264 |
| institution | Directory Open Access Journal |
| issn | 1474-760X |
| language | English |
| last_indexed | 2024-12-23T13:55:03Z |
| publishDate | 2018-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Biology |
| spelling | doaj.art-91e4d101fe1c4c1eb23526b6d8a392642022-12-21T17:44:29ZengBMCGenome Biology1474-760X2018-09-0119111210.1186/s13059-018-1525-yReduced intrinsic DNA curvature leads to increased mutation rateChaorui Duan0Qing Huan1Xiaoshu Chen2Shaohuan Wu3Lucas B. Carey4Xionglei He5Wenfeng Qian6State Key Laboratory of Plant Genomics, Institute of Genetics and Developmental Biology, Chinese Academy of SciencesState Key Laboratory of Plant Genomics, Institute of Genetics and Developmental Biology, Chinese Academy of SciencesHuman Genome Research Institute and Department of Medical Genetics, Zhongshan School of Medicine, Sun Yat-sen UniversityState Key Laboratory of Plant Genomics, Institute of Genetics and Developmental Biology, Chinese Academy of SciencesDepartment of Experimental and Health Sciences, Universitat Pompeu FabraState Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen UniversityState Key Laboratory of Plant Genomics, Institute of Genetics and Developmental Biology, Chinese Academy of SciencesAbstract 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.http://link.springer.com/article/10.1186/s13059-018-1525-yDNA shapeIntrinsic DNA curvatureMutation rateMutational landscapeMutagen sensitivity |
| spellingShingle | Chaorui Duan Qing Huan Xiaoshu Chen Shaohuan Wu Lucas B. Carey Xionglei He Wenfeng Qian Reduced intrinsic DNA curvature leads to increased mutation rate Genome Biology DNA shape Intrinsic DNA curvature Mutation rate Mutational landscape Mutagen sensitivity |
| title | Reduced intrinsic DNA curvature leads to increased mutation rate |
| title_full | Reduced intrinsic DNA curvature leads to increased mutation rate |
| title_fullStr | Reduced intrinsic DNA curvature leads to increased mutation rate |
| title_full_unstemmed | Reduced intrinsic DNA curvature leads to increased mutation rate |
| title_short | Reduced intrinsic DNA curvature leads to increased mutation rate |
| title_sort | reduced intrinsic dna curvature leads to increased mutation rate |
| topic | DNA shape Intrinsic DNA curvature Mutation rate Mutational landscape Mutagen sensitivity |
| url | http://link.springer.com/article/10.1186/s13059-018-1525-y |
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