Single-nucleotide mutation rate increases close to insertions/deletions in eukaryotes (original) (raw)
- Letter
- Published: 20 July 2008
- Qiang Wang1 na1,
- Pengfei Zhang1,
- Hitoshi Araki1,2,
- Sihai Yang1,
- Martin Kreitman3,
- Thomas Nagylaki3,
- Richard Hudson3,
- Joy Bergelson1,3 &
- …
- Jian-Qun Chen1
Nature volume 455, pages 105–108 (2008)Cite this article
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Abstract
Mutation hotspots are commonly observed in genomic sequences and certain human disease loci1,2,3,4,5,6,7, but general mechanisms for their formation remain elusive7,8,9,10,11. Here we investigate the distribution of single-nucleotide changes around insertions/deletions (indels) in six independent genome comparisons, including primates, rodents, fruitfly, rice and yeast. In each of these genomic comparisons, nucleotide divergence (D) is substantially elevated surrounding indels and decreases monotonically to near-background levels over several hundred bases. D is significantly correlated with both size and abundance of nearby indels. In comparisons of closely related species, derived nucleotide substitutions surrounding indels occur in significantly greater numbers in the lineage containing the indel than in the one containing the ancestral (non-indel) allele; the same holds within species for single-nucleotide mutations surrounding polymorphic indels. We propose that heterozygosity for an indel is mutagenic to surrounding sequences, and use yeast genome-wide polymorphism data to estimate the increase in mutation rate. The consistency of these patterns within and between species suggests that indel-associated substitution is a general mutational mechanism.
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References
- Hedrich, K. et al. Distribution, type, and origin of Parkin mutations: review and case studies. Mov. Disord. 19, 1146–1157 (2004)
Article Google Scholar - Bonneau, D. & Longy, M. Mutations of the human PTEN gene. Hum. Mutat. 16, 109–122 (2000)
Article CAS Google Scholar - Chi, Y. I. Homeodomain revisited: a lesson from disease-causing mutations. Hum. Genet. 116, 433–444 (2005)
Article CAS Google Scholar - Mortazavi, Y. et al. The spectrum of PIG-A gene mutations in aplastic anemia/paroxysmal nocturnal hemoglobinuria (AA/PNH): a high incidence of multiple mutations and evidence of a mutational hot spot. Blood 101, 2833–2841 (2003)
Article CAS Google Scholar - Iacobuzio-Donahue, C. A. et al. Missense mutations of MADH4: characterization of the mutational hot spot and functional consequences in human tumors. Clin. Cancer Res. 10, 1597–1604 (2004)
Article CAS Google Scholar - Galtier, N., Enard, D., Radondy, Y., Bazin, E. & Belkhir, K. Mutation hot spots in mammalian mitochondrial DNA. Genome Res. 16, 215–222 (2005)
Article Google Scholar - Maki, H. Origins of spontaneous mutations: specificity and directionality of base-substitution, frameshift, and sequence-substitution mutageneses. Annu. Rev. Genet. 36, 279–303 (2002)
Article CAS Google Scholar - Arndt, P. F., Hwa, T. & Petrov, D. A. Substantial Regional Variation in Substitution Rates in the Human Genome: Importance of GC Content, Gene Density, and Telomere-Specific Effects. J. Mol. Evol. 60, 748–763 (2005)
Article ADS CAS Google Scholar - Rogozin, I. B. & Pavlov, Y. I. Theoretical analysis of mutation hotspots and their DNA sequence context specificity. Mutat. Res. 544, 65–85 (2003)
Article CAS Google Scholar - Silva, J. C. & Kondrashov, A. S. Patterns in spontaneous mutation revealed by human-baboon sequence comparison. Trends Genet. 18, 544–547 (2002)
Article CAS Google Scholar - Crow, J. F. The high spontaneous mutation rate: is it a health risk? Proc. Natl Acad. Sci. USA 94, 8380–8386 (1997)
Article ADS CAS Google Scholar - Ellegren, H., Smith, N. G. & Webster, M. T. Mutation rate variation in the mammalian genome. Curr. Opin. Genet. Dev. 13, 562–568 (2003)
Article CAS Google Scholar - Denver, D. R., Morris, K., Lynch, M. & Thomas, W. K. High mutation rate and predominance of insertions in the Caenorhabditis elegans nuclear genome. Nature 430, 679–682 (2004)
Article ADS CAS Google Scholar - Longman-Jacobsen, N., Williamson, J. F., Dawkins, R. L. & Gaudieri, S. In polymorphic genomic regions indels cluster with nucleotide polymorphism: Quantum Genomics. Gene 312, 257–261 (2003)
Article CAS Google Scholar - Petrov, D. A. DNA loss and evolution of genome size in Drosophila . Genetica 115, 81–91 (2002)
Article CAS Google Scholar - Hardison, R. C. et al. Covariation in frequencies of substitution, deletion, transposition, and recombination during eutherian evolution. Genome Res. 13, 13–26 (2003)
Article CAS Google Scholar - Kondrashov, A. S. Direct estimates of human per nucleotide mutation rates at 20 loci causing Mendelian diseases. Hum. Mutat. 21, 12–27 (2003)
Article CAS Google Scholar - Dawkins, R. et al. Genomics of the major histocompatibility complex: haplotypes, duplication, retroviruses and disease. Immunol. Rev. 167, 275–304 (1999)
Article CAS Google Scholar - The Chimpanzee Sequencing and Analysis Consortium. Initial sequence of the chimpanzee genome and comparison with the human genome. Nature 437, 69–87 (2005)
- Rat Genome Sequencing Project Consortium. Genome sequence of the Brown Norway rat yields insights into mammalian evolution. Nature 428, 493–521 (2004)
- Strickberger, M. S. Evolution (Jones and Bartlett Publishers, 2000)
Google Scholar - Lercher, M. J. & Hurst, L. D. Human SNP variability and mutation rate are higher in regions of high recombination. Trends Genet. 18, 337–340 (2002)
Article CAS Google Scholar - Check, E. Human genome: patchwork people. Nature 437, 1084–1086 (2005)
Article ADS CAS Google Scholar - Conrad, D. F., Andrews, T. D., Carter, N. P., Hurles, M. E. & Pritchard, J. K. A high-resolution survey of deletion polymorphism in the human genome. Nature Genet. 38, 75–81 (2006)
Article CAS Google Scholar - Schwartz, S. et al. Human-mouse alignments with BLASTZ. Genome Res. 13, 103–107 (2003)
Article CAS Google Scholar - Thompson, J. D., Higgins, D. G. & Gibson, T. J. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res. 22, 4673–4680 (1994)
Article CAS Google Scholar - Jukes, T. H. & Cantor, C. R. in Mammalian Protein Metabolism (ed. Munro, H. N.) 21–132 (Academic, 1969)
Book Google Scholar - Ruderfer, D. M., Pratt, S. C., Seidel, H. S. & Kruglyak, L. Population genomic analysis of outcrossing and recombination in yeast. Nature Genet. 38, 1077–1081 (2006)
Article CAS Google Scholar
Acknowledgements
We thank A. Kondrashov (a reviewer) for suggesting the 3-species test and the possibility of a signature for indel-caused substitutions; M. Long and X. Gao for comments; and T. Petes for informing us about genome-wide measures of recombination in yeast. This study was supported by NSFC (30470924, 30470122 & 30570987) and Pre-program for NBRPC (2005CCA02100) to D.T. or J.-Q.C. and by 111 Project.
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Author notes
- Dacheng Tian and Qiang Wang: These authors contributed equally to this work.
Authors and Affiliations
- Department of Biology, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China
Dacheng Tian, Qiang Wang, Pengfei Zhang, Hitoshi Araki, Sihai Yang, Joy Bergelson & Jian-Qun Chen - Department of Fish Ecology and Evolution, EAWAG Center of Ecology, Evolution and Biogeochemistry, 6047 Kastanienbaum, Switzerland
Hitoshi Araki - Department of Ecology & Evolution, University of Chicago, Chicago, Illinois 60637, USA,
Martin Kreitman, Thomas Nagylaki, Richard Hudson & Joy Bergelson
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Correspondence toDacheng Tian or Jian-Qun Chen.
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Tian, D., Wang, Q., Zhang, P. et al. Single-nucleotide mutation rate increases close to insertions/deletions in eukaryotes.Nature 455, 105–108 (2008). https://doi.org/10.1038/nature07175
- Received: 19 January 2008
- Accepted: 17 June 2008
- Published: 20 July 2008
- Issue Date: 04 September 2008
- DOI: https://doi.org/10.1038/nature07175
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Editorial Summary
Mutation hotspots: the role of insertions and deletions
Recent genomic efforts have demonstrated that large chunks of DNA differ between individuals in many species, and that the differences are focused on mutation hot-spots. Six pairwise comparisons of the distributions of single nucleotide substitutions around insertions and deletions ('indels') using ten genomes including yeast, rice, fly, rodent and primate show that the level of genetic variation is strongly and negatively correlated with the distance from indels in all the comparisons. Furthermore, the size and abundance of indels significantly influences the level of local nucleotide diversity. This work suggests that indels are a common mechanism to induce mutations, and may play an important role in genome evolution.