Single-nucleotide mutation rate increases close to insertions/deletions in eukaryotes (original) (raw)

Nature volume 455, pages 105–108 (2008)Cite this article

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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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

  1. Dacheng Tian and Qiang Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. 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
  2. Department of Fish Ecology and Evolution, EAWAG Center of Ecology, Evolution and Biogeochemistry, 6047 Kastanienbaum, Switzerland
    Hitoshi Araki
  3. Department of Ecology & Evolution, University of Chicago, Chicago, Illinois 60637, USA,
    Martin Kreitman, Thomas Nagylaki, Richard Hudson & Joy Bergelson

Authors

  1. Dacheng Tian
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  2. Qiang Wang
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  3. Pengfei Zhang
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  4. Hitoshi Araki
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  5. Sihai Yang
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  6. Martin Kreitman
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  7. Thomas Nagylaki
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  8. Richard Hudson
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  9. Joy Bergelson
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  10. Jian-Qun Chen
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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

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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.