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Direct estimation of per nucleotide and genomic deleterious mutation rates in Drosophila

Nature volume 445, pages 82–85 (2007)Cite this article

A Corrigendum to this article was published on 01 May 2008

Abstract

Spontaneous mutations are the source of genetic variation required for evolutionary change, and are therefore important for many aspects of evolutionary biology. For example, the divergence between taxa at neutrally evolving sites in the genome is proportional to the per nucleotide mutation rate, u (ref. 1), and this can be used to date speciation events by assuming a molecular clock. The overall rate of occurrence of deleterious mutations in the genome each generation (U) appears in theories of nucleotide divergence and polymorphism2, the evolution of sex and recombination3, and the evolutionary consequences of inbreeding2. However, estimates of U based on changes in allozymes4 or DNA sequences5 and fitness traits are discordant6,7,8. Here we directly estimate u in Drosophila melanogaster by scanning 20 million bases of DNA from three sets of mutation accumulation lines by using denaturing high-performance liquid chromatography9. From 37 mutation events that we detected, we obtained a mean estimate for u of 8.4 × 10-9 per generation. Moreover, we detected significant heterogeneity in u among the three mutation-accumulation-line genotypes. By multiplying u by an estimate of the fraction of mutations that are deleterious in natural populations of Drosophila10, we estimate that U is 1.2 per diploid genome. This high rate suggests that selection against deleterious mutations may have a key role in explaining patterns of genetic variation in the genome, and help to maintain recombination and sexual reproduction.

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References

  1. Kimura, M. The Neutral Theory of Molecular Evolution (Cambridge University Press, Cambridge, 1983)

    Book  Google Scholar 

  2. Charlesworth, B. & Charlesworth, D. Some evolutionary consequences of deleterious mutations. Genetica 102–103, 3–19 (1998)

    Article  Google Scholar 

  3. Kondrashov, A. S. Deleterious mutations and the evolution of sexual reproduction. Nature 336, 435–440 (1988)

    Article  ADS  CAS  Google Scholar 

  4. Mukai, T. & Cockerham, C. C. Spontaneous mutation rates at enzyme loci in Drosophila melanogaster. Proc. Natl Acad. Sci. USA 74, 2514–2517 (1977)

    Article  ADS  CAS  Google Scholar 

  5. 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 

  6. Crow, J. F. & Simmons, M. J. in The Genetics and Biology of Drosophila Vol. 3C (eds Ashburner, M., Carson, H. L. & Thompson, J. N.) 1–35 (Academic, London, 1983)

    Google Scholar 

  7. Keightley, P. D. & Eyre-Walker, A. Terumi Mukai and the riddle of deleterious mutation rates. Genetics 153, 515–523 (1999)

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Lynch, M. et al. Perspective: Spontaneous deleterious mutation. Evolution 53, 645–663 (1999)

    Article  Google Scholar 

  9. Oefner, P. J. & Huber, C. G. A decade of high-resolution liquid chromatography of nucleic acids on styrene divinylbenzene copolymers. J. Chromatogr. B 782, 27–55 (2002)

    Article  CAS  Google Scholar 

  10. Halligan, D. L. & Keightley, P. D. Ubiquitous selective constraints in the Drosophila genome revealed by a genome-wide interspecies comparison. Genome Res. 16, 875–884 (2006)

    Article  CAS  Google Scholar 

  11. Keightley, P. D. & Otto, S. P. Interference among deleterious mutations favours sex and recombination in finite populations. Nature 443, 89–92 (2006)

    Article  ADS  CAS  Google Scholar 

  12. Presgraves, D. C. Recombination enhances protein adaptation in Drosophila melanogaster. Curr. Biol. 15, 1651–1656 (2005)

    Article  CAS  Google Scholar 

  13. Nachman, M. W. Single nucleotide polymorphisms and recombination rate in humans. Trends Genet. 17, 481–485 (2001)

    Article  CAS  Google Scholar 

  14. Kondrashov, A. S. & Crow, J. F. A molecular approach to estimating the human deleterious mutation rate. Hum. Mutat. 2, 229–234 (1993)

    Article  CAS  Google Scholar 

  15. Houle, D. & Nuzhdin, S. V. Mutation accumulation and the effect of copia insertions in Drosophila melanogaster. Genet. Res. 83, 7–18 (2004)

    Article  CAS  Google Scholar 

  16. Fernandez, J. & López-Fanjul, C. Spontaneous mutational variances and covariances for fitness-related traits in Drosophila melanogaster. Genetics 143, 829–837 (1996)

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Maside, X., Bartolome, C., Assimacopoulos, S. & Charlesworth, B. Rates of movement and distribution of transposable elements in Drosophila melanogaster: in situ hybridization vs Southern blotting data. Genet. Res. 78, 121–136 (2001)

    Article  CAS  Google Scholar 

  18. Dobson-Stone, C. et al. Comparison of fluorescent single-strand conformation polymorphism analysis and denaturing high-performance liquid chromatography for detection of EXT1 and EXT2 mutations in hereditary multiple exostoses. Eur. J. Hum. Genet. 8, 24–32 (2000)

    Article  CAS  Google Scholar 

  19. O’Donovan, M. C. et al. Blind analysis of denaturing high-performance liquid chromatography as a tool for mutation detection. Genomics 52, 44–49 (1998)

    Article  Google Scholar 

  20. Moriyama, E. N. & Powell, J. R. Intraspecific nuclear DNA variation in Drosophila. Mol. Biol. Evol. 13, 261–277 (1996)

    Article  CAS  Google Scholar 

  21. Petrov, D. A. DNA loss and evolution of genome size in Drosophila. Genetica 115, 81–91 (2002)

    Article  CAS  Google Scholar 

  22. Woodruff, R. C., Thompson, J. N., Seeger, M. A. & Spivey, W. E. Variation in spontaneous mutation and repair in natural population lines of Drosophila melanogaster. Heredity 53, 223–234 (1984)

    Article  Google Scholar 

  23. Baer, C. F. et al. Comparative evolutionary genetics of spontaneous mutations affecting fitness in rhabditid nematodes. Proc. Natl Acad. Sci. USA 102, 5785–5790 (2005)

    Article  ADS  CAS  Google Scholar 

  24. Tamura, K., Subramanian, S. & Kumar, S. Temporal patterns of fruit fly (Drosophila) evolution revealed by mutation clocks. Mol. Biol. Evol. 21, 36–44 (2004)

    Article  CAS  Google Scholar 

  25. Andolfatto, P. Adaptive evolution of non-coding DNA in Drosophila. Nature 437, 1149–1152 (2005)

    Article  ADS  CAS  Google Scholar 

  26. Fry, J. D. On the rate and linearity of viability declines in Drosophila mutation-accumulation experiments: Genomic mutation rates and synergistic epistasis revisited. Genetics 166, 797–806 (2004)

    Article  Google Scholar 

  27. Loewe, L. & Charlesworth, B. Inferring the distribution of mutational effects on fitness in Drosophila. Biol. Lett. 2, 426–430 (2006)

    Article  Google Scholar 

  28. Charlesworth, B. Mutation selection balance and the evolutionary advantage of sex and recombination. Genet. Res. 55, 199–221 (1990)

    Article  CAS  Google Scholar 

  29. Salathé, M., Salathé, R., Schmid-Hempel, P. & Bonhoeffer, S. Mutation accumulation in space and the maintenance of sexual reproduction. Ecol. Lett. 9, 941–946 (2006)

    Article  Google Scholar 

  30. Ravnik-Glavač, M., Atkinson, A., Glavač, D. & Dean, M. DHPLC screening of cystic fibrosis gene mutations. Hum. Mutat. 19, 374–383 (2002)

    Article  Google Scholar 

Download references

Acknowledgements

We thank D. Houle and C. López-Fanjul for providing samples of MA lines, P. Andolfatto for suggesting the use of PCR errors as positive controls, F. Oliver for help with DNA sequencing, and D. Charlesworth, J. Crow, J. Drake, A. Eyre-Walker, C. Haag, D. Houle and M. Lynch for comments on the manuscript. We are grateful to the Wellcome Trust for funding by a Functional Genomics Development Initiative grant.

Author Contributions S.M., C.H.-L. and M.D. performed the DHPLC analysis. M.D. cloned and sequenced putative variants. X.M. cloned and sequenced positive controls. D.L.H. analysed selective constraints on indel mutations. B.C. advised on Drosophila genetics and interpreting the data. P.D.K. conceived and designed the project. C.H.-L. and P.D.K. analysed the data and wrote the paper. All authors revised the draft manuscript.

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Author notes

  1. Xulio Maside

    Present address: Grupo de Medicina Xenómica, Instituto de Medicina Legal, Universidade de Santiago, S. Francisco s/n, 15782, Santiago de Compostela, Spain

  2. Steven Macaskill

    Present address: Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne, Victoria, 3002, Australia

  3. Cathy Haag-Liautard, Mark Dorris, Xulio Maside and Steven Macaskill: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Evolutionary Biology, School of Biological Sciences, University of Edinburgh, West Mains Road, Edinburgh, EH9 3JT, UK

    Cathy Haag-Liautard, Mark Dorris, Xulio Maside, Steven Macaskill, Daniel L. Halligan, Brian Charlesworth & Peter D. Keightley

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  1. Cathy Haag-Liautard
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Correspondence to Peter D. Keightley.

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Haag-Liautard, C., Dorris, M., Maside, X. et al. Direct estimation of per nucleotide and genomic deleterious mutation rates in Drosophila. Nature 445, 82–85 (2007). https://doi.org/10.1038/nature05388

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