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High mutation rate and predominance of insertions in the Caenorhabditis elegans nuclear genome

Naturevolume 430pages679682 (2004) | Download Citation



Mutations have pivotal functions in the onset of genetic diseases and are the fundamental substrate for evolution. However, present estimates of the spontaneous mutation rate and spectrum are derived from indirect and biased measurements. For instance, mutation rate estimates for Caenorhabditis elegans are extrapolated from observations on a few genetic loci with visible phenotypes and vary over an order of magnitude1. Alternative approaches in mammals, relying on phylogenetic comparisons of pseudogene loci2 and fourfold degenerate codon positions3, suffer from uncertainties in the actual number of generations separating the compared species and the inability to exclude biases associated with natural selection. Here we provide a direct and unbiased estimate of the nuclear mutation rate and its molecular spectrum with a set of C. elegans mutation-accumulation lines that reveal a mutation rate about tenfold higher than previous indirect estimates and an excess of insertions over deletions. Because deletions dominate patterns of C. elegans pseudogene variation4,5, our observations indicate that natural selection might be significant in promoting small genome size, and challenge the prevalent assumption that pseudogene divergence accurately reflects the spontaneous mutation spectrum.

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  1. 1

    Drake, J. W., Charlesworth, B., Charlesworth, D. & Crow, J. F. Rates of spontaneous mutation. Genetics 148, 1667–1686 (1998)

  2. 2

    Nachman, M. W. & Crowell, S. L. Estimate of the mutation rate per nucleotide in humans. Genetics 156, 297–304 (2000)

  3. 3

    Kumar, S. & Subramanian, S. Mutation rates in mammalian genomes. Proc. Natl Acad. Sci. USA 99, 803–808 (2002)

  4. 4

    Robertson, H. M. The large srh family of chemoreceptor genes in Caenorhabditis nematodes reveals processes of genome evolution involving large duplications and deletions and intron gains and losses. Genome Res. 10, 192–203 (2000)

  5. 5

    Witherspoon, D. J. & Robertson, H. M. Neutral evolution of ten types of mariner transposons in the genomes of Caenorhabditis elegans and Caenorhabditis briggsae. J. Mol. Evol. 56, 751–769 (2003)

  6. 6

    Vassilieva, L. L., Hook, A. M. & Lynch, M. The fitness effects of spontaneous mutations in Caenorhabditis elegans. Evolution 54, 1234–1246 (2000)

  7. 7

    Denver, D. R., Morris, K. & Thomas, W. K. Phylogenetics in Caenorhabditis elegans: an analysis of divergence and outcrossing. Mol. Biol. Evol. 20, 393–400 (2003)

  8. 8

    Denver, D. R., Morris, K., Lynch, M., Vassilieva, L. L. & Thomas, W. K. High direct estimate of the mutation rate in the mitochondrial genome of Caenorhabditis elegans. Science 289, 2342–2344 (2000)

  9. 9

    Ochman, H. Neutral mutations and neutral substitutions in bacterial genomes. Mol. Biol. Evol. 20, 2091–2096 (2003)

  10. 10

    Petrov, D. A., Lozovskaya, E. R. & Hartl, D. L. High intrinsic rate of DNA loss in Drosophila. Nature 384, 346–349 (1996)

  11. 11

    Petrov, D. A. & Hartl, D. L. Pseudogene evolution and natural selection for a compact genome. J. Hered. 91, 221–227 (2000)

  12. 12

    Hirotsune, S. et al. An expressed pseudogene regulates the messenger-RNA stability of its homologous coding gene. Nature 423, 91–96 (2003)

  13. 13

    Yamada, K. et al. Empirical analysis of transcriptional activity in the Arabidopsis genome. Science 302, 842–846 (2003)

  14. 14

    Balakirev, E. S. & Ayala, F. J. Pseudogenes: are they ‘junk’ or functional DNA? Annu. Rev. Genet. 37, 123–151 (2003)

  15. 15

    Charlesworth, B. The changing sizes of genes. Nature 384, 315–316 (1996)

  16. 16

    Lynch, M. & Conery, J. S. The origins of genome complexity. Science 302, 1401–1404 (2003)

  17. 17

    Marais, G., Mouchiroud, D. & Duret, L. Does recombination improve selection on codon usage? Lessons from nematode and fly complete genomes. Proc. Natl Acad. Sci. USA 98, 5688–5692 (2001)

  18. 18

    Hahn, M. W., Stajich, J. E. & Wray, G. A. The effects of selection against spurious transcription factor binding sites. Mol. Biol. Evol. 20, 901–906 (2003)

  19. 19

    Langley, C. H. & Ito, K. Spontaneous mutability in Drosophila melanogaster, in natural and laboratory environments. Mutat. Res. 36, 385–386 (1976)

  20. 20

    Gunsalus, K. C., Yueh, W. C., MacMenamin, P. & Piano, F. RNAiDB and PhenoBlast: web tools for genome-wide phenotypic mapping projects. Nucleic Acids Res. 32, D406–D410 (2004)

  21. 21

    Naclerio, G. et al. Molecular and genomic organization of clusters of repetitive DNA sequences in Caenorhabditis elegans. J. Mol. Biol. 226, 159–168 (1992)

  22. 22

    Keightley, P. D. & Ohnishi, O. EMS-induced polygenic mutation rates for nine quantitative characters in Drosophila melanogaster. Genetics 148, 753–766 (1998)

  23. 23

    Davies, E. K., Peters, A. D. & Keightley, P. D. High frequency of cryptic deleterious mutations in Caenorhabditis elegans. Science 285, 1748–1751 (1999)

  24. 24

    Stein, L. D. et al. The genome sequence of Caenorhabditis briggsae: a platform for comparative genomics. PLoS Biol. 1, 166–192 (2003)

  25. 25

    Kondrashov, A. S. & Houle, D. Genotype–environment interactions and the estimation of the genomic mutation rate in Drosophila melanogaster. Proc. R. Soc. Lond. B 258, 221–227 (1994)

  26. 26

    Higgins, D. G., Thompson, J. D. & Gibson, T. J. Using CLUSTAL for multiple sequence alignments. Methods Enzymol. 266, 383–402 (1994)

  27. 27

    Hill, F., Gemund, C., Benes, V., Ansorge, W. & Gibson, T. J. An estimate of large-scale sequencing accuracy. EMBO Rep. 1, 29–31 (2000)

  28. 28

    Richterich, P. Estimation of errors in ‘raw’ DNA sequences: a validation study. Genome Res. 8, 251–259 (1998)

  29. 29

    Denver, D. R. et al. Abundance, distribution, and mutation rates of homopolymeric nucleotide runs in the genome of Caenorhabditis elegans. J. Mol. Evol. 58, 584–595 (2004)

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We thank L. L. Vassilieva, S. Estes, V. Katju and C. Steding for their respective roles in propagating and maintaining the MA lines over the past 5 years; D. Ash for help with primer sequence design and DNA sequencing; and the Caenorhabditis Genetics Center for providing the C. elegans natural isolates. This work was supported by a University of Missouri Research Board grant to W.K.T., and an NIH grant to M.L. and W.K.T.

Author information


  1. Department of Biology, Indiana University, Bloomington, Indiana, 47405, USA

    • Dee R. Denver
    •  & Michael Lynch
  2. Hubbard Center for Genome Studies, University of New Hampshire, Durham, New Hampshire, 03824, USA

    • Krystalynne Morris
    •  & W. Kelley Thomas


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Competing interests

The authors declare that they have no competing financial interests.

Corresponding author

Correspondence to Dee R. Denver.

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  1. Supplementary Information

    This includes Table S1 and Figures S1 and S2 with their respective legends. (DOC 229 kb)

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