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High genomic deleterious mutation rates in hominids

Abstract

It has been suggested that humans may suffer a high genomic deleterious mutation rate1,2. Here we test this hypothesis by applying a variant of a molecular approach3 to estimate the deleterious mutation rate in hominids from the level of selective constraint in DNA sequences. Under conservative assumptions, we estimate that an average of 4.2 amino-acid-altering mutations per diploid per generation have occurred in the human lineage since humans separated from chimpanzees. Of these mutations, we estimate that at least 38% have been eliminated by natural selection, indicating that there have been more than 1.6 new deleterious mutations per diploid genome per generation. Thus, the deleterious mutation rate specific to protein-coding sequences alone is close to the upper limit tolerable by a species such as humans that has a low reproductive rate4, indicating that the effects of deleterious mutations may have combined synergistically. Furthermore, the level of selective constraint in hominid protein-coding sequences is atypically low. A large number of slightly deleterious mutations may therefore have become fixed in hominid lineages.

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References

  1. Kondrashov, A. S. Contamination of the genomes by very slightly deleterious mutations. Why have we not died 100 times over? J. Theor. Biol. 175, 583–594 (1995).

    CAS  Article  PubMed  Google Scholar 

  2. Crow, J. F. The high spontaneous mutation rate: is it a health risk? Proc. Natl Acad. Sci. USA 94, 8380–8386 (1997).

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  4. Kimura, M. & Maruyama, T. The mutational load with episatic gene interactions in fitness. Genetics 54, 1337–1351 (1966).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Muller, H. J. Our load of mutations. Am. J. Hum. Genet. 2, 111–176 (1950).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Lande, R. Risk of population extinction from fixation of new deleterious mutations. Evolution 48, 1460–1469 (1994).

    Article  PubMed  Google Scholar 

  7. Charlesworth, B., Charlesworth, D. & Morgan, M. T. Genetic loads and estimates of mutation rates in highly inbred plant populations. Nature 347, 380–382 (1990).

    ADS  Article  Google Scholar 

  8. Simmons, M. J. & Crow, J. F. Mutations affecting fitness in Drosophila populations. Annu. Rev. Genet. 11, 49–78 (1977).

    CAS  Article  PubMed  Google Scholar 

  9. Keightley, P. D. Nature of deleterious mutation load in Drosophila. Genetics 144, 1993–1999 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Kimura, M. The Neutral Theory of Molecular Evolution (Cambridge Univ. Press, Cambridge, (1983)).

    Google Scholar 

  11. Wolfe, K. H., Sharp, P. M. & Li, W. -H. Mutation rates differ among regions of the mammalian genome. Nature 337, 283–285 (1989).

    ADS  CAS  Article  PubMed  Google Scholar 

  12. Fields, C., Adams, M. D. & Venter, J. C. How many genes in the human genome? Nature Genet. 7, 345–346 (1994).

    CAS  Article  PubMed  Google Scholar 

  13. Duret, L., Mouchiroud, D. & Gouy, M. HOVERGEN—a database of homologous vertebrate genes. Nucleic Acids Res. 22, 2360–2365 (1994).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. Goodman, M. et al. Toward a phylogenetic classification of primates based on DNA evidence complemented by fossil evidence. Mol. Phylogenet. Evol. 9, 585–598 (1998).

    CAS  Article  PubMed  Google Scholar 

  15. Kumar, S. & Blair Hedges, S. Amolecular timescale for vertebrate evolution. Nature 392, 917–920 (1998).

    ADS  CAS  Article  PubMed  Google Scholar 

  16. Antequera, F. & Bird, A. Number of CpG islands and genes in human and mouse. Proc. Natl Acad. Sci. USA 90, 11995–11999 (1993).

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. Hill, K. & Hurtado, A. M. Ache Life History: The Ecology and Demography of a Foraging People (Aldone de Gruyter, New York, (1996)).

    Google Scholar 

  18. Howell, N. Demography of the Dobe Kung (Academic, New York, (1979)).

    Google Scholar 

  19. Melancon, T. F. Marriage and Reproduction among the Yanomamo Indians of Venezuela.Thesis, Pennsylvania State Univ.(1982).

    Google Scholar 

  20. Nishida, T., Takasaki, H. & Takahata, Y. in The Chimpanzees of the Mahale Mountains (ed. Nishida, T.) 63–97 (Tokyo Univ. Press, Tokyo, (1990)).

    Google Scholar 

  21. Ophir, R. & Graur, D. Patterns and rates of indel evolution in processed pseudogenes from humans and murids. Gene 205, 191–202 (1997).

    CAS  Article  PubMed  Google Scholar 

  22. Li, W. -H. Molecular Evolution (Sinauer, Sunderland, Massachusetts, (1997)).

    Google Scholar 

  23. Ohta, T. Synonymous and nonsynonymous substitutions in mammalian genes and the nearly neutral theory. J. Mol. Evol. 40, 56–63 (1995).

    CAS  Article  PubMed  Google Scholar 

  24. Wolfe, K. H. & Sharp, P. M. Mammalian gene evolution—nucleotide-sequence divergence between mouse and rat. J. Mol. Evol. 37, 441–456 (1993).

    ADS  CAS  Article  PubMed  Google Scholar 

  25. Neel, J. V. et al. Search for mutations altering protein charge and/or function in children of atomic-bomb survivors—final report. Am. J. Hum. Genet. 42, 663–676 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Mohrenweiser, H. W. & Neel, J. V. Frequency of thermostability variants—estimation of total rare variant frequency in human populations. Proc. Natl Acad. Sci. USA 78, 5729–5733 (1981).

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. Drake, J. W. et al. Rates of spontaneous mutation. Genetics 148, 1667–1686 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Thompson, J. D. et al. The ClustalX windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res. 24, 4876–4882 (1997).

    ADS  Article  Google Scholar 

  29. Ina, Y. Estimation of the transition/transversion ratio. J. Mol. Evolv. 46, 521–533 (1998).

    ADS  CAS  Article  Google Scholar 

  30. Hammer, M. F. Arecent common ancestry for human Y chromosomes. Nature 378, 376–378 (1995).

    ADS  CAS  Article  PubMed  Google Scholar 

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Acknowledgements

We thank B. Charlesworth, J. F. Crow, E. K. Davies, W. G. Hill, T. Johnson, A. S. Kondrashov, G. McVean, J. R. Peck, A. D. Peters, M. W. Simmen, D. B. Smith and H. B. Trotter for comments and helpful discussions; K. H. Wolfe for a database of rodent gene sequences; and the Royal Society for support.

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Correspondence to Adam Eyre-Walker.

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Eyre-Walker, A., Keightley, P. High genomic deleterious mutation rates in hominids. Nature 397, 344–347 (1999). https://doi.org/10.1038/16915

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