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.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
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).
Crow, J. F. The high spontaneous mutation rate: is it a health risk? Proc. Natl Acad. Sci. USA 94, 8380–8386 (1997).
Kondrashov, A. S. & Crow, J. F. Amolecular approach to estimating the human deleterious mutation rate. Hum. Mutat. 2, 229–234 (1993).
Kimura, M. & Maruyama, T. The mutational load with episatic gene interactions in fitness. Genetics 54, 1337–1351 (1966).
Muller, H. J. Our load of mutations. Am. J. Hum. Genet. 2, 111–176 (1950).
Lande, R. Risk of population extinction from fixation of new deleterious mutations. Evolution 48, 1460–1469 (1994).
Charlesworth, B., Charlesworth, D. & Morgan, M. T. Genetic loads and estimates of mutation rates in highly inbred plant populations. Nature 347, 380–382 (1990).
Simmons, M. J. & Crow, J. F. Mutations affecting fitness in Drosophila populations. Annu. Rev. Genet. 11, 49–78 (1977).
Keightley, P. D. Nature of deleterious mutation load in Drosophila. Genetics 144, 1993–1999 (1996).
Kimura, M. The Neutral Theory of Molecular Evolution (Cambridge Univ. Press, Cambridge, (1983)).
Wolfe, K. H., Sharp, P. M. & Li, W. -H. Mutation rates differ among regions of the mammalian genome. Nature 337, 283–285 (1989).
Fields, C., Adams, M. D. & Venter, J. C. How many genes in the human genome? Nature Genet. 7, 345–346 (1994).
Duret, L., Mouchiroud, D. & Gouy, M. HOVERGEN—a database of homologous vertebrate genes. Nucleic Acids Res. 22, 2360–2365 (1994).
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).
Kumar, S. & Blair Hedges, S. Amolecular timescale for vertebrate evolution. Nature 392, 917–920 (1998).
Antequera, F. & Bird, A. Number of CpG islands and genes in human and mouse. Proc. Natl Acad. Sci. USA 90, 11995–11999 (1993).
Hill, K. & Hurtado, A. M. Ache Life History: The Ecology and Demography of a Foraging People (Aldone de Gruyter, New York, (1996)).
Howell, N. Demography of the Dobe Kung (Academic, New York, (1979)).
Melancon, T. F. Marriage and Reproduction among the Yanomamo Indians of Venezuela.Thesis, Pennsylvania State Univ.(1982).
Nishida, T., Takasaki, H. & Takahata, Y. in The Chimpanzees of the Mahale Mountains (ed. Nishida, T.) 63–97 (Tokyo Univ. Press, Tokyo, (1990)).
Ophir, R. & Graur, D. Patterns and rates of indel evolution in processed pseudogenes from humans and murids. Gene 205, 191–202 (1997).
Li, W. -H. Molecular Evolution (Sinauer, Sunderland, Massachusetts, (1997)).
Ohta, T. Synonymous and nonsynonymous substitutions in mammalian genes and the nearly neutral theory. J. Mol. Evol. 40, 56–63 (1995).
Wolfe, K. H. & Sharp, P. M. Mammalian gene evolution—nucleotide-sequence divergence between mouse and rat. J. Mol. Evol. 37, 441–456 (1993).
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).
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).
Drake, J. W. et al. Rates of spontaneous mutation. Genetics 148, 1667–1686 (1998).
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).
Ina, Y. Estimation of the transition/transversion ratio. J. Mol. Evolv. 46, 521–533 (1998).
Hammer, M. F. Arecent common ancestry for human Y chromosomes. Nature 378, 376–378 (1995).
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.
About this article
Cite this article
Eyre-Walker, A., Keightley, P. High genomic deleterious mutation rates in hominids. Nature 397, 344–347 (1999). https://doi.org/10.1038/16915
Genetics Selection Evolution (2019)
Journal of the History of Biology (2019)
BMC Genomics (2018)
Genome Biology (2016)