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