Estimate of the mutation rate per nucleotide in humans (original) (raw)

Abstract

Many previous estimates of the mutation rate in humans have relied on screens of visible mutants. We investigated the rate and pattern of mutations at the nucleotide level by comparing pseudogenes in humans and chimpanzees to (i) provide an estimate of the average mutation rate per nucleotide, (ii) assess heterogeneity of mutation rate at different sites and for different types of mutations, (iii) test the hypothesis that the X chromosome has a lower mutation rate than autosomes, and (iv) estimate the deleterious mutation rate. Eighteen processed pseudogenes were sequenced, including 12 on autosomes and 6 on the X chromosome. The average mutation rate was estimated to be approximately 2.5 x 10(-8) mutations per nucleotide site or 175 mutations per diploid genome per generation. Rates of mutation for both transitions and transversions at CpG dinucleotides are one order of magnitude higher than mutation rates at other sites. Single nucleotide substitutions are 10 times more frequent than length mutations. Comparison of rates of evolution for X-linked and autosomal pseudogenes suggests that the male mutation rate is 4 times the female mutation rate, but provides no evidence for a reduction in mutation rate that is specific to the X chromosome. Using conservative calculations of the proportion of the genome subject to purifying selection, we estimate that the genomic deleterious mutation rate (U) is at least 3. This high rate is difficult to reconcile with multiplicative fitness effects of individual mutations and suggests that synergistic epistasis among harmful mutations may be common.

Full Text

The Full Text of this article is available as a PDF (161.9 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anagnostopoulos T., Green P. M., Rowley G., Lewis C. M., Giannelli F. DNA variation in a 5-Mb region of the X chromosome and estimates of sex-specific/type-specific mutation rates. Am J Hum Genet. 1999 Feb;64(2):508–517. doi: 10.1086/302250. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Arnason U., Gullberg A., Janke A. Molecular timing of primate divergences as estimated by two nonprimate calibration points. J Mol Evol. 1998 Dec;47(6):718–727. doi: 10.1007/pl00006431. [DOI] [PubMed] [Google Scholar]
  3. Bird A. P. Gene number, noise reduction and biological complexity. Trends Genet. 1995 Mar;11(3):94–100. doi: 10.1016/S0168-9525(00)89009-5. [DOI] [PubMed] [Google Scholar]
  4. Crow J. F. The high spontaneous mutation rate: is it a health risk? Proc Natl Acad Sci U S A. 1997 Aug 5;94(16):8380–8386. doi: 10.1073/pnas.94.16.8380. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Drake J. W., Charlesworth B., Charlesworth D., Crow J. F. Rates of spontaneous mutation. Genetics. 1998 Apr;148(4):1667–1686. doi: 10.1093/genetics/148.4.1667. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dunham I., Shimizu N., Roe B. A., Chissoe S., Hunt A. R., Collins J. E., Bruskiewich R., Beare D. M., Clamp M., Smink L. J. The DNA sequence of human chromosome 22. Nature. 1999 Dec 2;402(6761):489–495. doi: 10.1038/990031. [DOI] [PubMed] [Google Scholar]
  7. Ellegren H., Fridolfsson A. K. Male-driven evolution of DNA sequences in birds. Nat Genet. 1997 Oct;17(2):182–184. doi: 10.1038/ng1097-182. [DOI] [PubMed] [Google Scholar]
  8. Eyre-Walker A., Keightley P. D. High genomic deleterious mutation rates in hominids. Nature. 1999 Jan 28;397(6717):344–347. doi: 10.1038/16915. [DOI] [PubMed] [Google Scholar]
  9. Fry J. D., Keightley P. D., Heinsohn S. L., Nuzhdin S. V. New estimates of the rates and effects of mildly deleterious mutation in Drosophila melanogaster. Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):574–579. doi: 10.1073/pnas.96.2.574. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Goodman M., Porter C. A., Czelusniak J., Page S. L., Schneider H., Shoshani J., Gunnell G., Groves C. P. Toward a phylogenetic classification of Primates based on DNA evidence complemented by fossil evidence. Mol Phylogenet Evol. 1998 Jun;9(3):585–598. doi: 10.1006/mpev.1998.0495. [DOI] [PubMed] [Google Scholar]
  11. Hammer M. F. A recent common ancestry for human Y chromosomes. Nature. 1995 Nov 23;378(6555):376–378. doi: 10.1038/378376a0. [DOI] [PubMed] [Google Scholar]
  12. Huang W., Chang B. H., Gu X., Hewett-Emmett D., Li W. Sex differences in mutation rate in higher primates estimated from AMG intron sequences. J Mol Evol. 1997 Apr;44(4):463–465. doi: 10.1007/pl00006166. [DOI] [PubMed] [Google Scholar]
  13. Hurst L. D., Ellegren H. Sex biases in the mutation rate. Trends Genet. 1998 Nov;14(11):446–452. doi: 10.1016/s0168-9525(98)01577-7. [DOI] [PubMed] [Google Scholar]
  14. Keightley P. D. Nature of deleterious mutation load in Drosophila. Genetics. 1996 Dec;144(4):1993–1999. doi: 10.1093/genetics/144.4.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Ketterling R. P., Vielhaber E., Bottema C. D., Schaid D. J., Cohen M. P., Sexauer C. L., Sommer S. S. Germ-line origins of mutation in families with hemophilia B: the sex ratio varies with the type of mutation. Am J Hum Genet. 1993 Jan;52(1):152–166. [PMC free article] [PubMed] [Google Scholar]
  16. Kibota T. T., Lynch M. Estimate of the genomic mutation rate deleterious to overall fitness in E. coli. Nature. 1996 Jun 20;381(6584):694–696. doi: 10.1038/381694a0. [DOI] [PubMed] [Google Scholar]
  17. Kimura M. Evolutionary rate at the molecular level. Nature. 1968 Feb 17;217(5129):624–626. doi: 10.1038/217624a0. [DOI] [PubMed] [Google Scholar]
  18. Kimura M., Maruyama T. The mutational load with epistatic gene interactions in fitness. Genetics. 1966 Dec;54(6):1337–1351. doi: 10.1093/genetics/54.6.1337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kondrashov A. S., Crow J. F. A molecular approach to estimating the human deleterious mutation rate. Hum Mutat. 1993;2(3):229–234. doi: 10.1002/humu.1380020312. [DOI] [PubMed] [Google Scholar]
  20. Koop B. F., Hood L. Striking sequence similarity over almost 100 kilobases of human and mouse T-cell receptor DNA. Nat Genet. 1994 May;7(1):48–53. doi: 10.1038/ng0594-48. [DOI] [PubMed] [Google Scholar]
  21. Kumar S., Hedges S. B. A molecular timescale for vertebrate evolution. Nature. 1998 Apr 30;392(6679):917–920. doi: 10.1038/31927. [DOI] [PubMed] [Google Scholar]
  22. Li W. H., Tanimura M., Sharp P. M. An evaluation of the molecular clock hypothesis using mammalian DNA sequences. J Mol Evol. 1987;25(4):330–342. doi: 10.1007/BF02603118. [DOI] [PubMed] [Google Scholar]
  23. Marshall E. A high-stakes gamble on genome sequencing. Science. 1999 Jun 18;284(5422):1906–1909. doi: 10.1126/science.284.5422.1906. [DOI] [PubMed] [Google Scholar]
  24. McVean G. T., Hurst L. D. Evidence for a selectively favourable reduction in the mutation rate of the X chromosome. Nature. 1997 Mar 27;386(6623):388–392. doi: 10.1038/386388a0. [DOI] [PubMed] [Google Scholar]
  25. Miyamoto M. M., Slightom J. L., Goodman M. Phylogenetic relations of humans and African apes from DNA sequences in the psi eta-globin region. Science. 1987 Oct 16;238(4825):369–373. doi: 10.1126/science.3116671. [DOI] [PubMed] [Google Scholar]
  26. Miyata T., Hayashida H., Kuma K., Mitsuyasu K., Yasunaga T. Male-driven molecular evolution: a model and nucleotide sequence analysis. Cold Spring Harb Symp Quant Biol. 1987;52:863–867. doi: 10.1101/sqb.1987.052.01.094. [DOI] [PubMed] [Google Scholar]
  27. Mukai T., Chigusa S. I., Mettler L. E., Crow J. F. Mutation rate and dominance of genes affecting viability in Drosophila melanogaster. Genetics. 1972 Oct;72(2):335–355. doi: 10.1093/genetics/72.2.335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Ohta T. Synonymous and nonsynonymous substitutions in mammalian genes and the nearly neutral theory. J Mol Evol. 1995 Jan;40(1):56–63. doi: 10.1007/BF00166595. [DOI] [PubMed] [Google Scholar]
  29. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  30. Shimmin L. C., Chang B. H., Li W. H. Male-driven evolution of DNA sequences. Nature. 1993 Apr 22;362(6422):745–747. doi: 10.1038/362745a0. [DOI] [PubMed] [Google Scholar]
  31. Smith N. G., Hurst L. D. The causes of synonymous rate variation in the rodent genome. Can substitution rates be used to estimate the sex bias in mutation rate? Genetics. 1999 Jun;152(2):661–673. doi: 10.1093/genetics/152.2.661. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Sommer S. S., Ketterling R. P. The factor IX gene as a model for analysis of human germline mutations: an update. Hum Mol Genet. 1996;5(Spec No):1505–1514. doi: 10.1093/hmg/5.supplement_1.1505. [DOI] [PubMed] [Google Scholar]
  33. Sommer S. S. Recent human germ-line mutation: inferences from patients with hemophilia B. Trends Genet. 1995 Apr;11(4):141–147. doi: 10.1016/s0168-9525(00)89028-9. [DOI] [PubMed] [Google Scholar]
  34. Takahata N., Satta Y. Evolution of the primate lineage leading to modern humans: phylogenetic and demographic inferences from DNA sequences. Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4811–4815. doi: 10.1073/pnas.94.9.4811. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Wolfe K. H., Sharp P. M., Li W. H. Mutation rates differ among regions of the mammalian genome. Nature. 1989 Jan 19;337(6204):283–285. doi: 10.1038/337283a0. [DOI] [PubMed] [Google Scholar]