Skip to main content
PMC home page
Genetics logoLink to Genetics
. 2003 Jun;164(2):797–805. doi: 10.1093/genetics/164.2.797

Estimating mutation rate: how to count mutations?

Yun-Xin Fu 1, Haying Huai 1
PMCID: PMC1462584  PMID: 12807798

Abstract

Mutation rate is an essential parameter in genetic research. Counting the number of mutant individuals provides information for a direct estimate of mutation rate. However, mutant individuals in the same family can share the same mutations due to premeiotic mutation events, so that the number of mutant individuals can be significantly larger than the number of mutation events observed. Since mutation rate is more closely related to the number of mutation events, whether one should count only independent mutation events or the number of mutants remains controversial. We show in this article that counting mutant individuals is a correct approach for estimating mutation rate, while counting only mutation events will result in underestimation. We also derived the variance of the mutation-rate estimate, which allows us to examine a number of important issues about the design of such experiments. The general strategy of such an experiment should be to sample as many families as possible and not to sample much more offspring per family than the reciprocal of the pairwise correlation coefficient within each family. To obtain a reasonably accurate estimate of mutation rate, the number of sampled families needs to be in the same or higher order of magnitude as the reciprocal of the mutation rate.

Full Text

The Full Text of this article is available as a PDF (111.9 KB).

Selected References

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

  1. AUERBACH C. Spontaneous mutations in dry spores of Neurospora crassa. Z Vererbungsl. 1959;90:335–346. doi: 10.1007/BF00888808. [DOI] [PubMed] [Google Scholar]
  2. Abrahamson S., Wolff S. Re-analysis of radiation-induced specific locus mutations in the mouse. Nature. 1976 Dec 23;264(5588):715–719. doi: 10.1038/264715a0. [DOI] [PubMed] [Google Scholar]
  3. Arrault Xavier, Michel Valérie, Quillardet Philippe, Hofnung Maurice, Touati Eliette. Comparison of kinetics of induction of DNA adducts and gene mutations by a nitrofuran compound, 7-methoxy-2-nitronaphtho[2,1-b]furan (R7000), in the caecum and small intestine of Big Blue mice. Mutagenesis. 2002 Jul;17(4):353–359. doi: 10.1093/mutage/17.4.353. [DOI] [PubMed] [Google Scholar]
  4. Badge R. M., Brookfield J. F. A novel repressor of P element transposition in Drosophila melanogaster. Genet Res. 1998 Feb;71(1):21–30. doi: 10.1017/s0016672397003066. [DOI] [PubMed] [Google Scholar]
  5. Brown A. J., Ross S. J., Alphey L. S., Flavell A. J., Gerasimova T. I. Instability in the ctMR2 strain of Drosophila melanogaster: role of P element functions and structure of revertants. Mol Gen Genet. 1989 Aug;218(2):208–213. doi: 10.1007/BF00331270. [DOI] [PubMed] [Google Scholar]
  6. Castle W. E. The Mutation Theory of Organic Evolution, from the Standpoint of Animal Breeding. Science. 1905 Apr 7;21(536):521–525. doi: 10.1126/science.21.536.521. [DOI] [PubMed] [Google Scholar]
  7. Crow J. F. How much do we know about spontaneous human mutation rates? Environ Mol Mutagen. 1993;21(2):122–129. doi: 10.1002/em.2850210205. [DOI] [PubMed] [Google Scholar]
  8. Dobzhansky T, Wright S. Genetics of Natural Populations. V. Relations between Mutation Rate and Accumulation of Lethals in Populations of Drosophila Pseudoobscura. Genetics. 1941 Jan;26(1):23–51. doi: 10.1093/genetics/26.1.23. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. 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]
  10. Drake J. W. Spontaneous mutation. Annu Rev Genet. 1991;25:125–146. doi: 10.1146/annurev.ge.25.120191.001013. [DOI] [PubMed] [Google Scholar]
  11. Drost J. B., Lee W. R. The developmental basis for germline mosaicism in mouse and Drosophila melanogaster. Genetica. 1998;102-103(1-6):421–443. [PubMed] [Google Scholar]
  12. Favor J., Neuhäuser-Klaus A. Genetic mosaicism in the house mouse. Annu Rev Genet. 1994;28:27–47. doi: 10.1146/annurev.ge.28.120194.000331. [DOI] [PubMed] [Google Scholar]
  13. Fu Y. X. A phylogenetic estimator of effective population size or mutation rate. Genetics. 1994 Feb;136(2):685–692. doi: 10.1093/genetics/136.2.685. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hartl D. L., Green M. M. Genetic studies of germinal mosaicism in Drosophila melanogaster using the mutable wc gene. Genetics. 1970 Jul;65(3):449–456. doi: 10.1093/genetics/65.3.449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Heddle J. A., Cosentino L., Dawod G., Swiger R. R., Paashuis-Lew Y. Why do stem cells exist? Environ Mol Mutagen. 1996;28(4):334–341. doi: 10.1002/(SICI)1098-2280(1996)28:4<334::AID-EM6>3.0.CO;2-B. [DOI] [PubMed] [Google Scholar]
  16. Huai H., Woodruff R. C. Clusters of identical new mutations can account for the "overdispersed" molecular clock. Genetics. 1997 Sep;147(1):339–348. doi: 10.1093/genetics/147.1.339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Huai H., Woodruff R. C. Clusters of new identical mutants and the fate of underdominant mutations. Genetica. 1998;102-103(1-6):489–505. [PubMed] [Google Scholar]
  18. Huai H., Woodruff R. C. With the correct concept of mutation rate, cluster mutations can explain the overdispersed molecular clock. Genetics. 1998 May;149(1):467–469. doi: 10.1093/genetics/149.1.467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Johnson T. Beneficial mutations, hitchhiking and the evolution of mutation rates in sexual populations. Genetics. 1999 Apr;151(4):1621–1631. doi: 10.1093/genetics/151.4.1621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Keightley P. D., Eyre-Walker A. Terumi Mukai and the riddle of deleterious mutation rates. Genetics. 1999 Oct;153(2):515–523. doi: 10.1093/genetics/153.2.515. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. 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]
  22. Lewis S. E. Life cycle of the mammalian germ cell: implication for spontaneous mutation frequencies. Teratology. 1999 Apr;59(4):205–209. doi: 10.1002/(SICI)1096-9926(199904)59:4<205::AID-TERA3>3.0.CO;2-Y. [DOI] [PubMed] [Google Scholar]
  23. Luria S. E., Delbrück M. Mutations of Bacteria from Virus Sensitivity to Virus Resistance. Genetics. 1943 Nov;28(6):491–511. doi: 10.1093/genetics/28.6.491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. MORGAN W. C. A new tail-short mutation in the mouse whose lethal effects are conditioned by the residual genotypes. J Hered. 1950 Aug;41(8):208–215. doi: 10.1093/oxfordjournals.jhered.a106131. [DOI] [PubMed] [Google Scholar]
  25. Margulies L., Briscoe D. I., Wallace S. S. The relationship between radiation-induced and transposon-induced genetic damage during Drosophila oogenesis. Mutat Res. 1986 Aug;162(1):55–68. doi: 10.1016/0027-5107(86)90071-0. [DOI] [PubMed] [Google Scholar]
  26. Mason J. M., Aaron C. S., Lee W. R., Smith P. D., Thakar A., Valencia R., Woodruff R. C., Würgler F. E., Zimmering S. A guide for performing germ cell mutagenesis assays using Drosophila melanogaster. Mutat Res. 1987 Oct;189(2):93–102. doi: 10.1016/0165-1218(87)90015-2. [DOI] [PubMed] [Google Scholar]
  27. Mason J. M., Valencia R., Woodruff R. C., Zimmering S. Genetic drift and seasonal variation in spontaneous mutation frequencies in Drosophila. Environ Mutagen. 1985;7(5):663–676. doi: 10.1002/em.2860070506. [DOI] [PubMed] [Google Scholar]
  28. Mohrenweiser H., Zingg B. Mosaicism: the embryo as a target for induction of mutations leading to cancer and genetic disease. Environ Mol Mutagen. 1995;25 (Suppl 26):21–29. doi: 10.1002/em.2850250606. [DOI] [PubMed] [Google Scholar]
  29. Neel J. V., Rothman E. D. Indirect estimates of mutation rates in tribal Amerindians. Proc Natl Acad Sci U S A. 1978 Nov;75(11):5585–5588. doi: 10.1073/pnas.75.11.5585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Nishino H., Schaid D. J., Buettner V. L., Haavik J., Sommer S. S. Mutation frequencies but not mutant frequencies in Big Blue mice fit a Poisson distribution. Environ Mol Mutagen. 1996;28(4):414–417. doi: 10.1002/(SICI)1098-2280(1996)28:4<414::AID-EM16>3.0.CO;2-I. [DOI] [PubMed] [Google Scholar]
  31. Paashuis-Lew Y. R., Heddle J. A. Spontaneous mutation during fetal development and post-natal growth. Mutagenesis. 1998 Nov;13(6):613–617. doi: 10.1093/mutage/13.6.613. [DOI] [PubMed] [Google Scholar]
  32. Purdom C. E., Dyer K. F., Papworth D. G. Allelic clusters among spontaneous mutations in Drosophila. Mutat Res. 1968 Mar-Apr;5(2):305–307. doi: 10.1016/0027-5107(68)90030-4. [DOI] [PubMed] [Google Scholar]
  33. Russell L. B., Russell W. L. Spontaneous mutations recovered as mosaics in the mouse specific-locus test. Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):13072–13077. doi: 10.1073/pnas.93.23.13072. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Russell W. L. Mutation frequencies in female mice and the estimation of genetic hazards of radiation in women. Proc Natl Acad Sci U S A. 1977 Aug;74(8):3523–3527. doi: 10.1073/pnas.74.8.3523. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Selby P. B. Discovery of numerous clusters of spontaneous mutations in the specific-locus test in mice necessitates major increases in estimates of doubling doses. Genetica. 1998;102-103(1-6):463–487. [PubMed] [Google Scholar]
  36. Selby P. B. Major impacts of gonadal mosaicism on hereditary risk estimation, origin of hereditary diseases, and evolution. Genetica. 1998;102-103(1-6):445–462. [PubMed] [Google Scholar]
  37. Shukla P. T., Sankaranarayanan K., Sobels F. H. Is there a proportionality between the spontaneous and the X-ray-induction rates of mutations? Experiments with mutations at 13 X-chromosome loci in Drosophila melanogaster. Mutat Res. 1979 Jul;61(2):229–248. doi: 10.1016/0027-5107(79)90130-1. [DOI] [PubMed] [Google Scholar]
  38. Spencer W. P., Stern C. Experiments to Test the Validity of the Linear R-Dose/Mutation Frequency Relation in Drosophila at Low Dosage. Genetics. 1948 Jan;33(1):43–74. doi: 10.1093/genetics/33.1.43. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Stuart G. R., Glickman B. W. Through a glass, darkly: reflections of mutation from lacI transgenic mice. Genetics. 2000 Jul;155(3):1359–1367. doi: 10.1093/genetics/155.3.1359. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Thompson J. N., Jr, Woodruff R. C., Huai H. Mutation rate: a simple concept has become complex. Environ Mol Mutagen. 1998;32(4):292–300. doi: 10.1002/(sici)1098-2280(1998)32:4<292::aid-em2>3.0.co;2-v. [DOI] [PubMed] [Google Scholar]
  41. Wijsman E. M. Recurrence risk of a new dominant mutation in children of unaffected parents. Am J Hum Genet. 1991 Apr;48(4):654–661. [PMC free article] [PubMed] [Google Scholar]
  42. Woodruff R. C., Huai H., Thompson J. N., Jr Clusters of identical new mutation in the evolutionary landscape. Genetica. 1996 Oct;98(2):149–160. doi: 10.1007/BF00121363. [DOI] [PubMed] [Google Scholar]
  43. Wright S, Eaton O N. Mutational Mosaic Coat Patterns of the Guinea Pig. Genetics. 1926 Jul;11(4):333–351. doi: 10.1093/genetics/11.4.333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Yang H. P., Tanikawa A. Y., Van Voorhies W. A., Silva J. C., Kondrashov A. S. Whole-genome effects of ethyl methanesulfonate-induced mutation on nine quantitative traits in outbred Drosophila melanogaster. Genetics. 2001 Mar;157(3):1257–1265. doi: 10.1093/genetics/157.3.1257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Zlotogora J. Germ line mosaicism. Hum Genet. 1998 Apr;102(4):381–386. doi: 10.1007/s004390050708. [DOI] [PubMed] [Google Scholar]
  46. van Essen A. J., Abbs S., Baiget M., Bakker E., Boileau C., van Broeckhoven C., Bushby K., Clarke A., Claustres M., Covone A. E. Parental origin and germline mosaicism of deletions and duplications of the dystrophin gene: a European study. Hum Genet. 1992 Jan;88(3):249–257. doi: 10.1007/BF00197255. [DOI] [PubMed] [Google Scholar]

Articles from Genetics are provided here courtesy of Oxford University Press

RESOURCES