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. 2000 Mar;154(3):1403–1417. doi: 10.1093/genetics/154.3.1403

Understanding the overdispersed molecular clock.

D J Cutler 1
PMCID: PMC1461005  PMID: 10757779

Abstract

Rates of molecular evolution at some protein-encoding loci are more irregular than expected under a simple neutral model of molecular evolution. This pattern of excessive irregularity in protein substitutions is often called the "overdispersed molecular clock" and is characterized by an index of dispersion, R(T) > 1. Assuming infinite sites, no recombination model of the gene R(T) is given for a general stationary model of molecular evolution. R(T) is shown to be affected by only three things: fluctuations that occur on a very slow time scale, advantageous or deleterious mutations, and interactions between mutations. In the absence of interactions, advantageous mutations are shown to lower R(T); deleterious mutations are shown to raise it. Previously described models for the overdispersed molecular clock are analyzed in terms of this work as are a few very simple new models. A model of deleterious mutations is shown to be sufficient to explain the observed values of R(T). Our current best estimates of R(T) suggest that either most mutations are deleterious or some key population parameter changes on a very slow time scale. No other interpretations seem plausible. Finally, a comment is made on how R(T) might be used to distinguish selective sweeps from background selection.

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Selected References

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  1. Araki H., Tachida H. Bottleneck effect on evolutionary rate in the nearly neutral mutation model. Genetics. 1997 Oct;147(2):907–914. doi: 10.1093/genetics/147.2.907. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Birky C. W., Jr, Walsh J. B. Effects of linkage on rates of molecular evolution. Proc Natl Acad Sci U S A. 1988 Sep;85(17):6414–6418. doi: 10.1073/pnas.85.17.6414. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Charlesworth B., Morgan M. T., Charlesworth D. The effect of deleterious mutations on neutral molecular variation. Genetics. 1993 Aug;134(4):1289–1303. doi: 10.1093/genetics/134.4.1289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cherry J. L. Should we expect substitution rate to depend on population size? Genetics. 1998 Oct;150(2):911–919. doi: 10.1093/genetics/150.2.911. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Gillespie J. H. A general model to account for enzyme variation in natural populations. V. The SAS--CFF model. Theor Popul Biol. 1978 Aug;14(1):1–45. doi: 10.1016/0040-5809(78)90002-3. [DOI] [PubMed] [Google Scholar]
  6. Gillespie J. H., Langley C. H. Are evolutionary rates really variable? J Mol Evol. 1979 Jun 8;13(1):27–34. doi: 10.1007/BF01732751. [DOI] [PubMed] [Google Scholar]
  7. Gillespie J. H. Substitution processes in molecular evolution. III. Deleterious alleles. Genetics. 1994 Nov;138(3):943–952. doi: 10.1093/genetics/138.3.943. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gillespie J. H. The molecular clock may be an episodic clock. Proc Natl Acad Sci U S A. 1984 Dec;81(24):8009–8013. doi: 10.1073/pnas.81.24.8009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Goldman N. Variance to mean ratio, R(t), for poisson processes on phylogenetic trees. Mol Phylogenet Evol. 1994 Sep;3(3):230–239. doi: 10.1006/mpev.1994.1025. [DOI] [PubMed] [Google Scholar]
  10. Hartl D. L., Dykhuizen D. E., Dean A. M. Limits of adaptation: the evolution of selective neutrality. Genetics. 1985 Nov;111(3):655–674. doi: 10.1093/genetics/111.3.655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Iwasa Y. Overdispersed molecular evolution in constant environments. J Theor Biol. 1993 Oct 7;164(3):373–393. doi: 10.1006/jtbi.1993.1161. [DOI] [PubMed] [Google Scholar]
  12. Kaplan N. L., Hudson R. R., Langley C. H. The "hitchhiking effect" revisited. Genetics. 1989 Dec;123(4):887–899. doi: 10.1093/genetics/123.4.887. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kimura M. Model of effectively neutral mutations in which selective constraint is incorporated. Proc Natl Acad Sci U S A. 1979 Jul;76(7):3440–3444. doi: 10.1073/pnas.76.7.3440. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Langley C. H., Fitch W. M. An examination of the constancy of the rate of molecular evolution. J Mol Evol. 1974;3(3):161–177. doi: 10.1007/BF01797451. [DOI] [PubMed] [Google Scholar]
  15. Nachman M. W., Boyer S. N., Aquadro C. F. Nonneutral evolution at the mitochondrial NADH dehydrogenase subunit 3 gene in mice. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6364–6368. doi: 10.1073/pnas.91.14.6364. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Nielsen R. Robustness of the estimator of the index of dispersion for DNA sequences. Mol Phylogenet Evol. 1997 Jun;7(3):346–351. doi: 10.1006/mpev.1997.0411. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Ohta T., Tachida H. Theoretical study of near neutrality. I. Heterozygosity and rate of mutant substitution. Genetics. 1990 Sep;126(1):219–229. doi: 10.1093/genetics/126.1.219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Ohta T, Gillespie JH. Development of Neutral and Nearly Neutral Theories. Theor Popul Biol. 1996 Apr;49(2):128–142. doi: 10.1006/tpbi.1996.0007. [DOI] [PubMed] [Google Scholar]
  20. Ota T., Kimura M. On the constancy of the evolutionary rate of cistrons. J Mol Evol. 1971;1(1):18–25. doi: 10.1007/BF01659391. [DOI] [PubMed] [Google Scholar]
  21. Tachida H. A study on a nearly neutral mutation model in finite populations. Genetics. 1991 May;128(1):183–192. doi: 10.1093/genetics/128.1.183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Takahata N., Ishii K., Matsuda H. Effect of temporal fluctuation of selection coefficient on gene frequency in a population. Proc Natl Acad Sci U S A. 1975 Nov;72(11):4541–4545. doi: 10.1073/pnas.72.11.4541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Takahata N. On the overdispersed molecular clock. Genetics. 1987 May;116(1):169–179. doi: 10.1093/genetics/116.1.169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Takahata N. Statistical models of the overdispersed molecular clock. Theor Popul Biol. 1991 Jun;39(3):329–344. doi: 10.1016/0040-5809(91)90027-d. [DOI] [PubMed] [Google Scholar]
  25. Watterson G. A. On the number of segregating sites in genetical models without recombination. Theor Popul Biol. 1975 Apr;7(2):256–276. doi: 10.1016/0040-5809(75)90020-9. [DOI] [PubMed] [Google Scholar]
  26. Zeng L. W., Comeron J. M., Chen B., Kreitman M. The molecular clock revisited: the rate of synonymous vs. replacement change in Drosophila. Genetica. 1998;102-103(1-6):369–382. [PubMed] [Google Scholar]

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