Synonymous and nonsynonymous substitutions in mammalian genes and the nearly neutral theory

Abstract

The nearly neutral theory of molecular evolution predicts larger generation-time effects for synonymous than for nonsynonymous substitutions. This prediction is tested using the sequences of 49 single-copy genes by calculating the average and variance of synonymous and nonsynonymous substitutions in mammalian star phylogenies (rodentia, artiodactyla, and primates). The average pattern of the 49 genes supports the prediction of the nearly neutral theory, with some notable exceptions.

The nearly neutral theory also predicts that the variance of the evolutionary rate is larger than the value predicted by the completely neutral theory. This prediction is tested by examining the dispersion index (ratio of the variance to the mean), which is positively correlated with the average substitution number. After weighting by the lineage effects, this correlation almost disappears for nonsynonymous substitutions, but not quite so for synonymous substitutions. After weighting, the dispersion indices of both synonymous and nonsynonymous substitutions still exceed values expected under the simple Poisson process. The results indicate that both the systematic bias in evolutionary rate among the lineages and the episodic type of rate variation are contributing to the large variance. The former is more significant to synonymous substitutions than to nonsynonymous substitutions. Isochore evolution may be similar to synonymous substitutions. The rate and pattern found here are consistent with the nearly neutral theory, such that the relative contributions of drift and selection differ between the two types of substitutions. The results are also consistent with Gillespie's episodic selection theory.

This is a preview of subscription content, log in to check access.

References

  1. Bernardi G (1989) The isochore organization of the human genome. Ann Rev Genet 23:637–661

    Google Scholar 

  2. Bernardi G, Olofsson B, Filipski J, Zerial M, Salinas J, Cuny G, Meunier-Rotival M, Rodier F (1985) The mosaic genome of warmblooded vertebrates. Science 228:953–958

    Google Scholar 

  3. Borriello F, Krauter KS (1991) Multiple murine α1-protease inhibitor genes show unusual evolutionary divergence. Proc Natl Acad Sci USA 88:9417–9421

    Google Scholar 

  4. Bulmer M (1989) Estimating the variability of substitution rates. Genetics 123:615–619

    Google Scholar 

  5. Chao L, Carr DE (1993) The molecular clock and the relationship between population size and generation time. Evolution 47:688–690

    Google Scholar 

  6. Chen EY, Liao YC, Smith DH, Barrera-Saldana HA, Gelinas RE, Seeburg PH (1989) The human growth hormone locus: nucleotide sequence, biology and evolution. Genomics 4:479–497

    Google Scholar 

  7. Easteal S (1990) The pattern of mammalian evolution and the relative rate of molecular evolution. Genetics 124:165–173

    Google Scholar 

  8. Easteal S, Collet C (1994) Consistent variation in amino-acid substitution rate, despite uniformity of mutation rate: protein evolution in mammals is not neutral. Mol Biol Evol 11:643–647

    Google Scholar 

  9. Fitch DHA, Bailey WJ, Tagle DA, Goodman M, Sieu L, Slightom JL (1991) Duplication of the γ-globin gene mediated by repetitive L1 LINE sequences in an early ancestor of simian primates. Proc Natl Acad Sci USA 88:7396–7400

    Google Scholar 

  10. Gillespie JH (1987) Molecular evolution and the neutral allele theory. Oxf Surv Evol Biol 4:10–37

    Google Scholar 

  11. Gillespie JH (1991) The causes of molecular evolution. Oxford University Press, Oxford

    Google Scholar 

  12. Holmquist G (1992) Review article: chromosome bands, their chromatin flavors and their functional features. Am J Hum Genet 51:17–37

    Google Scholar 

  13. Ina Y (1992) ODEN. National Institute of Genetics, Mishima, Japan

    Google Scholar 

  14. Ina Y (1994) New methods for estimating the numbers of synonymous and nonsynonymous substitutions. J Mol Evol (in press)

  15. Irwin DM, Wilson AC (1990) Concerted evolution of ruminant stomach lysozymes. J Biol Chem 265:4944–4952

    Google Scholar 

  16. Kimura M (1981) Possibility of extensive neutral evolution under stabilizing selection with special reference to nonrandom usage of synonymous codons. Proc Natl Acad Sci USA 78:5773–5777

    Google Scholar 

  17. Kimura M (1983) The neutral theory of molecular evolution. Cambridge University Press, Cambridge

    Google Scholar 

  18. Li W-H (1993) Unbiased estimation of the rates of synonymous and nonsynonymous substitution. J Mol Evol 36:96–99

    Google Scholar 

  19. Li W-H, Grant D (1991) Fundamentals of molecular evolution. Sinauer, Sunderland

    Google Scholar 

  20. Nei M, Gojobori T (1986) Simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions. Mol Biol Evol 3:418–426

    Google Scholar 

  21. Ohta T (1973) Slightly deleterious mutant substitutions in evolution. Nature 246:96–98

    Google Scholar 

  22. Ohta T (1974) Mutational pressure as the main cause of molecular evolution and polymorphisms. Nature 252:351–354

    Google Scholar 

  23. Ohta T (1991) Multigene families and the evolution of complexity. J Mol Evol 33:34–41

    Google Scholar 

  24. Ohta T (1992) The nearly neutral theory of molecular evolution. Ann Rev Syst Ecol 23:263–286

    Google Scholar 

  25. Ohta T (1993a) An examination of the generation-time effect on molecular evolution. Proc Natl Acad Sci USA 90:10676–10680

    Google Scholar 

  26. Ohta T (1993b) Pattern of nucleotide substitutions in growth hormone-prolactin gene family: a paradigm for evolution by gene duplication. Genetics 134:1271–1276

    Google Scholar 

  27. Ohta T (1994a) Further examples of evolution by gene duplication revealed through DNA sequence comparisons. Genetics (in press)

  28. Ohta T (1994b) On hypervariability at the reactive centre of proteolytic enzymes and their inhibitors. J Mol Evol (in press)

  29. Parmacek MS, Bengur AR, Vara AJ, Leiden JM (1990) The structure and regulation of expression of the murine fast skeletal troponin C gene. J Biol Chem 265:15970–15976

    Google Scholar 

  30. Rheaume C, Goodwin RL, Latimer JJ, Baumann H, Berger FG (1994) Evolution of routine α1-proteinase inhibitors: gene amplification and reactive center divergence. J Mol Evol 38:121–131

    Google Scholar 

  31. Wallis M (1994) Variable evolutionary rates in the molecular evolution of mammalian growth hormone. J Mol Evol 38:619–627

    Google Scholar 

  32. Wolfe KH, Sharp PM (1993) Mammalian gene evolution: nucleotide sequence divergence between mouse and rat. J Mol Evol 37:441–456

    Google Scholar 

  33. Wolfe KH, Sharp PM, Li W-H (1989) Mutation rates differ among regions of the mammalian genome. Nature 337:283–285

    Google Scholar 

  34. Yokoyama S, Yokoyama R (1990) Molecular evolution of visual pigment genes and other G-protein-coupled genes. In: Takahata, N, Crow JF (eds) Population biology of genes and molecules. Baifukan, Tokyo

    Google Scholar 

Download references

Author information

Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Tomoko, O. Synonymous and nonsynonymous substitutions in mammalian genes and the nearly neutral theory. J Mol Evol 40, 56–63 (1995). https://doi.org/10.1007/BF00166595

Download citation

Key words

  • Nearly neutral theory
  • Synonymous substitution
  • Nonsynonymous substitution
  • Mammalian genes