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. 2000 Nov;156(3):1299–1308. doi: 10.1093/genetics/156.3.1299

Rates of nucleotide substitution and mammalian nuclear gene evolution. Approximate and maximum-likelihood methods lead to different conclusions.

J P Bielawski 1, K A Dunn 1, Z Yang 1
PMCID: PMC1461304  PMID: 11063703

Abstract

Rates and patterns of synonymous and nonsynonymous substitutions have important implications for the origin and maintenance of mammalian isochores and the effectiveness of selection at synonymous sites. Previous studies of mammalian nuclear genes largely employed approximate methods to estimate rates of nonsynonymous and synonymous substitutions. Because these methods did not account for major features of DNA sequence evolution such as transition/transversion rate bias and unequal codon usage, they might not have produced reliable results. To evaluate the impact of the estimation method, we analyzed a sample of 82 nuclear genes from the mammalian orders Artiodactyla, Primates, and Rodentia using both approximate and maximum-likelihood methods. Maximum-likelihood analysis indicated that synonymous substitution rates were positively correlated with GC content at the third codon positions, but independent of nonsynonymous substitution rates. Approximate methods, however, indicated that synonymous substitution rates were independent of GC content at the third codon positions, but were positively correlated with nonsynonymous rates. Failure to properly account for transition/transversion rate bias and unequal codon usage appears to have caused substantial biases in approximate estimates of substitution rates.

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Selected References

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  1. Akashi H. Synonymous codon usage in Drosophila melanogaster: natural selection and translational accuracy. Genetics. 1994 Mar;136(3):927–935. doi: 10.1093/genetics/136.3.927. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alvarez-Valin F., Jabbari K., Bernardi G. Synonymous and nonsynonymous substitutions in mammalian genes: intragenic correlations. J Mol Evol. 1998 Jan;46(1):37–44. doi: 10.1007/pl00006281. [DOI] [PubMed] [Google Scholar]
  3. Bernardi G., Bernardi G. Compositional constraints and genome evolution. J Mol Evol. 1986;24(1-2):1–11. doi: 10.1007/BF02099946. [DOI] [PubMed] [Google Scholar]
  4. Bernardi G., Mouchiroud D., Gautier C., Bernardi G. Compositional patterns in vertebrate genomes: conservation and change in evolution. J Mol Evol. 1988 Dec;28(1-2):7–18. doi: 10.1007/BF02143493. [DOI] [PubMed] [Google Scholar]
  5. Bernardi G., Mouchiroud D., Gautier C. Silent substitutions in mammalian genomes and their evolutionary implications. J Mol Evol. 1993 Dec;37(6):583–589. doi: 10.1007/BF00182744. [DOI] [PubMed] [Google Scholar]
  6. Bernardi G., Olofsson B., Filipski J., Zerial M., Salinas J., Cuny G., Meunier-Rotival M., Rodier F. The mosaic genome of warm-blooded vertebrates. Science. 1985 May 24;228(4702):953–958. doi: 10.1126/science.4001930. [DOI] [PubMed] [Google Scholar]
  7. Bernardi G. The vertebrate genome: isochores and evolution. Mol Biol Evol. 1993 Jan;10(1):186–204. doi: 10.1093/oxfordjournals.molbev.a039994. [DOI] [PubMed] [Google Scholar]
  8. Bulmer M., Wolfe K. H., Sharp P. M. Synonymous nucleotide substitution rates in mammalian genes: implications for the molecular clock and the relationship of mammalian orders. Proc Natl Acad Sci U S A. 1991 Jul 15;88(14):5974–5978. doi: 10.1073/pnas.88.14.5974. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Clay O., Cacciò S., Zoubak S., Mouchiroud D., Bernardi G. Human coding and noncoding DNA: compositional correlations. Mol Phylogenet Evol. 1996 Feb;5(1):2–12. doi: 10.1006/mpev.1996.0002. [DOI] [PubMed] [Google Scholar]
  10. Eyre-Walker A. DNA mismatch repair and synonymous codon evolution in mammals. Mol Biol Evol. 1994 Jan;11(1):88–98. doi: 10.1093/oxfordjournals.molbev.a040095. [DOI] [PubMed] [Google Scholar]
  11. Eyre-Walker A. Evidence of selection on silent site base composition in mammals: potential implications for the evolution of isochores and junk DNA. Genetics. 1999 Jun;152(2):675–683. doi: 10.1093/genetics/152.2.675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Filipski J. Why the rate of silent codon substitutions is variable within a vertebrate's genome. J Theor Biol. 1988 Sep 17;134(2):159–164. doi: 10.1016/s0022-5193(88)80199-1. [DOI] [PubMed] [Google Scholar]
  13. Francino M. P., Ochman H. Isochores result from mutation not selection. Nature. 1999 Jul 1;400(6739):30–31. doi: 10.1038/21804. [DOI] [PubMed] [Google Scholar]
  14. Galtier N., Mouchiroud D. Isochore evolution in mammals: a human-like ancestral structure. Genetics. 1998 Dec;150(4):1577–1584. doi: 10.1093/genetics/150.4.1577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Goldman N., Yang Z. A codon-based model of nucleotide substitution for protein-coding DNA sequences. Mol Biol Evol. 1994 Sep;11(5):725–736. doi: 10.1093/oxfordjournals.molbev.a040153. [DOI] [PubMed] [Google Scholar]
  16. Graur D. Amino acid composition and the evolutionary rates of protein-coding genes. J Mol Evol. 1985;22(1):53–62. doi: 10.1007/BF02105805. [DOI] [PubMed] [Google Scholar]
  17. Lanave C., Preparata G., Saccone C., Serio G. A new method for calculating evolutionary substitution rates. J Mol Evol. 1984;20(1):86–93. doi: 10.1007/BF02101990. [DOI] [PubMed] [Google Scholar]
  18. Li W. H., Wu C. I., Luo C. C. A new method for estimating synonymous and nonsynonymous rates of nucleotide substitution considering the relative likelihood of nucleotide and codon changes. Mol Biol Evol. 1985 Mar;2(2):150–174. doi: 10.1093/oxfordjournals.molbev.a040343. [DOI] [PubMed] [Google Scholar]
  19. Makalowski W., Boguski M. S. Synonymous and nonsynonymous substitution distances are correlated in mouse and rat genes. J Mol Evol. 1998 Aug;47(2):119–121. doi: 10.1007/pl00006367. [DOI] [PubMed] [Google Scholar]
  20. Matassi G., Sharp P. M., Gautier C. Chromosomal location effects on gene sequence evolution in mammals. 1999 Jul 29-Aug 12Curr Biol. 9(15):786–791. doi: 10.1016/s0960-9822(99)80361-3. [DOI] [PubMed] [Google Scholar]
  21. Miyata T., Hayashida H., Kikuno R., Hasegawa M., Kobayashi M., Koike K. Molecular clock of silent substitution: at least six-fold preponderance of silent changes in mitochondrial genes over those in nuclear genes. J Mol Evol. 1982;19(1):28–35. doi: 10.1007/BF02100221. [DOI] [PubMed] [Google Scholar]
  22. Mouchiroud D., D'Onofrio G., Aïssani B., Macaya G., Gautier C., Bernardi G. The distribution of genes in the human genome. Gene. 1991 Apr;100:181–187. doi: 10.1016/0378-1119(91)90364-h. [DOI] [PubMed] [Google Scholar]
  23. Mouchiroud D., Gautier C., Bernardi G. Frequencies of synonymous substitutions in mammals are gene-specific and correlated with frequencies of nonsynonymous substitutions. J Mol Evol. 1995 Jan;40(1):107–113. doi: 10.1007/BF00166602. [DOI] [PubMed] [Google Scholar]
  24. Mouchiroud D., Gautier C. Codon usage changes and sequence dissimilarity between human and rat. J Mol Evol. 1990 Aug;31(2):81–91. doi: 10.1007/BF02109477. [DOI] [PubMed] [Google Scholar]
  25. Muse S. V., Gaut B. S. A likelihood approach for comparing synonymous and nonsynonymous nucleotide substitution rates, with application to the chloroplast genome. Mol Biol Evol. 1994 Sep;11(5):715–724. doi: 10.1093/oxfordjournals.molbev.a040152. [DOI] [PubMed] [Google Scholar]
  26. Ohta T., Ina Y. Variation in synonymous substitution rates among mammalian genes and the correlation between synonymous and nonsynonymous divergences. J Mol Evol. 1995 Dec;41(6):717–720. doi: 10.1007/BF00173150. [DOI] [PubMed] [Google Scholar]
  27. Pamilo P., Bianchi N. O. Evolution of the Zfx and Zfy genes: rates and interdependence between the genes. Mol Biol Evol. 1993 Mar;10(2):271–281. doi: 10.1093/oxfordjournals.molbev.a040003. [DOI] [PubMed] [Google Scholar]
  28. Powell J. R., Moriyama E. N. Evolution of codon usage bias in Drosophila. Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):7784–7790. doi: 10.1073/pnas.94.15.7784. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Saccone C., Pesole G., Preparata G. DNA microenvironments and the molecular clock. J Mol Evol. 1989 Nov;29(5):407–411. doi: 10.1007/BF02602910. [DOI] [PubMed] [Google Scholar]
  30. Shields D. C., Sharp P. M., Higgins D. G., Wright F. "Silent" sites in Drosophila genes are not neutral: evidence of selection among synonymous codons. Mol Biol Evol. 1988 Nov;5(6):704–716. doi: 10.1093/oxfordjournals.molbev.a040525. [DOI] [PubMed] [Google Scholar]
  31. Smith N. G., Hurst L. D. The effect of tandem substitutions on the correlation between synonymous and nonsynonymous rates in rodents. Genetics. 1999 Nov;153(3):1395–1402. doi: 10.1093/genetics/153.3.1395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Ticher A., Graur D. Nucleic acid composition, codon usage, and the rate of synonymous substitution in protein-coding genes. J Mol Evol. 1989 Apr;28(4):286–298. doi: 10.1007/BF02103424. [DOI] [PubMed] [Google Scholar]
  33. 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]
  34. Wolfe K. H., Sharp P. M. Mammalian gene evolution: nucleotide sequence divergence between mouse and rat. J Mol Evol. 1993 Oct;37(4):441–456. doi: 10.1007/BF00178874. [DOI] [PubMed] [Google Scholar]
  35. Wright F. The 'effective number of codons' used in a gene. Gene. 1990 Mar 1;87(1):23–29. doi: 10.1016/0378-1119(90)90491-9. [DOI] [PubMed] [Google Scholar]
  36. Yang Z., Nielsen R. Estimating synonymous and nonsynonymous substitution rates under realistic evolutionary models. Mol Biol Evol. 2000 Jan;17(1):32–43. doi: 10.1093/oxfordjournals.molbev.a026236. [DOI] [PubMed] [Google Scholar]
  37. Yang Z., Nielsen R. Synonymous and nonsynonymous rate variation in nuclear genes of mammals. J Mol Evol. 1998 Apr;46(4):409–418. doi: 10.1007/pl00006320. [DOI] [PubMed] [Google Scholar]

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