• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of geneticsGeneticsCurrent IssueInformation for AuthorsEditorial BoardSubscribeSubmit a Manuscript
Genetics. Nov 2003; 165(3): 1587–1597.
PMCID: PMC1462865

The problem of counting sites in the estimation of the synonymous and nonsynonymous substitution rates: implications for the correlation between the synonymous substitution rate and codon usage bias.

Abstract

Most methods for estimating the rate of synonymous and nonsynonymous substitution per site define a site as a mutational opportunity: the proportion of sites that are synonymous is equal to the proportion of mutations that would be synonymous under the model of evolution being considered. Here we demonstrate that this definition of a site can give misleading results and that a physical definition of site should be used in some circumstances. We illustrate our point by reexamining the relationship between codon usage bias and the synonymous substitution rate. It has recently been shown that the rate of synonymous substitution, calculated using the Goldman-Yang method, which encapsulates the mutational-opportunity definition of a site at a high level of sophistication, is either positively correlated or uncorrelated to synonymous codon bias in Drosophila. Using other methods, which account for synonymous codon bias but define a site physically, we show that there is a negative correlation between the synonymous substitution rate and codon bias and that the lack of a negative correlation using the Goldman-Yang method is due to the way in which the number of synonymous sites is counted. We also show that there is a positive correlation between the synonymous substitution rate and third position GC content in mammals, but that the relationship is considerably weaker than that obtained using the Goldman-Yang method. We argue that the Goldman-Yang method is misleading in this context and conclude that methods that rely on a mutational-opportunity definition of a site should be used with caution.

Full Text

The Full Text of this article is available as a PDF (146K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Li WH, Wu CI, Luo CC. 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. [PubMed]
  • Akashi H. Synonymous codon usage in Drosophila melanogaster: natural selection and translational accuracy. Genetics. 1994 Mar;136(3):927–935. [PMC free article] [PubMed]
  • Moriyama EN, Hartl DL. Codon usage bias and base composition of nuclear genes in Drosophila. Genetics. 1993 Jul;134(3):847–858. [PMC free article] [PubMed]
  • Berg OG, Martelius M. Synonymous substitution-rate constants in Escherichia coli and Salmonella typhimurium and their relationship to gene expression and selection pressure. J Mol Evol. 1995 Oct;41(4):449–456. [PubMed]
  • Muse SV. Estimating synonymous and nonsynonymous substitution rates. Mol Biol Evol. 1996 Jan;13(1):105–114. [PubMed]
  • Muse SV, Gaut BS. 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. [PubMed]
  • Bernardi G, Mouchiroud D, Gautier C. Silent substitutions in mammalian genomes and their evolutionary implications. J Mol Evol. 1993 Dec;37(6):583–589. [PubMed]
  • Nei M, Gojobori T. Simple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions. Mol Biol Evol. 1986 Sep;3(5):418–426. [PubMed]
  • Betancourt Andrea J, Presgraves Daven C. Linkage limits the power of natural selection in Drosophila. Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13616–13620. [PMC free article] [PubMed]
  • Pamilo P, Bianchi NO. Evolution of the Zfx and Zfy genes: rates and interdependence between the genes. Mol Biol Evol. 1993 Mar;10(2):271–281. [PubMed]
  • Bielawski JP, Dunn KA, Yang Z. Rates of nucleotide substitution and mammalian nuclear gene evolution. Approximate and maximum-likelihood methods lead to different conclusions. Genetics. 2000 Nov;156(3):1299–1308. [PMC free article] [PubMed]
  • Perler F, Efstratiadis A, Lomedico P, Gilbert W, Kolodner R, Dodgson J. The evolution of genes: the chicken preproinsulin gene. Cell. 1980 Jun;20(2):555–566. [PubMed]
  • Sharp PM, Li WH. The rate of synonymous substitution in enterobacterial genes is inversely related to codon usage bias. Mol Biol Evol. 1987 May;4(3):222–230. [PubMed]
  • Bulmer M, Wolfe KH, Sharp PM. 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. [PMC free article] [PubMed]
  • Sharp PM, Li WH. On the rate of DNA sequence evolution in Drosophila. J Mol Evol. 1989 May;28(5):398–402. [PubMed]
  • Comeron JM. A method for estimating the numbers of synonymous and nonsynonymous substitutions per site. J Mol Evol. 1995 Dec;41(6):1152–1159. [PubMed]
  • Dunn KA, Bielawski JP, Yang Z. Substitution rates in Drosophila nuclear genes: implications for translational selection. Genetics. 2001 Jan;157(1):295–305. [PMC free article] [PubMed]
  • Eyre-Walker A, Bulmer M. Synonymous substitution rates in enterobacteria. Genetics. 1995 Aug;140(4):1407–1412. [PMC free article] [PubMed]
  • 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. [PubMed]
  • Tajima F, Nei M. Estimation of evolutionary distance between nucleotide sequences. Mol Biol Evol. 1984 Apr;1(3):269–285. [PubMed]
  • Hasegawa M, Kishino H, Yano T. Dating of the human-ape splitting by a molecular clock of mitochondrial DNA. J Mol Evol. 1985;22(2):160–174. [PubMed]
  • Tamura K. Estimation of the number of nucleotide substitutions when there are strong transition-transversion and G+C-content biases. Mol Biol Evol. 1992 Jul;9(4):678–687. [PubMed]
  • Ina Y. New methods for estimating the numbers of synonymous and nonsynonymous substitutions. J Mol Evol. 1995 Feb;40(2):190–226. [PubMed]
  • Tamura K, Nei M. Estimation of the number of nucleotide substitutions in the control region of mitochondrial DNA in humans and chimpanzees. Mol Biol Evol. 1993 May;10(3):512–526. [PubMed]
  • Wolfe KH, Sharp PM, Li WH. Mutation rates differ among regions of the mammalian genome. Nature. 1989 Jan 19;337(6204):283–285. [PubMed]
  • Kimura M. A simple method for estimating evolutionary rates of base substitutions through comparative studies of nucleotide sequences. J Mol Evol. 1980 Dec;16(2):111–120. [PubMed]
  • Yang Z. PAML: a program package for phylogenetic analysis by maximum likelihood. Comput Appl Biosci. 1997 Oct;13(5):555–556. [PubMed]
  • Kusumi Junko, Tsumura Yoshihiko, Yoshimaru Hiroshi, Tachida Hidenori. Molecular evolution of nuclear genes in Cupressacea, a group of conifer trees. Mol Biol Evol. 2002 May;19(5):736–747. [PubMed]

Articles from Genetics are provided here courtesy of Genetics Society of America

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...