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Are Radical and Conservative Substitution Rates Useful Statistics in Molecular Evolution?

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Abstract

A DNA mutation in a protein coding gene which causes an amino acid change can be classified as “conservative” or “radical” depending on the magnitude of the physicochemical difference between the two amino acids: radical mutations involve larger changes than conservative mutations. Here, I examine two key issues in determining whether radical and conservative substitution rates are useful statistics in molecular evolution. The first issue is whether such rates can be estimated reliably, and for this purpose I demonstrate considerable improvements achieved by simple modifications to an existing method. The second issue is whether conservative and radical substitution rates can tell us something about selection on protein function. I address this problem by estimating positive and negative selection on conservative and radical mutations using polymorphism and divergence data from Drosophila. These analyses show that negative selection, but not positive selection, differs significantly between conservative and radical mutations. The power of conservative and radical substitution rates in testing the nearly neutral theory of molecular evolution is illustrated by the analysis of two mammalian datasets.

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References

  1. CD Bustamante R Nielsen SA Sawyer KM Olsen MD Purugganan DL Hartl (2002) ArticleTitleThe cost of inbreeding in Arabidopsis. Nature 416 531–534 Occurrence Handle10.1038/416531a Occurrence Handle1:CAS:528:DC%2BD38XivVOntr0%3D Occurrence Handle11932744

    Article  CAS  PubMed  Google Scholar 

  2. T Dagan Y Talmor D Graur (2002) ArticleTitleRatios of radical to conservative amino acid replacement are affected by mutational and compositional factors and may not be indicative of positive Darwinian selection. Mol Biol Evol 19 1022–1025 Occurrence Handle1:CAS:528:DC%2BD38Xlt1aksbs%3D Occurrence Handle12082122

    CAS  PubMed  Google Scholar 

  3. MO Dayhoff RM Schwartz BC Orcutt (1978) A model of evolutionary change in proteins. MO Dayhoff (Eds) Atlas of protein sequence and structure. National Biomedical Research Foundation Washington, D.C. 345–352

    Google Scholar 

  4. L Duret D Mouchiroud (2000) ArticleTitleDeterminants of substitution rates in mammalian genes: expression pattern affects selection intensity but not mutation rate. Mol Biol Evol 17 68–74 Occurrence Handle1:CAS:528:DC%2BD3cXotF2quw%3D%3D Occurrence Handle10666707

    CAS  PubMed  Google Scholar 

  5. CJ Epstein (1966) ArticleTitleRole of the amino-acid “code” and of selection for conformation in the evolution of proteins. Nature 210 25–28 Occurrence Handle1:CAS:528:DyaF28XpsVOksg%3D%3D Occurrence Handle5956344

    CAS  PubMed  Google Scholar 

  6. A Eyre-Walker PD Keightley NGC Smith D Gaffney (2002) ArticleTitleQuantifying the slightly deleterious mutation model of molecular evolution. Mol Biol Evol 19 2142–2149 Occurrence Handle1:CAS:528:DC%2BD38Xps12hs7o%3D Occurrence Handle12446806

    CAS  PubMed  Google Scholar 

  7. RA Fisher (1930) The genetical theory of natural selection. Clarendon Press Oxford

    Google Scholar 

  8. D Gamerman (1997) Markov chain Monte Carlo. Chapman and Hall London

    Google Scholar 

  9. N Goldman Z Yang (1994) ArticleTitleA codon-based model of nucleotide substitution for protein-coding DNA sequences. Mol Biol Evol 11 725–736 Occurrence Handle7968486

    PubMed  Google Scholar 

  10. R Grantham (1974) ArticleTitleAmino acid difference formula to help explain protein evolution. Science 185 862–864 Occurrence Handle1:CAS:528:DyaE2cXlsVOiuro%3D Occurrence Handle4843792

    CAS  PubMed  Google Scholar 

  11. D Graur W-H Li (2000) Fundamentals of molecular evolution. Sinauer Sunderland, MA

    Google Scholar 

  12. AL Hughes JA Green JM Garbayo RM Roberts (2000) ArticleTitleAdaptive diversification within a large family of recently duplicated, placentally expressed genes. Proc Natl Acad Sci USA 97 3319–3323 Occurrence Handle10.1073/pnas.050002797 Occurrence Handle1:CAS:528:DC%2BD3cXitlWqsbo%3D Occurrence Handle10725351

    Article  CAS  PubMed  Google Scholar 

  13. AL Hughes T Ota M Nei (1990) ArticleTitlePositive Darwinian selection promotes charge profile diversity in the antigen binding cleft of class I MHC molecules. Mol Biol Evol 7 515–524 Occurrence Handle1:STN:280:By6C3szisF0%3D Occurrence Handle2283951

    CAS  PubMed  Google Scholar 

  14. TH Jukes CR Cantor (1969) Evolution of protein molecules. HN Munro (Eds) Mammalian protein metabolism. Academic Press New York 21–123

    Google Scholar 

  15. WH Li (1997) Molecular evolution. Sinauer Associates Sunderland, MA

    Google Scholar 

  16. P Lio N Goldman (1998) ArticleTitleModels of molecular evolution and phylogeny. Genome Res 8 1233–1244 Occurrence Handle1:CAS:528:DyaK1MXmtVSitQ%3D%3D Occurrence Handle9872979

    CAS  PubMed  Google Scholar 

  17. M Nei T Gojobori (1986) ArticleTitleSimple methods for estimating the numbers of synonymous and nonsynonymous nucleotide substitutions. Mol Biol Evol 3 418–426 Occurrence Handle1:CAS:528:DyaL28Xmt1aisbs%3D Occurrence Handle3444411

    CAS  PubMed  Google Scholar 

  18. T Ohta (1992) ArticleTitleThe nearly neutral theory of molecular evolution. Annu Rev Ecol Syst 23 263–286 Occurrence Handle10.1146/annurev.es.23.110192.001403

    Article  Google Scholar 

  19. SA Sawyer DL Hartl (1992) ArticleTitlePopulation genetics of polymorphism and divergence. Genetics 132 1161–1176 Occurrence Handle1:STN:280:ByyD1MzksVQ%3D Occurrence Handle1459433

    CAS  PubMed  Google Scholar 

  20. NGC Smith A Eyre-Walker (2002) ArticleTitleAdaptive protein evolution in Drosophila. Nature 415 1022–1024 Occurrence Handle10.1038/4151022a Occurrence Handle1:CAS:528:DC%2BD38XhvVWjsLs%3D Occurrence Handle11875568

    Article  CAS  PubMed  Google Scholar 

  21. Z Yang (1997) ArticleTitlePAML: A program package for phylogenetic analysis by maximum likelihood. Comput Appl Biosci 13 555–556 Occurrence Handle9367129

    PubMed  Google Scholar 

  22. Z Yang R Nielsen (2000) ArticleTitleEstimating synonymous and nonsynonymous substitution rates under realistic evolutionary models. Mol Biol Evol 17 32–43 Occurrence Handle1:CAS:528:DC%2BD3cXotF2qtA%3D%3D Occurrence Handle10666704

    CAS  PubMed  Google Scholar 

  23. ZH Yang JP Bielawski (2000) ArticleTitleStatistical methods for detecting molecular adaptation. Trends Ecol Evol 15 496–503 Occurrence Handle10.1016/S0169-5347(00)01994-7 Occurrence Handle11114436

    Article  PubMed  Google Scholar 

  24. J Zhang (2000) ArticleTitleRates of conservative and radical nonsynonymous nucleotide substitutions in mammalian nuclear genes. J Mol Evol 50 56–68 Occurrence Handle1:CAS:528:DC%2BD3cXotFSmtA%3D%3D Occurrence Handle10654260

    CAS  PubMed  Google Scholar 

  25. J Zhang Y-P Zhang HF Rosenberg (2002) ArticleTitleAdaptive evolution of a duplicated pancreatic ribonuclease gene in a leaf-eating monkey. Nat Gene 30 411–415 Occurrence Handle10.1038/ng852 Occurrence Handle1:CAS:528:DC%2BD38Xisl2lsLc%3D

    Article  CAS  Google Scholar 

  26. JZ Zhang HF Rosenberg M Nei (1998) ArticleTitlePositive Darwinian selection after gene duplication in primate ribonuclease genes. Proc Natl Acad Sci USA 95 3708 Occurrence Handle10.1073/pnas.95.7.3708 Occurrence Handle1:CAS:528:DyaK1cXitlKjtrc%3D Occurrence Handle9520431

    Article  CAS  PubMed  Google Scholar 

  27. E Zuckerkandl L Pauling (1965) Evolutionary divergence and convergence in proteins. V Bryson HJ Vogel (Eds) Evolving genes and proteins. Academic Press New York 97–166

    Google Scholar 

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Acknowledgements

Thanks to Jianzhi Zhang and one anonymous referee for suggesting numerous improvements, particularly the distinction between testing for the presence of positive selection and examining the nature of positive selection.

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  1. Department of Evolutionary Biology, Evolutionary Biology Centre, Uppsala University, Norbyvägen 18D, 752 36 Uppsala, Sweden

    Nick G. C. Smith

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  1. Nick G. C. Smith
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Correspondence to Nick G. C. Smith.

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Smith, N.G. Are Radical and Conservative Substitution Rates Useful Statistics in Molecular Evolution? . J Mol Evol 57, 467–478 (2003). https://doi.org/10.1007/s00239-003-2500-z

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  • DOI: https://doi.org/10.1007/s00239-003-2500-z

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