Journal of Molecular Evolution

, Volume 57, Supplement 1, pp S154–S164 | Cite as

Bayesian Analysis Suggests that Most Amino Acid Replacements in Drosophila Are Driven by Positive Selection

  • Stanley A. Sawyer
  • Rob J. Kulathinal
  • Carlos D. Bustamante
  • Daniel L. HartlEmail author


One of the principal goals of population genetics is to understand the processes by which genetic variation within species (polymorphism) becomes converted into genetic differences between species (divergence). In this transformation, selective neutrality, near neutrality, and positive selection may each play a role, differing from one gene to the next. Synonymous nucleotide sites are often used as a uniform standard of comparison across genes on the grounds that synonymous sites are subject to relatively weak selective constraints and so may, to a first approximation, be regarded as neutral. Synonymous sites are also interdigitated with nonsynonymous sites and so are affected equally by genomic context and demographic factors. Hence a comparison of levels of polymorphism and divergence between synonymous sites and amino acid replacement sites in a gene is potentially informative about the magnitude of selective forces associated with amino acid replacements. We have analyzed 56 genes in which polymorphism data from D. simulans are compared with divergence from a reference strain of D. melanogaster. The framework of the analysis is Bayesian and assumes that the distribution of selective effects (Malthusian fitnesses) is Gaussian with a mean that differs for each gene. In such a model, the average scaled selection intensity (γ =N e s) of amino acid replacements eligible to become polymorphic or fixed is −7.31, and the standard deviation of selective effects within each locus is 6.79 (assuming homoscedasticity across loci). For newly arising mutations of this type that occur in autosomal or X-linked genes, the average proportion of beneficial mutations is 19.7%. Among the amino acid polymorphisms in the sample, the expected average proportion of beneficial mutations is 47.7%, and among amino acid replacements that become fixed the average proportion of beneficial mutations is 94.3%. The average scaled selection intensity of fixed mutations is +5.1. The presence of positive selection is pervasive with the single exception of kl-5, a Y-linked fertility gene. We find no evidence that a significant fraction of fixed amino acid replacements is neutral or nearly neutral or that positive selection drives amino acid replacements at only a subset of the loci. These results are model dependent and we discuss possible modifications of the model that might allow more neutral and nearly neutral amino acid replacements to be fixed.


Polymorphism/divergence Selective neutrality Positive selection Beneficial/deleterious mutations Poisson random field Markov chain Monte Carlo (MCMC) 


  1. 1.
    Adams, MD, Celniker, SE, Holt, RA,  et al. 2000The genome sequence of Drosophila melanogaster.Science28721852195CrossRefPubMedGoogle Scholar
  2. 2.
    Akashi, H 1995Inferring weak selection from patterns of polymorphism and divergence at “silent” sites in Drosophila DNA.Genetics13910671076Google Scholar
  3. 3.
    Bustamante, CD, Nielsen, R, Hartl, DL 2002aA maximum likelihood method for analyzing pseudogene evolution: Implications for silent site evolution in humans and rodents.Mol Biol Evol19110117Google Scholar
  4. 4.
    Bustamante, CD, Nielsen, R, Sawyer, SA, Olsen, KM, Purugganan, MD, Hartl, DL 2002bThe cost of inbreeding in Arabidopsis.Nature416531534Google Scholar
  5. 5.
    Carlin, BP, Louis, TA 2000Bayes and empirical Bayes methods for data analysis.Chapman & HallLondonGoogle Scholar
  6. 6.
    Charlesworth, B, Charlesworth, D 1997Rapid fixation of deleterious alleles can be caused by Muller’s ratchet.Genet Res706373CrossRefPubMedGoogle Scholar
  7. 7.
    Comeron, JM, Kreitman, M 2002Population, evolutionary and genomic consequences of interference selection.Genetics161389410Google Scholar
  8. 8.
    Ewens, WJ 1972The sampling theory of selectively neutral alleles.Theor Popul Biol387112PubMedGoogle Scholar
  9. 9.
    Fay, JC, Wu, C-I 2000Hitchhiking under positive Darwinian selection.Genetics15514051413PubMedGoogle Scholar
  10. 10.
    Fay, JC, Wyckoff, GJ, Wu, C-I 2002Testing the neutral theory of molecular evolution with genomic data from Drosophila.Nature41510241026CrossRefPubMedGoogle Scholar
  11. 11.
    Fu, Y-X, Li, W-H 1993Statistical tests of neutrality of mutations.Genetics133693709PubMedGoogle Scholar
  12. 12.
    Galtier, N, Depaulis, F, Barton, NH 2000Detecting bottlenecks and selective sweeps from DNA sequence polymorphism.Genetics155981987PubMedGoogle Scholar
  13. 13.
    Gelman, A, Carlin, JS, Stern, HS, Rubin, DB 1997Bayesian data analysis.Chapman & HallLondonGoogle Scholar
  14. 14.
    Gilks, R, Richardson, S, Spiegelhalter, DJ 1996Markov chain Monte Carlo in practice.Chapman & HallLondonGoogle Scholar
  15. 15.
    Gillespie, JH 2000Genetic drift in an infinite population. The pseudohitchhiking model.Genetics155909919PubMedGoogle Scholar
  16. 16.
    Gould, SJ 1989Tires to sandals: As we strive to understand nature, do we seek truth or solace?Nat Hist98815Google Scholar
  17. 17.
    Hartl, DL, Clark, AG 1997Principles of population genetics.Sinauer AssociatesSunderland, MAGoogle Scholar
  18. 18.
    Hartl, DL, Taubes, CH 1996Compensatory nearly neutral mutations: Selection without adaptation.J Theor Biol182303309CrossRefPubMedGoogle Scholar
  19. 19.
    Hartl, DL, Moriyama, EN, Sawyer, SA 1994Selection intensity for codon bias.Genetics138227234PubMedGoogle Scholar
  20. 20.
    Hudson, RR 1990Gene geneologies and the coalescent process.Futuyma, DAntonovics, J eds. Oxford surveys in evolutionary biology,Oxford University PressOxford144Google Scholar
  21. 21.
    Hudson, RR, Bailey, K, Skarecky, D, Kwiatowski, J, Ayala, FJ 1994Evidence for positive selection in the superoxide dismutase (Sod) region of Drosophila melanogaster.Genetics13613291340PubMedGoogle Scholar
  22. 22.
    Kim, Y, Stephan, W 2000Joint effects of genetic hitchhiking and background selection on neutral variation.Genetics15514151427Google Scholar
  23. 23.
    Kimura, M 1983The neutral theory of molecular evolution.Cambridge University PressCambridgeGoogle Scholar
  24. 24.
    Kirby, DA, Stephan, W 1996Multi-locus selection and the structure of variation at the white gene of Drosophila melanogaster.Genetics144635645PubMedGoogle Scholar
  25. 25.
    Lewontin, RC 1974The genetic basis of evolutionary change.Columbia University PressNew YorkGoogle Scholar
  26. 26.
    Liu, JS 2001Monte Carlo strategies in scientific computing.SpringerNew YorkGoogle Scholar
  27. 27.
    Maynard Smith, J, Haigh, J 1974The hitch-hiking effect of a favorable gene.Genet Res232335PubMedGoogle Scholar
  28. 28.
    McDonald, JH, Kreitman, M 1991Adaptive protein evolution at the Adh locus in Drosophila.Nature351652654PubMedGoogle Scholar
  29. 29.
    Metropolis, N, Rosenbluth, A, Rosenbluth, M, Teller, A, Teller, E 1953Equations of state calculations by fast computing machines.J Chem Phys2110871091Google Scholar
  30. 30.
    Nielsen, R, Yang, Z 1998Likelihood models for detecting positively selected amino acid sites and applications to the HIV-1 envelope gene.Genetics148929936PubMedGoogle Scholar
  31. 31.
    Nurminsky, DI 2001Genes in sweeping competition.Cell Mol Life Sci58125134PubMedGoogle Scholar
  32. 32.
    Ohta, T 1992The nearly neutral theory of molecular evolution.Annu Rev Ecol Syst23263286CrossRefGoogle Scholar
  33. 33.
    Sawyer, SA, Hartl, DL 1992Population genetics of polymorphism and divergence.Genetics13211611176Google Scholar
  34. 34.
    Schmid, KJ, Tautz, D 1997A screen for fast evolving genes from Drosophila.Proc Natl Acad Sci USA9497469750CrossRefPubMedGoogle Scholar
  35. 35.
    Smith, NGC, Eyre-Walker, A 2002Adaptive protein evolution in Drosophila.Nature41510221024CrossRefPubMedGoogle Scholar
  36. 36.
    Stephan, W 1996The rate of compensatory evolution.Genetics144419426PubMedGoogle Scholar
  37. 37.
    Swanson, WJ, Clark, AG, Waldrip-Dail, HM, Wolfner, MF, Aquadro, CF 2001Evolutionary EST analysis identifies rapidly evolving male reproductive proteins in Drosophila.Proc Natl Acad Sci USA9873757379CrossRefPubMedGoogle Scholar
  38. 38.
    Tajima, F 1989Statistical method for testing the neutral mutation hypothesis by DNA polymorphism.Genetics123585595PubMedGoogle Scholar
  39. 39.
    Templeton, AR 1998Nested clade analysis of phylogeographical data: Testing hypotheses about gene flow and population history.Mol Ecol7381397PubMedGoogle Scholar
  40. 40.
    Templeton, AR 2002Out of Africa again and again.Nature4164551PubMedGoogle Scholar
  41. 41.
    Wakeley, J 2000The effects of subdivision on the genetic divergence of populations and species.Evol Int J Org Evol5410921101Google Scholar
  42. 42.
    Yang, Z 1998Likelihood ratio tests for detecting positive selection and application to primate lysozyme evolution.Mol Biol Evol15568573PubMedGoogle Scholar

Copyright information

© Springer-Verlag New York LLC 2003

Authors and Affiliations

  • Stanley A. Sawyer
    • 1
  • Rob J. Kulathinal
    • 2
  • Carlos D. Bustamante
    • 3
  • Daniel L. Hartl
    • 2
    Email author
  1. 1.Department of MathematicsWashington University, St. Louis, MO 63130USA
  2. 2.Department of Organismic and Evolutionary BiologyHarvard University, Cambridge, MA 02138USA
  3. 3.Department of Biological Statistics and Computational BiologyCornell University, Ithaca, NY 14853AUSA

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