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Mechanistic approaches to the study of evolution: the functional synthesis

Nature Reviews Genetics volume 8, pages 675–688 (2007)Cite this article

Key Points

  • By combining evolutionary sequence analyses and manipulative molecular experiments, the functional synthesis of molecular evolution provides a powerful framework to elucidate the mechanisms by which historical mutations have altered biochemical processes and produced novel phenotypes. By using this approach, inferred ancestral sequences can be resurrected and their phenotypes and fitness effects assessed experimentally.

  • The functional synthesis of molecular evolution provides independent corroboration of statistical inferences that have been drawn from sequence analyses.

  • The functional synthesis of molecular evolution explicitly connects genotype with phenotype to allow mechanistic insights into the causes of adaptive change and evolutionary constraint.

  • The functional synthesis of molecular evolution provides decisive tests of recent adaptations where genetic variation still segregates in present-day species, and of ancient adaptations where genetic variation is fixed in present-day species.

  • The functional synthesis of molecular evolution can resolve long-standing questions about evolutionary processes and important evolutionary questions about metabolic, cellular, developmental and behavioural systems.

  • The functional synthesis of molecular evolution can be used to characterize adaptive landscapes and explore the evolution of complexity.

  • The functional synthesis of molecular evolution is poised to move beyond studies of single genes to allow the analysis of the evolution of pathways and networks that are made up of multiple genes.

  • The functional synthesis of molecular evolution should become routine in studies of molecular evolution.

Abstract

An emerging synthesis of evolutionary biology and experimental molecular biology is providing much stronger and deeper inferences about the dynamics and mechanisms of evolution than were possible in the past. The new approach combines statistical analyses of gene sequences with manipulative molecular experiments to reveal how ancient mutations altered biochemical processes and produced novel phenotypes. This functional synthesis has set the stage for major advances in our understanding of fundamental questions in evolutionary biology. Here we describe this emerging approach, highlight important new insights that it has made possible, and suggest future directions for the field.

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Figure 1: Evolution of insecticide resistance by a single amino-acid change.
Figure 2: Evolution of spectral sensitivity in vertebrate opsins.
Figure 3: Uphill adaptive walks among amino-acid replacements in the adaptive landscape of TEM β-lactamase.
Figure 4: Constraint and opportunity in the evolution of coenzyme use by paralogous dehydrogenases.
Figure 5: Evolution of corticosteroid-receptor specificity.

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References

  1. Dykhuizen, D. E. & Hartl, D. L. Selection in chemostats. Microbiol. Rev. 47, 150–168 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Elena, S. F. & Lenski, R. E. Evolution experiments with microorganisms: the dynamics and genetic bases of adaptation. Nature Rev. Genet. 4, 457–469 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Losos, J. B., Jackman, T. R., Larson, A., Queiroz, K. & Rodriguez-Schettino, L. Contingency and determinism in replicated adaptive radiations of island lizards. Science 279, 2115–2118 (1998).

    Article  CAS  PubMed  Google Scholar 

  4. Powers, D. A., Lauerman, T., Crawford, D. & DiMichele, L. Genetic mechanisms for adapting to a changing environment. Annu. Rev. Genet. 25, 629–659 (1991).

    Article  CAS  PubMed  Google Scholar 

  5. Wourms, M. K. & Wasserman, F. E. Butterfly wing markings are more advantageous during handling than during the initial strike of an avian predator. Evolution 39, 845–851 (1985).

    Article  PubMed  Google Scholar 

  6. Moller, A. P. Female choice selects for male sexual tail ornaments in the monogamous swallow. Nature 332, 640–642 (1988).

    Article  Google Scholar 

  7. Rainey, P. B. & Rainey, K. Evolution of cooperation and conflict in experimental bacterial populations. Nature 425, 72–74 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Denver, D. R. et al. The transcriptional consequences of mutation and natural selection in Caenorhabditis elegans. Nature Genet. 37, 544–548 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Endler, J. A. Natural selection on color patterns in Poecilia reticulata. Evolution 34, 76–91 (1980).

    Article  PubMed  Google Scholar 

  10. Thornton, J. W. Resurrecting ancient genes: experimental analysis of extinct molecules. Nature Rev. Genet. 5, 366–375 (2004). An introduction to gene 'resurrection' — that is, phylogenetic reconstruction, biochemical synthesis and functional characterization of ancient sequences — as a strategy for testing evolutionary hypotheses.

    Article  CAS  PubMed  Google Scholar 

  11. Fitzpatrick, M. J., Feder, E., Rowe, L. & Sokolowski, M. B. Maintaining a behaviour polymorphism by frequency-dependent selection on a single gene. Nature 447, 210–212 (2007). Polymorphism in activity of a cGMP-dependent protein kinase that elicits different foraging behaviours in Drosophila melanogaster larva is maintained by negative frequency-dependent selection during starvation.

    Article  CAS  PubMed  Google Scholar 

  12. Douglas, S. J., Dawson-Scully, K. & Sokolowski, M. B. The neurogenetics and evolution of food-related behaviour. Trends Neurosci. 28, 644–652 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Toth, A. L. & Robinson, G. E. Evo–devo and the evolution of social behavior. Trends Genet. 23, 334–341 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Colosimo, P. F. et al. Widespread parallel evolution in sticklebacks by repeated fixation of Ectodysplasin alleles. Science 307, 1928–1933 (2005). Using transgenic, phylogenetic and quantitative genetic analysis, the authors identify an allele that is involved in the loss of external armour during the evolution of numerous freshwater stickleback populations.

    Article  CAS  PubMed  Google Scholar 

  15. Gompel, N., Prud'homme, B., Wittkopp, P. J., Kassner, V. A. & Carroll, S. B. Chance caught on the wing: cis-regulatory evolution and the origin of pigment patterns in Drosophila. Nature 433, 481–487 (2005). This pioneering study in the evolution of development (along with reference 16) used transgenic techniques to identify decisively specific regulatory elements that underlie evolutionary differences in the expression of genes that drive pigmentation patterns between fruitfly species.

    Article  CAS  PubMed  Google Scholar 

  16. Prud'homme, B. et al. Repeated morphological evolution through cis-regulatory changes in a pleiotropic gene. Nature 440, 1050–1053 (2006).

    Article  CAS  PubMed  Google Scholar 

  17. Konishi, S. et al. An SNP caused loss of seed shattering during rice domestication. Science 312, 1392–1396 (2006). A beautiful example of the functional synthesis to study the evolution of development: fine quantitative genetic mapping identified a single substitution associated with the loss of seed shattering that occurs during rice domestication; transgenic and functional analysis established the specific effects of the historical mutation on gene expression, seed development and the shattering phenotype.

    Article  CAS  PubMed  Google Scholar 

  18. Wang, H. et al. The origin of the naked grains of maize. Nature 436, 714–719 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Daborn, P. J. et al. A single p450 allele associated with insecticide resistance in Drosophila. Science 297, 2253–2256 (2002).

    Article  CAS  PubMed  Google Scholar 

  20. Chung, H. et al. Cis-regulatory elements in the accord retrotransposon result in tissue-specific expression of the Drosophila melanogaster insecticide resistance gene Cyp6g1. Genetics 175, 1071–1077 (2007). Using genetic manipulation in fruitflies, the authors show decisively that a transposon insertion in the regulatory region of a gene that metabolizes insecticides is sufficient to recapitulate the evolution of DDT (dichloro-diphenyl-trichloroethane) resistance.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bantinaki, E. et al. Adaptive divergence in experimental populations of Pseudomonas fluorescens. III. Mutational origins of wrinkly spreader diversity. Genetics 176, 441–453 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gilbert, S. F., Opitz, J. M. & Raff, R. A. Resynthesizing evolutionary and developmental biology. Dev. Biol. 173, 357–372 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Wilson, E. O. Sociobiology: The New Synthesis (Belknap, Cambridge, 1975).

    Google Scholar 

  24. Hubby, J. L. & Lewontin, R. C. A molecular approach to the study of genic heterozygosity in natural populations. I. The number of alleles at different loci in Drosophila pseudoobscura. Genetics 54, 577–594 (1966).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Kreitman, M. Nucleotide polymorphism at the alcohol dehydrogenase locus of Drosophila melanogaster. Nature 304, 412–417 (1983).

    Article  CAS  PubMed  Google Scholar 

  26. Golding, G. B. & Dean, A. M. The structural basis of molecular adaptation. Mol. Biol. Evol. 15, 355–369 (1998). A review summarizing classic early work in the functional synthesis.

    Article  CAS  PubMed  Google Scholar 

  27. McDonald, J. H. & Kreitman, M. Adaptive protein evolution at the adh locus in Drosophila. Nature 351, 652–654 (1991).

    Article  CAS  PubMed  Google Scholar 

  28. Yang, Z. & Nielsen, R. Codon-substitution models for detecting molecular adaptation at individual sites along specific lineages. Mol. Biol. Evol. 19, 908–917 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Tajima, F. Statistical method for testing the neutral mutation hypothesis by DNA polymorphism. Genetics 123, 585–596 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Nielsen, R. Molecular signatures of natural selection. Annu. Rev. Genet. 39, 197–218 (2005).

    Article  CAS  PubMed  Google Scholar 

  31. Nielsen, R. Statistical tests of selective neutrality in the age of genomics. Heredity 86, 641–647 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Eyre-Walker, A. Changing effective population size and the McDonald–Kreitman test. Genetics 62, 2017–2024 (2002).

    Google Scholar 

  33. Koehn, R. K. & Hilbish, T. J. The adaptive importance of genetic variation. Am. Sci. 75, 134–141 (1987).

    Google Scholar 

  34. Watt, W. B. in The Evolution of Population Biology (eds Singh, R. S. & Uyenoyama, M. K.) (Cambridge Univ. Press, Cambridge, 2004).

    Google Scholar 

  35. Wheat, C. W., Watt, W. B., Pollock, D. D. & Schulte, P. M. From DNA to fitness differences: sequences and structures of adaptive variants of Colias phosphoglucose isomerase (PGI). Mol. Biol. Evol. 23, 499–512 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Brideau, N. J. et al. Two Dobzhansky–Muller genes interact to cause hybrid lethality in Drosophila. Science 314, 1292–1295 (2006).

    Article  CAS  PubMed  Google Scholar 

  37. Geffeney, S. L., Fujimoto, E., Brodie, E. D. 3rd, Brodie, E. D. Jr & Ruben, P. C. Evolutionary diversification of TTX-resistant sodium channels in a predator–prey interaction. Nature 434, 759–763 (2005). An elegant mechanistic-structural explanation of the repeated evolution of resistance to the tetrodotoxin of toxic newt prey, caused by amino-acid replacements in the voltage-gated sodium channels of garter snake muscles.

    Article  CAS  PubMed  Google Scholar 

  38. Zhang, J. Parallel adaptive origins of digestive RNases in Asian and African leaf monkeys. Nature Genet. 38, 819–823 (2006). Evolution of foregut fermentation in Asian and African leaf-eating monkeys is characterized by parallel amino-acid replacements that produce similar functional shifts in digestive RNases.

    Article  CAS  PubMed  Google Scholar 

  39. Zhang, J. et al. The crystal structure of a high oxygen affinity species of haemoglobin (bar-headed goose haemoglobin in the oxy form). J. Mol. Biol. 255, 484–493 (1996).

    Article  CAS  PubMed  Google Scholar 

  40. Zhang, J. & Rosenberg, H. F. Complementary advantageous substitutions in the evolution of an antiviral RNase of higher primates. Proc. Natl Acad. Sci. USA 99, 5486–5491 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Jermann, T. M., Opitz, J. G., Stackhouse, J. & Benner, S. A. Reconstructing the evolutionary history of the artiodactyl ribonuclease superfamily. Nature 374, 57–59 (1995).

    Article  CAS  PubMed  Google Scholar 

  42. Jessen, T. H., Weber, R. E., Fermi, G., Tame, J. & Braunitzer, G. Adaptation of bird hemoglobins to high altitudes: demonstration of molecular mechanism by protein engineering. Proc. Natl Acad. Sci. USA 88, 6519–6522 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gaucher, E. A., Thomson, J. M., Burgan, M. F. & Benner, S. A. Inferring the palaeoenvironment of ancient bacteria on the basis of resurrected proteins. Nature 425, 285–288 (2003).

    Article  CAS  PubMed  Google Scholar 

  44. Chang, B. S., Jonsson, K., Kazmi, M. A., Donoghue, M. J. & Sakmar, T. P. Recreating a functional ancestral archosaur visual pigment. Mol. Biol. Evol. 19, 1483–1489 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. Thomson, J. M. et al. Resurrecting ancestral alcohol dehydrogenases from yeast. Nature Genet. 37, 630–635 (2005). Ancestral yeast alcohol dehydrogenase (ADH) was reconstructed, expressed and shown to have the functional characteristics that are typical of extant ADH1, which is involved in ethanol production, rather than ADH2, which is involved in ethanol consumption.

    Article  CAS  PubMed  Google Scholar 

  46. Ugalde, J. A., Chang, B. S. & Matz, M. V. Evolution of coral pigments recreated. Science 305, 1433 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Soong, T. W. & Venkatesh, B. Adaptive evolution of tetrodotoxin resistance in animals. Trends Genet. 22, 621–626 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Doebley, J., Stec, A. & Hubbard, L. The evolution of apical dominance in maize. Nature 386, 485–488 (1997).

    Article  CAS  PubMed  Google Scholar 

  49. Shapiro, M. D. et al. Genetic and developmental basis of evolutionary pelvic reduction in threespine sticklebacks. Nature 428, 717–723 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Stern, D. L. Evolutionary developmental biology and the problem of variation. Evolution 54, 1079–1091 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Sucena, E., Delon, I., Jones, I., Payre, F. & Stern, D. L. Regulatory evolution of shavenbaby/ovo underlies multiple cases of morphological parallelism. Nature 424, 935–938 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Shimizu, K. K. et al. Darwinian selection on a selfing locus. Science 306, 2081–2084 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. de Meaux, J., Pop, A. & Mitchell-Olds, T. cis-regulatory evolution of chalcone-synthase expression in the genus Arabidopsis. Genetics 174, 2181–2202 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Benderoth, M. et al. Positive selection driving diversification in plant secondary metabolism. Proc. Natl Acad. Sci. USA 103, 9118–9123 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Protas, M. E. et al. Genetic analysis of cavefish reveals molecular convergence in the evolution of albinism. Nature Genet. 38, 107–111 (2006).

    Article  CAS  PubMed  Google Scholar 

  56. Osborne, K. A. et al. Natural behavior polymorphism due to a cGMP-dependent protein kinase of Drosophila. Science 277, 834–836 (1997).

    Article  CAS  PubMed  Google Scholar 

  57. Newcomb, R. D. et al. A single amino acid substitution converts a carboxylesterase to an organophosphorus hydrolase and confers insecticide resistance on a blowfly. Proc. Natl Acad. Sci. USA 94, 7464–7468 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Newcomb, R. D., East, P. D., Russell, R. J. & Oakeshott, J. G. Isolation of α cluster esterase genes associated with organophosphate resistance in Lucilia cuprina. Insect Mol. Biol. 5, 211–216 (1996).

    Article  CAS  PubMed  Google Scholar 

  59. Parker, A. G., Campbell, P. M., Spackman, M. E., Russell, R. J. & Oakeshott, J. G. Comparison of an esterase associated with organophosphate resistance in Lucilia cuprina with an orthologue not associated with resistance in Drosophila melanogaster. Pestic. Biochem. Physiol. 55, 85–99 (1996).

    Article  CAS  PubMed  Google Scholar 

  60. Newcomb, R. D., Campbell, P. M., Russell, R. J. & Oakeshott, J. G. cDNA cloning, baculovirus-expression and kinetic properties of the esterase, E3, involved in organophosphorus resistance in Lucilia cuprina. Insect Biochem. Mol. Biol. 27, 15–25 (1997).

    Article  CAS  PubMed  Google Scholar 

  61. Hartley, C. J. et al. Amplification of DNA from preserved specimens shows blowflies were preadapted for the rapid evolution of insecticide resistance. Proc. Natl Acad. Sci. USA 103, 8757–8762 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Claudianos, C., Russell, R. J. & Oakeshott, J. G. The same amino acid substitution in orthologous esterases confers organophosphate resistance on the house fly and a blowfly. Insect Biochem. Mol. Biol. 29, 675–686 (1999).

    Article  CAS  PubMed  Google Scholar 

  63. Hoekstra, H. E., Hirschmann, R. J., Bundey, R. A., Insel, P. A. & Crossland, J. P. A single amino acid mutation contributes to adaptive beach mouse color pattern. Science 313, 101–104 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Steiner, C. C., Weber, J. N. & Hoekstra, H. E. Adaptive variation in beach mice produced by interacting pigmentation genes. PLoS Biol. 5, e219 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Yokoyama, S., Zhang, H., Radlwimmer, F. B. & Blow, N. S. Adaptive evolution of color vision of the Comoran coelacanth (Latimeria chalumnae). Proc. Natl Acad. Sci. USA 96, 6279–6284 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Yokoyama, S. & Tada, T. Adaptive evolution of the African and Indonesian coelacanths to deep-sea environments. Gene 261, 35–42 (2000).

    Article  CAS  PubMed  Google Scholar 

  67. Yokoyama, S. Color vision of the coelacanth (Latimeria chalumnae) and adaptive evolution of rhodopsin (RH1) and rhodopsin-like (RH2) pigments. J. Hered. 91, 215–220 (2000).

    Article  CAS  PubMed  Google Scholar 

  68. Shi, Y., Radlwimmer, F. B. & Yokoyama, S. Molecular genetics and the evolution of ultraviolet vision in vertebrates. Proc. Natl Acad. Sci. USA 98, 11731–11736 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Shi, Y. & Yokoyama, S. Molecular analysis of the evolutionary significance of ultraviolet vision in vertebrates. Proc. Natl Acad. Sci. USA 100, 8308–8313 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Yokoyama, S., Starmer, W. T., Takahashi, Y. & Tada, T. Tertiary structure and spectral tuning of UV and violet pigments in vertebrates. Gene 365, 95–103 (2006).

    Article  CAS  PubMed  Google Scholar 

  71. Yokoyama, S. & Radlwimmer, F. B. The molecular genetics and evolution of red and green color vision in vertebrates. Genetics 158, 1697–1710 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Yokoyama, S. & Radlwimmer, F. B. The molecular genetics of red and green color vision in mammals. Genetics 153, 919–932 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Yokoyama, S. & Radlwimmer, F. B. The 'five-sites' rule and the evolution of red and green color vision in mammals. Mol. Biol. Evol. 15, 560–567 (1998).

    Article  CAS  PubMed  Google Scholar 

  74. Wright, S. The roles of mutation, inbreeding, crossbreeding, and selection in evolution. Proc. 6th Int. Cong. Genet. 1, 356–366 (1932).

    Google Scholar 

  75. Phillips, P. C. & Arnold, S. J. Visualizing multivariate selection. Evolution 43, 1209–1222 (1989).

    Article  PubMed  Google Scholar 

  76. Gavrilets, S. A dynamical theory of speciation on holey adaptive landscapes. Am. Nat. 154, 1–22 (1999).

    Article  PubMed  Google Scholar 

  77. Gillespie, J. H. Molecular evolution over the mutational landscape. Evolution 38, 1116–1129 (1984).

    Article  CAS  PubMed  Google Scholar 

  78. Kauffman, S. A. The Origins of Order: Self-organization and Selection in Evolution (Oxford Univ. Press, Oxford, 1993).

    Google Scholar 

  79. Fisher, R. A. The Genetical Theory of Natural Selection (Oxford Univ. Press, Oxford, 1930).

    Book  Google Scholar 

  80. Maynard Smith, J. Natural selection and the concept of a protein space. Nature 225, 563–564 (1970).

    Article  Google Scholar 

  81. Weinreich, D. M., Delaney, N. F., Depristo, M. A. & Hartl, D. L. Darwinian evolution can follow only very few mutational paths to fitter proteins. Science 312, 111–114 (2006).

    Article  CAS  PubMed  Google Scholar 

  82. Gillespie, J. H. A simple stochastic gene substitution model. Theor. Popul. Biol. 23, 2020–2015 (1983).

    Article  Google Scholar 

  83. Weinreich, D. M., Watson, R. A. & Chao, L. Perspective: sign epistasis and genetic constraint on evolutionary trajectories. Evolution 59, 1165–1174 (2005).

    CAS  PubMed  Google Scholar 

  84. Lunzer, M., Miller, S. P., Felsheim, R. & Dean, A. M. The biochemical architecture of an ancient adaptive landscape. Science 310, 499–501 (2005).

    Article  CAS  PubMed  Google Scholar 

  85. Zhu, G., Golding, G. B. & Dean, A. M. The selective cause of an ancient adaptation. Science 307, 1279–1282 (2005).

    Article  CAS  PubMed  Google Scholar 

  86. Hurley, J. H. & Dean, A. M. Structure of 3-isopropylmalate dehydrogenase in complex with NAD+: ligand-induced loop closing and mechanism for cofactor specificity. Structure 2, 1007–1016 (1994).

    Article  CAS  PubMed  Google Scholar 

  87. Hurley, J. H., Dean, A. M., Koshland, D. E. Jr & Stroud, R. M. Catalytic mechanism of NADP+-dependent isocitrate dehydrogenase: implications from the structures of magnesium-isocitrate and NADP+ complexes. Biochemistry 30, 8671–8678 (1991).

    Article  CAS  PubMed  Google Scholar 

  88. Miller, S. P., Lunzer, M. & Dean, A. M. Direct demonstration of an adaptive constraint. Science 314, 458–461 (2006).

    Article  CAS  PubMed  Google Scholar 

  89. Dean, A. M. & Golding, G. B. Protein engineering reveals ancient adaptive replacements in isocitrate dehydrogenase. Proc. Natl Acad. Sci. USA 94, 3104–3109 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Chen, R., Greer, A. & Dean, A. M. A highly active decarboxylating dehydrogenase with rationally inverted coenzyme specificity. Proc. Natl Acad. Sci. USA 92, 11666–11670 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Gould, S. J. & Lewontin, R. C. The spandrels of San Marco and the Panglossian paradigm: a critique of the adaptationist programme. Proc. R. Soc. Lond. B Biol. Sci. 205, 581–598 (1979).

    Article  CAS  PubMed  Google Scholar 

  92. Bridgham, J. T., Carroll, S. M. & Thornton, J. W. Evolution of hormone-receptor complexity by molecular exploitation. Science 312, 97–101 (2006).

    Article  CAS  PubMed  Google Scholar 

  93. Ortlund, E. A., Bridgham, J. T., Redinbo, M. R. & Thornton, J. W. Crystal structure of an ancient protein: evolution of a new function by conformational epistasis. Science 16 August 2007 (doi:101126/science.1142819).

  94. Thornton, J. W., Need, E. & Crews, D. Resurrecting the ancestral steroid receptor: ancient origin of estrogen signaling. Science 301, 1714–1717 (2003).

    Article  CAS  PubMed  Google Scholar 

  95. Thornton, J. W. Evolution of vertebrate steroid receptors from an ancestral estrogen receptor by ligand exploitation and serial genome expansions. Proc. Natl Acad. Sci. USA 98, 5671–5676 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Paley, W. Natural Theology: or, Evidences of the Existence and Attributes of the Deity, Collected from the Appearances of Nature (E. Paulder, London, 1802).

    Google Scholar 

  97. Force, A. et al. Preservation of duplicate genes by complementary, degenerative mutations. Genetics 151, 1531–1545 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Ohno, S. Evolution by Gene Duplication (Springer, New York, 1970).

    Book  Google Scholar 

  99. Copley, S. D. Enzymes with extra talents: moonlighting functions and catalytic promiscuity. Curr. Opin. Chem. Biol. 7, 265–272 (2003).

    Article  CAS  PubMed  Google Scholar 

  100. O'Brien, P. J. & Herschlag, D. Catalytic promiscuity and the evolution of new enzymatic activities. Chem. Biol. (London) 6, R91–R105 (1999).

    CAS  Google Scholar 

  101. Khersonsky, O., Roodveldt, C. & Tawfik, D. S. Enzyme promiscuity: evolutionary and mechanistic aspects. Curr. Opin. Chem. Biol. 10, 498–508 (2006).

    Article  CAS  PubMed  Google Scholar 

  102. Gerlt, J. A. & Babbitt, P. C. Divergent evolution of enzymatic function: mechanistically diverse superfamilies and functionally distinct suprafamilies. Annu. Rev. Biochem. 70, 209–246 (2001).

    Article  CAS  PubMed  Google Scholar 

  103. Carroll, S. B. Endless forms: the evolution of gene regulation and morphological diversity. Cell 101, 577–580 (2000).

    Article  CAS  PubMed  Google Scholar 

  104. Hoekstra, H. E. & Coyne, J. A. The locus of evolution: evo devo and the genetics of adaptation. Evolution 61, 995–1016 (2007).

    Article  PubMed  Google Scholar 

  105. Leu, J. Y. & Murray, A. W. Experimental evolution of mating discrimination in budding yeast. Curr. Biol. 16, 280–286 (2006).

    Article  CAS  PubMed  Google Scholar 

  106. Velicer, G. J. et al. Comprehensive mutation identification in an evolved bacterial cooperator and its cheating ancestor. Proc. Natl Acad. Sci. USA 103, 8107–8112 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Woods, R., Schneider, D., Winkworth, C. L., Riley, M. A. & Lenski, R. E. Tests of parallel molecular evolution in a long-term experiment with Escherichia coli. Proc. Natl Acad. Sci. USA 103, 9107–9112 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Zhong, S., Khodursky, A., Dykhuizen, D. E. & Dean, A. M. Evolutionary genomics of ecological specialization. Proc. Natl Acad. Sci. USA 101, 11719–11724 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Davidson, E. H. The Regulatory Genome: Gene Regulatory Networks in Development and Evolution (Academic, Burlington, 2006).

    Google Scholar 

  110. Kuhn, T. The Structure of Scientific Revolutions (Univ. Chicago Press, Chicago, 1996).

    Book  Google Scholar 

  111. Kornegay, J. R., Schilling, J. W. & Wilson, A. C. Molecular adaptation of a leaf-eating bird: stomach lysozyme of the hoatzin. Mol. Biol. Evol. 11, 921–928 (1994).

    CAS  PubMed  Google Scholar 

  112. Nachman, M. W., Hoekstra, H. E. & D'Agostino, S. L. The genetic basis of adaptive melanism in pocket mice. Proc. Natl Acad. Sci. USA 100, 5268–5273 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Hiebl, I., Braunitzer, G. & Schneeganss, D. The primary structures of the major and minor hemoglobin-components of adult Andean goose (Chloephaga melanoptera, Anatidae): the mutation Leu>Ser in position 55 of the β-chains. Biol. Chem. Hoppe-Seyler 368, 1559–1569 (1987).

    Article  CAS  PubMed  Google Scholar 

  114. Bateson, W. Preface from Mendel's Principles of Heredity: A Defense (Cambridge Univ. Press, Cambridge, 1902).

    Book  Google Scholar 

  115. Goldschmidt, R. The material basis of evolution (Yale, New Haven, 1940).

    Google Scholar 

  116. Bateson, W. Materials for the Study of Variation Treated with Especial Regard to Discontinuity in the Origin of Species (Macmillan, London, 1894).

    Google Scholar 

  117. Wilks, H. M. et al. A specific, highly active malate dehydrogenase by redesign of a lactate dehydrogenase framework. Science 242, 1541–1544 (1988).

    Article  CAS  PubMed  Google Scholar 

  118. Cresko, W. A. et al. Parallel genetic basis for repeated evolution of armor loss in Alaskan threespine stickleback populations. Proc. Natl Acad. Sci. USA 101, 6050–6055 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Spiller, B., Gershenson, A., Arnold, F. H. & Stevens, R. C. A structural view of evolutionary divergence. Proc. Natl Acad. Sci. USA 96, 12305–12310 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Rothman, S. C., Voorhies, M. & Kirsch, J. F. Directed evolution relieves product inhibition and confers in vivo function to a rationally designed tyrosine aminotransferase. Protein Sci. 13, 763–772 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Oue, S., Okamoto, A., Yano, T. & Kagamiyama, H. Redesigning the substrate specificity of an enzyme by cumulative effects of the mutations of non-active site residues. J. Biol. Chem. 274, 2344–2349 (1999).

    Article  CAS  PubMed  Google Scholar 

  122. Hsu, C. C., Hong, Z., Wada, M., Franke, D. & Wong, C. H. Directed evolution of D-sialic acid aldolase to L-3-deoxy-manno-2-octulosonic acid (L-KDO) aldolase. Proc. Natl Acad. Sci. USA 102, 9122–9126 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Whitlock, M. C., Phillips, P. C., Moore, F. B. G. & Tonsor, S. J. Multiple fitness peaks and epistasis. Annu. Rev. Ecol. Syst. 26, 601–629 (1995).

    Article  Google Scholar 

  124. Provine, W. B. The origins of theoretical population genetics (Univ. Chicago Press, Chicago, 1971).

    Google Scholar 

  125. Gavrilets, S. Evolution and speciation on holey adaptive landscapes. Trends Ecol. Evol. 12, 307–312 (1997).

    Article  CAS  PubMed  Google Scholar 

  126. Yokoyama, S. Molecular evolution of color vision in vertebrates. Gene 300, 69–78 (2002).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank M. Borello, M. Travisano, P. Phillips, B. Cresko, P. Rainey, A. Kondrashov, S. Yokoyama, R. Newcomb, D.Weinreich, B. Hall, an anonymous referee and members of the Thornton and Dean laboratories for comments. Supported by the US National Science Foundation (NSF IOB-0546906), the US National Institutes of Health (NIH R01-GM081592), and a Sloan Foundation Fellowship to J.W.T. and NIH R01-GM060,611 to A.M.D.

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  1. 140 Gortner Laboratories, University of Minnesota, St Paul, 55108, Minnesota, USA

    Antony M. Dean

  2. 5289 University of Oregon, Eugene, 97403, Oregon, USA

    Joseph W. Thornton

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Glossary

Evo–devo synthesis

The study of the origin and evolution of development, originally restricted to comparative methods, but increasingly using experimental approaches.

Coalescent theory

A mathematical framework, based on the genealogy of alleles, for estimating population genetic alleles.

Strong selection–weak mutation model

A population genetic model in which beneficial mutations are fixed sequentially in the population through a series of selective sweeps, and in which neutral and deleterious mutations can be ignored as having low probabilities of fixation.

Chemostat competition assay

A precise assay of the relative growth rates (fitnesses) of competing strains can be obtained in the chemostat, a continuous culture device that is used to impose starvation for a specific resource in a constant environment.

Directed evolution

A library of random mutants that have been generated by PCR amplification of a gene is ligated into a plasmid, transformed into a strain and screened for a desired function.

Michaelis complex

A complex of substrate bound to enzyme just before catalysis.

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Dean, A., Thornton, J. Mechanistic approaches to the study of evolution: the functional synthesis. Nat Rev Genet 8, 675–688 (2007). https://doi.org/10.1038/nrg2160

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