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Empirical fitness landscapes reveal accessible evolutionary paths


When attempting to understand evolution, we traditionally rely on analysing evolutionary outcomes, despite the fact that unseen intermediates determine its course. A handful of recent studies has begun to explore these intermediate evolutionary forms, which can be reconstructed in the laboratory. With this first view on empirical evolutionary landscapes, we can now finally start asking why particular evolutionary paths are taken.

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Figure 1: Schematic representations of fitness landscape features.
Figure 2: Molecular structures in different evolutionary forms.
Figure 3: Evolution of molecular interactions based on reconstructed intermediates.


  1. Darwin, C. On the Origin of Species by Means of Natural Selection Ch VI (Murray, London, 1859)

    Google Scholar 

  2. Pauling, L. & Zuckerkandl, E. Chemical paleogenetics; Molecular “restoration studies” of extinct forms of life. Acta Chem. Scand. A 17, S9–S16 (1963)

    Article  CAS  Google Scholar 

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

    Article  ADS  Google Scholar 

  4. Malcolm, B. A. et al. Ancestral lysozymes reconstructed, neutrality tested, and thermostability linked to hydrocarbon packing. Nature 345, 86–89 (1990)

    Article  ADS  CAS  Google Scholar 

  5. Stackhouse, J., Presnell, S. R., McGeehan, G. M., Nambiar, K. P. & Benner, S. A. The ribonuclease from an extinct bovid ruminant. FEBS Lett. 262, 104–106 (1990)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Thornton, J. W. Resurrecting ancient genes: Experimental analysis of extinct molecules. Nature Rev. Genet. 5, 366–375 (2004)

    Article  CAS  Google Scholar 

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

  9. Gillespie, J. H. The Causes of Molecular Evolution (Oxford Univ. Press, Oxford, 1991)

    Google Scholar 

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

    Google Scholar 

  11. Gavrilets, S. Fitness Landscapes and the Origin of Species (Princeton Univ. Press, Princeton, 2004)

    Google Scholar 

  12. van Nimwegen, E. & Crutchfield, J. P. Metastable evolutionary dynamics: crossing fitness barriers or escaping via neutral paths? Bull. Math. Biol. 62, 799–848 (2000)

    Article  CAS  Google Scholar 

  13. Weinreich, D. M., Watson, R. A. & Chao, L. Sign epistasis and genetic constraint on evolutionary trajectories. Evol. Int. J. Org. Evol. 59, 1165–1174 (2005)

    CAS  Google Scholar 

  14. 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  ADS  CAS  Google Scholar 

  15. Kimura, M. On the probability of fixation of mutant genes in a population. Genetics 47, 713–719 (1962)

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Poelwijk, F. J., Kiviet, D. J. & Tans, S. J. Evolutionary potential of a duplicated repressor-operator pair: simulating pathways using mutation data. PLoS Comput. Biol. 2, e58 (2006)

    Article  ADS  Google Scholar 

  17. DePristo, M. A., Weinreich, D. M. & Hartl, D. L. Missense meanderings in sequence space: a biophysical view of protein evolution. Nature Rev. Genet. 6, 678–687 (2005)

    Article  CAS  Google Scholar 

  18. Bloom, J. D., Labthavikul, S. T., Otey, C. R. & Arnold, F. H. Protein stability promotes evolvability. Proc. Natl Acad. Sci. USA 103, 5869–5874 (2006)

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  MathSciNet  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  22. Lehming, N., Sartorius, J., Kisters-Woike, B., von Wilcken-Bergmann, B. & Müller-Hill, B. Mutant lac repressors with new specificities hint at rules for protein-DNA recognition. EMBO J. 9, 615–621 (1990)

    Article  CAS  Google Scholar 

  23. Barkai, N. & Leibler, S. Robustness in simple biochemical networks. Nature 387, 913–917 (1997)

    Article  ADS  CAS  Google Scholar 

  24. Kirschner, M. & Gerhart, J. Evolvability. Proc. Natl Acad. Sci. USA 95, 8420–8427 (1998)

    Article  ADS  CAS  Google Scholar 

  25. Kitano, H. Biological robustness. Nature Rev. Genet. 5, 826–837 (2004)

    Article  CAS  Google Scholar 

  26. Stelling, J., Sauer, U., Szallasi, Z., Doyle, F. J. & Doyle, J. Robustness of cellular functions. Cell 118, 675–685 (2004)

    Article  CAS  Google Scholar 

  27. Thattai, M. & van Oudenaarden, A. Stochastic gene expression in fluctuating environments. Genetics 167, 523–530 (2004)

    Article  Google Scholar 

  28. Kussell, E. & Leibler, S. Phenotypic diversity, population growth, and information in fluctuating environments. Science 309, 2075–2078 (2005)

    Article  ADS  CAS  Google Scholar 

  29. Arnold, F. H., Wintrode, P. C., Miyazaki, K. & Gershenson, A. How enzymes adapt: lessons from directed evolution. Trends Biochem. Sci. 26, 100–106 (2001)

    Article  CAS  Google Scholar 

  30. 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  Google Scholar 

  31. Couñago, R., Chen, S. & Shamoo, Y. In vivo molecular evolution reveals biophysical origins of organismal fitness. Mol. Cell 22, 441–449 (2006)

    Article  Google Scholar 

  32. Lenski, R. E. & Travisano, M. Dynamics of adaptation and diversification: a 10,000-generation experiment with bacterial populations. Proc. Natl Acad. Sci. USA 91, 6808–6814 (1994)

    Article  ADS  CAS  Google Scholar 

  33. Dekel, E. & Alon, U. Optimality and evolutionary tuning of the expression level of a protein. Nature 436, 588–592 (2005)

    Article  ADS  CAS  Google Scholar 

  34. Hurley, J. H., Dean, A. M., Koshland, D. E. & 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  Google Scholar 

  35. Hurley, J. H., Chen, R. & Dean, A. M. Determinants of cofactor specificity in isocitrate dehydrogenase: structure of an engineered NADP+ → NAD+ specificity-reversal mutant. Biochemistry 35, 5670–5678 (1996)

    Article  CAS  Google Scholar 

  36. Kalodimos, C. G. et al. Plasticity in protein-DNA recognition: lac repressor interacts with its natural operator 01 through alternative conformations of its DNA-binding domain. EMBO J. 21, 2866–2876 (2002)

    Article  CAS  Google Scholar 

  37. Kopke Salinas, R. et al. Altered specificity in DNA binding by the lac repressor: a mutant lac headpiece that mimics the gal repressor. ChemBioChem 6, 1628–1637 (2005)

    Article  Google Scholar 

  38. Koradi, R., Billeter, M. & Wüthrich, K. MOLMOL: a program for display and analysis of macromolecular structures. J. Mol. Graph. 14, 51–55 (1996)

    Article  CAS  Google Scholar 

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We thank A. Dean, D. Hartl, J. Thornton and W. Vos for critical reading of the manuscript, and S. Tănase-Nicola for discussions. We thank A. Bonvin and R. Salinas for supplying the data for Fig. 2b. This work is part of the research programme of the Stichting voor Fundamenteel Onderzoek der Materie (FOM), which is financially supported by the Nederlandse Organisatie voor Wetenschappelijke Onderzoek (NWO).

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Correspondence to Sander J. Tans.

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Poelwijk, F., Kiviet, D., Weinreich, D. et al. Empirical fitness landscapes reveal accessible evolutionary paths. Nature 445, 383–386 (2007).

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