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Evolution of complex adaptations in molecular systems

Nature Ecology & Evolution volume 1, pages 1084–1092 (2017)Cite this article

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Abstract

A central challenge in evolutionary biology concerns the mechanisms by which complex adaptations arise. Such adaptations depend on the fixation of multiple, highly specific mutations, where intermediate stages of evolution seemingly provide little or no benefit. It is generally assumed that the establishment of complex adaptations is very slow in nature, as evolution of such traits demands special population genetic or environmental circumstances. However, blueprints of complex adaptations in molecular systems are pervasive, indicating that they can readily evolve. We discuss the prospects and limitations of non-adaptive scenarios, which assume numerous neutral or deleterious steps in the evolution of complex adaptations. Next, we examine how complex adaptations can evolve by natural selection in a changing environment. Finally, we argue that molecular ‘springboards’ such as phenotypic heterogeneity and promiscuous interactions facilitate this process by providing access to new adaptive paths.

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Figure 1: Concept of complex adaptations.
Figure 2: Main classes and examples of complex adaptations in molecular systems.
Figure 3: Evolutionary mechanisms of establishing complex adaptations.
Figure 4: Molecular springboards of complex adaptations Molecular mechanisms that potentiate the establishment of complex adaptations by eliminating fitness valleys (A) or opening up more direct mutational paths (B–C).

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References

  1. Smith, J. M. et al. Developmental constraints and evolution: a perspective from the Mountain Lake conference on development and evolution. Q. Rev. Biol. 60, 265–287 (1985).

    Article  Google Scholar 

  2. Darwin, C. On the Origin of Species (John Murray, London, 1859).

  3. Fisher, R. A. The Genetical Theory of Natural Selection: a Complete Variorum Edition (Oxford Univ. Press, Oxford, 1930).

  4. Wright, S. Surfaces of selective value revisited. Am. Nat. 131, 115–123 (1988).

    Article  Google Scholar 

  5. Romero, P. A. & Arnold, F. H. Exploring protein fitness landscapes by directed evolution. Nat. Rev. Mol. Cell. Biol. 10, 866–876 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Banzhaf, W. et al. Guidelines: From artificial evolution to computational evolution: a research agenda. Nat. Rev. Genet. 7, 729–735 (2006).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Parter, M., Kashtan, N. & Alon, U. Facilitated variation: how evolution learns from past environments to generalize to new environments. PLoS Comput. Biol. 4, e1000206 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Wagner, G. P. & Altenberg, L. Perspective: complex adaptations and the evolution of evolvability. Evolution 50, 967–976 (1996).

    Article  PubMed  Google Scholar 

  10. Givnish, T. J. & Sytsma, K. J. Molecular Evolution and Adaptive Radiation (Cambridge Univ. Press, Cambridge, 2000).

  11. Harms, M. J. & Thornton, J. W. Evolutionary biochemistry: revealing the historical and physical causes of protein properties. Nat. Rev. Genet. 14, 559–571 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Meer, M. V., Kondrashov, A. S., Artzy-Randrup, Y. & Kondrashov, F. A. Compensatory evolution in mitochondrial tRNAs navigates valleys of low fitness. Nature 464, 279–282 (2010).

    Article  CAS  PubMed  Google Scholar 

  13. Ivankov, D. N., Finkelstein, A. V. & Kondrashov, F. A. A structural perspective of compensatory evolution. Curr. Opin. Struct. Biol. 26, 104–112 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lynch, M. & Hagner, K. Evolutionary meandering of intermolecular interactions along the drift barrier. Proc. Natl Acad. Sci. USA 112, E30–E38 (2015).

    Article  CAS  PubMed  Google Scholar 

  15. Yamada, T. & Bork, P. Evolution of biomolecular networks: lessons from metabolic and protein interactions. Nat. Rev. Mol. Cell. Biol. 10, 791–803 (2009).

    Article  CAS  PubMed  Google Scholar 

  16. Liu, R. & Ochman, H. Stepwise formation of the bacterial flagellar system. Proc. Natl Acad. Sci. USA 104, 7116–7121 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Pallen, M. J. & Matzke, N. J. From The Origin of Species to the origin of bacterial flagella. Nat. Rev. Microbiol. 4, 784–790 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Pereira-Leal, J. B., Levy, E. D., Kamp, C. & Teichmann, S. A. Evolution of protein complexes by duplication of homomeric interactions. Genome Biol. 8, R51 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Dietrich, M. R. From hopeful monsters to homeotic effects: Richard Goldschmidt’s integration of development, evolution, and genetics. Am. Zool. 40, 738–747 (2000).

    Google Scholar 

  20. Theiβen, G. Saltational evolution: hopeful monsters are here to stay. Theor. Biosci. 128, 43–51 (2009).

    Article  Google Scholar 

  21. Schrider, D., Hourmozdi, J. & Hahn, M. Pervasive multinucleotide mutational events in eukaryotes. Curr. Biol. 21, 1051–1054 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nik-Zainal, S. et al. Mutational processes molding the genomes of 21 breast cancers. Cell 149, 979–993 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. De, S. & Babu, M. M. A time-invariant principle of genome evolution. Proc. Natl Acad. Sci. USA 107, 13004–13009 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hicks, W. M., Kim, M. & Haber, J. E. Increased mutagenesis and unique mutation signature associated with mitotic gene conversion. Science 329, 82–85 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Peisajovich, S. G., Garbarino, J. E., Wei, P. & Lim, W. A. Rapid diversification of cell signaling phenotypes by modular domain recombination. Science 328, 368–372 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhang, Y. X. et al. Genome shuffling leads to rapid phenotypic improvement in bacteria. Nature 415, 644–646 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Gogarten, J. P. & Townsend, J. P. Horizontal gene transfer, genome innovation and evolution. Nat. Rev. Microbiol. 3, 679–687 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Pál, C., Papp, B. & Lercher, M. J. Adaptive evolution of bacterial metabolic networks by horizontal gene transfer. Nat. Genet. 37, 1372–1375 (2005).

    Article  PubMed  CAS  Google Scholar 

  29. Sheltzer, J. M. & Amon, A. The aneuploidy paradox: costs and benefits of an incorrect karyotype. Trends Genet. 27, 446–453 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rancati, G. et al. Aneuploidy underlies rapid adaptive evolution of yeast cells deprived of a conserved cytokinesis motor. Cell 135, 879–893 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lynch, M. The evolution of genetic networks by non-adaptive processes. Nat. Rev. Genet. 8, 803–813 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Amitai, G., Gupta, R. D. & Tawfik, D. S. Latent evolutionary potentials under the neutral mutational drift of an enzyme. HFSP J. 1, 67–78 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wagner, A. The Origins of Evolutionary Innovations: a Theory of Transformative Change in Living Systems (Oxford Univ. Press, Oxford, 2011).

  34. Hayden, E. J., Ferrada, E. & Wagner, A. Cryptic genetic variation promotes rapid evolutionary adaptation in an RNA enzyme. Nature 474, 92–95 (2011).

    Article  CAS  PubMed  Google Scholar 

  35. Bershtein, S., Goldin, K. & Tawfik, D. S. Intense neutral drifts yield robust and evolvable consensus proteins. J. Mol. Biol. 379, 1029–1044 (2008).

    Article  CAS  PubMed  Google Scholar 

  36. Bloom, J. D., Romero, P. A., Lu, Z. & Arnold, F. H. Neutral genetic drift can alter promiscuous protein functions, potentially aiding functional evolution. Biol. Direct 2, 17 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Gray, M. W., Lukes, J., Archibald, J. M., Keeling, P. J. & Doolittle, W. F. Cell biology. Irremediable complexity? Science 330, 920–921 (2010).

    CAS  PubMed  Google Scholar 

  38. Lynch, M. The evolution of multimeric protein assemblages. Mol. Biol. Evol. 29, 1353–1366 (2012).

    Article  CAS  PubMed  Google Scholar 

  39. Anderson, D. W., McKeown, A. N. & Thornton, J. W. Intermolecular epistasis shaped the function and evolution of an ancient transcription factor and its DNA binding sites. eLife 4, e07864 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Finnigan, G. C., Hanson-Smith, V., Stevens, T. H. & Thornton, J. W. Evolution of increased complexity in a molecular machine. Nature 481, 360–364 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Petrie, K. L. & Joyce, G. F. Limits of neutral drift: lessons from the in vitro evolution of two ribozymes. J. Mol. Evol. 79, 75–90 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Smith, W. S., Hale, J. R. & Neylon, C. Applying neutral drift to the directed molecular evolution of a β-glucuronidase into a β-galactosidase: two different evolutionary pathways lead to the same variant. BMC Res. Notes 4, 138 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Szappanos, B. et al. Adaptive evolution of complex innovations through stepwise metabolic niche expansion. Nat. Commun. 7, 11607 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Mira, A., Ochman, H. & Moran, N. A. Deletional bias and the evolution of bacterial genomes. Trends Genet. 17, 589–596 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Kuo, C. H. & Ochman, H. Deletional bias across the three domains of life. Genome Biol. Evol. 1, 145–152 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Meléndez-Hevia, E., Waddell, T. G. & Cascante, M. The puzzle of the Krebs citric acid cycle: assembling the pieces of chemically feasible reactions, and opportunism in the design of metabolic pathways during evolution. J. Mol. Evol. 43, 293–303 (1996).

    Article  PubMed  Google Scholar 

  47. Huynen, M. A., Dandekar, T. & Bork, P. Variation and evolution of the citric-acid cycle: a genomic perspective. Trends Microbiol. 7, 281–291 (1999).

    Article  CAS  PubMed  Google Scholar 

  48. Lenski, R. E., Ofria, C., Pennock, R. T. & Adami, C. The evolutionary origin of complex features. Nature 423, 139–144 (2003).

    Article  CAS  PubMed  Google Scholar 

  49. Notebaart, R. A., Kensche, P. R., Huynen, M. A. & Dutilh, B. E. Asymmetric relationships between proteins shape genome evolution. Genome Biol. 10, R19 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Madan Babu, M., Teichmann, S. A. & Aravind, L. Evolutionary dynamics of prokaryotic transcriptional regulatory networks. J. Mol. Biol. 358, 614–633 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Costanzo, M. et al. A global genetic interaction network maps a wiring diagram of cellular function. Science 353, aaf1420 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Chen, H. D., Jewett, M. W. & Groisman, E. A. Ancestral genes can control the ability of horizontally acquired loci to confer new traits. PLoS Genet. 7, e1002184 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Press, M. O., Queitsch, C. & Borenstein, E. Evolutionary assembly patterns of prokaryotic genomes. Genome Res. 26, 826–833 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 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 

  55. Wu, N. C., Dai, L., Olson, C. A., Lloyd-Smith, J. O. & Sun, R. Adaptation in protein fitness landscapes is facilitated by indirect paths. eLife 5, e16965 (2016).

    PubMed  PubMed Central  Google Scholar 

  56. Palmer, A. C. et al. Delayed commitment to evolutionary fate in antibiotic resistance fitness landscapes. Nat. Commun. 6, 7385 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Weinreich, D. M., Lan, Y., Wylie, C. S. & Heckendorn, R. B. Should evolutionary geneticists worry about higher-order epistasis? Curr. Opin. Genet. Dev 23, 700–707 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Mustonen, V. & Lässig, M. From fitness landscapes to seascapes: non-equilibrium dynamics of selection and adaptation. Trends Genet. 25, 111–119 (2009).

    Article  CAS  PubMed  Google Scholar 

  59. Wagner, A. The white-knight hypothesis, or does the environment limit innovations? Trends Ecol. Evol. 32, 131–140 (2017).

    Article  PubMed  Google Scholar 

  60. Kashtan, N., Noor, E. & Alon, U. Varying environments can speed up evolution. Proc. Natl Acad. Sci. USA 104, 13711–13716 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Horowitz, N. H. On the evolution of biochemical syntheses. Proc. Natl Acad. Sci. USA 31, 153–157 (1945).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bell, G. Fluctuating selection: the perpetual renewal of adaptation in variable environments. Phil. Trans. R. Soc. B 365, 87–97 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Hayden, E. J. & Wagner, A. Environmental change exposes beneficial epistatic interactions in a catalytic RNA. Proc. R. Soc. B 279, 3418–3425 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Taute, K. M., Gude, S., Nghe, P. & Tans, S. J. Evolutionary constraints in variable environments, from proteins to networks. Trends Genet. 30, 192–198 (2014).

    Article  CAS  PubMed  Google Scholar 

  65. Bershtein, S. & Tawfik, D. S. Ohno’s model revisited: measuring the frequency of potentially adaptive mutations under various mutational drifts. Mol. Biol. Evol. 25, 2311–2318 (2008).

    Article  CAS  PubMed  Google Scholar 

  66. Stiffler, M. A., Hekstra, D. R. & Ranganathan, R. Evolvability as a function of purifying selection in TEM-1 β-lactamase. Cell 160, 882–892 (2015).

    Article  CAS  PubMed  Google Scholar 

  67. Steinberg, B. & Ostermeier, M. Environmental changes bridge evolutionary valleys. Sci. Adv. 2, e1500921–e1500921 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. de Vos, M. G., Dawid, A., Sunderlikova, V. & Tans, S. J. Breaking evolutionary constraint with a tradeoff ratchet. Proc. Natl Acad. Sci. USA 112, 14906–14911 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Blount, Z. D., Borland, C. Z. & Lenski, R. E. Historical contingency and the evolution of a key innovation in an experimental population of Escherichia coli. Proc. Natl Acad. Sci. USA 105, 7899–7906 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Lázár, V. et al. Bacterial evolution of antibiotic hypersensitivity. Mol. Syst. Biol. 9, 700 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. 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  CAS  PubMed  PubMed Central  Google Scholar 

  72. Gong, L. I., Suchard, M. A. & Bloom, J. D. Stability-mediated epistasis constrains the evolution of an influenza protein. eLife 2, e00631 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Bogumil, D. & Dagan, T. Cumulative impact of chaperone-mediated folding on genome evolution. Biochemistry 51, 9941–9953 (2012).

    Article  CAS  PubMed  Google Scholar 

  74. Fares, M. A., Moya, A. & Barrio, E. GroEL and the maintenance of bacterial endosymbiosis. Trends Genet. 20, 413–416 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Tokuriki, N. & Tawfik, D. S. Chaperonin overexpression promotes genetic variation and enzyme evolution. Nature 459, 668–673 (2009).

    Article  CAS  PubMed  Google Scholar 

  76. Copley, S. D. An evolutionary biochemist’s perspective on promiscuity. Trends Biochem. Sci. 40, 72–78 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Notebaart, R. A. et al. Network-level architecture and the evolutionary potential of underground metabolism. Proc. Natl Acad. Sci. USA 111, 11762–11767 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Levy, E. D., Landry, C. R. & Michnick, S. W. How perfect can protein interactomes be? Sci. Signal. 2, pe11 (2009).

    Article  PubMed  Google Scholar 

  79. Aharoni, A. et al. The ‘evolvability’ of promiscuous protein functions. Nat. Genet. 37, 73–76 (2004).

    Article  PubMed  CAS  Google Scholar 

  80. Aakre, C. D. et al. Evolving new protein-protein interaction specificity through promiscuous intermediates. Cell 163, 594–606 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Copley, S. D. Evolution of a metabolic pathway for degradation of a toxic xenobiotic: the patchwork approach. Trends Biochem. Sci. 25, 261–265 (2000).

    Article  CAS  PubMed  Google Scholar 

  82. 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 

  83. Nourmohammad, A. & Lässig, M. Formation of regulatory modules by local sequence duplication. PLoS Comput. Biol. 7, e1002167 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Yanagida, H. et al. The evolutionary potential of phenotypic mutations. PLoS Genet. 11, e1005445 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Whitehead, D. J., Wilke, C. O., Vernazobres, D. & Bornberg-Bauer, E. The look-ahead effect of phenotypic mutations. Biol. Direct 3, 18 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Kalapis, D. et al. Evolution of robustness to protein mistranslation by accelerated protein turnover. PLoS Biol. 13, e1002291 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Pouplana, L. R., Santos, M. A., Zhu, J. H., Farabaugh, P. J. & Javid, B. Protein mistranslation: friend or foe? Trends Biochem. Sci. 39, 355–362 (2014).

    Article  CAS  Google Scholar 

  88. Weinreich, D. M. & Chao, L. Rapid evolutionary escape by large populations from local fitness peaks is likely in nature. Evolution 59, 1175–1182 (2005).

    Article  CAS  PubMed  Google Scholar 

  89. Bloom, J. D., Gong, L. I. & Baltimore, D. Permissive secondary mutations enable the evolution of influenza oseltamivir resistance. Science 328, 1272–1275 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Trudeau, D. L., Kaltenbach, M. & Tawfik, D. S. On the potential origins of the high stability of reconstructed ancestral proteins. Mol. Biol. Evol. 33, 2633–2641 (2016).

    Article  CAS  PubMed  Google Scholar 

  91. Qian, W., Ma, D., Xiao, C., Wang, Z. & Zhang, J. The genomic landscape and evolutionary resolution of antagonistic pleiotropy in yeast. Cell Rep. 2, 1399–1410 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Fowler, D. M. & Fields, S. Deep mutational scanning: a new style of protein science. Nat. Methods 11, 801–807 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Wang, H. H. et al. Programming cells by multiplex genome engineering and accelerated evolution. Nature 460, 894–898 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Nyerges, Á. et al. A highly precise and portable genome engineering method allows comparison of mutational effects across bacterial species. Proc. Natl Acad. Sci. USA 113, 2502–2507 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Lutz, S. Beyond directed evolution—semi-rational protein engineering and design. Curr. Opin. Biotechnol. 21, 734–743 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Tokuriki, N. & Tawfik, D. S. Stability effects of mutations and protein evolvability. Curr. Opin. Struct. Biol. 19, 596–604 (2009).

    Article  CAS  PubMed  Google Scholar 

  97. Goldsmith, M. & Tawfik, D. S. Enzyme engineering by targeted libraries. Methods Enzymol. 523, 257–283 (2013).

    Article  CAS  PubMed  Google Scholar 

  98. O’Neill, M., Vanneschi, L., Gustafson, S. & Banzhaf, W. Open issues in genetic programming. Genet. Program. Evol. M 11, 339–363 (2010).

    Article  Google Scholar 

  99. Coyne, J. A., Barton, N. H. & Turelli, M. Perspective: a critique of Sewall Wright’s shifting balance theory of evolution. Evolution 51, 643–671 (1997).

    Article  PubMed  Google Scholar 

  100. Orr, H. A. The genetic theory of adaptation: a brief history. Nat. Rev. Genet. 6, 119–127 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Doniger, S. W. et al. A catalog of neutral and deleterious polymorphism in yeast. PLoS Genet. 4, e1000183 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Henn, B. M., Botigué, L. R., Bustamante, C. D., Clark, A. G. & Gravel, S. Estimating the mutation load in human genomes. Nat. Rev. Genet. 16, 333–343 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. MacArthur, D. G. et al. A systematic survey of loss-of-function variants in human protein-coding genes. Science 335, 823–828 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Lynch, M. & Abegg, A. The rate of establishment of complex adaptations. Mol. Biol. Evol. 27, 1404–1414 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Lynch, M. Scaling expectations for the time to establishment of complex adaptations. Proc. Natl Acad. Sci. USA 107, 16577–16582 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Weissman, D. B., Feldman, M. W. & Fisher, D. S. The rate of fitness-valley crossing in sexual populations. Genetics 186, 1389–1410 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Ramani, A. K. & Marcotte, E. M. Exploiting the co-evolution of interacting proteins to discover interaction specificity. J. Mol. Biol. 327, 273–284 (2003).

    Article  CAS  PubMed  Google Scholar 

  108. Podgornaia, A. I. & Laub, M. T. Pervasive degeneracy and epistasis in a protein–protein interface. Science 347, 673–677 (2015).

    Article  CAS  PubMed  Google Scholar 

  109. Bridgham, J. T., Ortlund, E. A. & Thornton, J. W. An epistatic ratchet constrains the direction of glucocorticoid receptor evolution. Nature 461, 515–519 (2009).

    Article  CAS  PubMed  Google Scholar 

  110. Papp, B., Notebaart, R. A. & Pál, C. Systems-biology approaches for predicting genomic evolution. Nat. Rev. Genet. 12, 591–602 (2011).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank D. Tawfik for his valuable comments on an earlier version of this paper. This work was supported by the ‘Lendület’ programme of the Hungarian Academy of Sciences (B.P. and C.P.), the Wellcome Trust (C.P. and B.P.), H202-ERC-2014-CoG (C.P.), GINOP-2.3.2-15-2016-00014 (EVOMER, C.P. and B.P.) and GINOP-2.3.2-15-2016-00020 (MolMedEx TUMORDNS, C.P.).

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    Csaba Pál & Balázs Papp

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Pál, C., Papp, B. Evolution of complex adaptations in molecular systems. Nat Ecol Evol 1, 1084–1092 (2017). https://doi.org/10.1038/s41559-017-0228-1

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