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Cryptic genetic variation promotes rapid evolutionary adaptation in an RNA enzyme

Nature volume 474, pages 92–95 (2011)Cite this article

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Abstract

Cryptic variation is caused by the robustness of phenotypes to mutations1. Cryptic variation has no effect on phenotypes in a given genetic or environmental background, but it can have effects after mutations or environmental change2,3,4,5. Because evolutionary adaptation by natural selection requires phenotypic variation, phenotypically revealed cryptic genetic variation may facilitate evolutionary adaptation6,7,8. This is possible if the cryptic variation happens to be pre-adapted, or “exapted”9, to a new environment, and is thus advantageous once revealed. However, this facilitating role for cryptic variation has not been proven, partly because most pertinent work focuses on complex phenotypes of whole organisms whose genetic basis is incompletely understood. Here we show that populations of RNA enzymes with accumulated cryptic variation adapt more rapidly to a new substrate than a population without cryptic variation. A detailed analysis of our evolving RNA populations in genotype space shows that cryptic variation allows a population to explore new genotypes that become adaptive only in a new environment. Our observations show that cryptic variation contains new genotypes pre-adapted to a changed environment. Our results highlight the positive role that robustness and epistasis can have in adaptive evolution10,11.

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Figure 1: Evolution during selection for the native activity.
Figure 2: Evolution during selection for the new activity.
Figure 3: Evolution in genotype space.

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References

  1. Wagner, A. Robustness and Evolvability in Living Systems. (Princeton University Press, 2005)

    Google Scholar 

  2. Gibson, G. & Dworkin, I. Uncovering cryptic genetic variation. Nature Rev. Genet. 5, 681–690 (2004)

    Article  CAS  Google Scholar 

  3. Waddington, C. H. Genetic assimilation of an acquired character. Evolution 7, 118–126 (1953)

    Article  Google Scholar 

  4. Rutherford, S. L. From genotype to phenotype: buffering mechanisms and the storage of genetic information. Bioessays 22, 1095–1105 (2000)

    Article  CAS  Google Scholar 

  5. Le Rouzic, A. & Carlborg, O. Evolutionary potential of hidden genetic variation. Trends Ecol. Evol. 23, 33–37 (2008)

    Article  Google Scholar 

  6. Rutherford, S. L. & Lindquist, S. Hsp90 as a capacitor for morphological evolution. Nature 396, 336–342 (1998)

    Article  ADS  CAS  Google Scholar 

  7. True, H. L. & Lindquist, S. L. A yeast prion provides a mechanism for genetic variation and phenotypic diversity. Nature 407, 477–483 (2000)

    Article  ADS  CAS  Google Scholar 

  8. Masel, J. Cryptic genetic variation is enriched for potential adaptations. Genetics 172, 1985–1991 (2006)

    Article  CAS  Google Scholar 

  9. Gould, S. J. & Vrba, E. S. Exaptation—a missing term in the science of form. Paleobiology 8, 4–15 (1982)

    Article  Google Scholar 

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

    Article  Google Scholar 

  11. 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 

  12. Tanner, M. & Cech, T. Activity and thermostability of the small self-splicing group I intron in the pre-tRNA(lle) of the purple bacterium Azoarcus . RNA 2, 74–83 (1996)

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Kuo, L. Y., Davidson, L. A. & Pico, S. Characterization of the Azoarcus ribozyme: tight binding to guanosine and substrate by an unusually small group I ribozyme. Biochim. Biophys. Acta 1489, 281–292 (1999)

    Article  CAS  Google Scholar 

  14. Stahley, M. R. & Strobel, S. A. Structural evidence for a two-metal-ion mechanism of group I intron splicing. Science 309, 1587–1590 (2005)

    Article  ADS  CAS  Google Scholar 

  15. Rangan, P., Masquida, B., Westhof, E. & Woodson, S. A. Assembly of core helices and rapid tertiary folding of a small bacterial group I ribozyme. Proc. Natl Acad. Sci. USA 100, 1574–1579 (2003)

    Article  ADS  CAS  Google Scholar 

  16. Pan, J. & Woodson, S. A. Folding intermediates of a self-splicing RNA: mispairing of the catalytic core. J. Mol. Biol. 280, 597–609 (1998)

    Article  CAS  Google Scholar 

  17. Beaudry, A. A. & Joyce, G. F. Directed evolution of an RNA enzyme. Science 257, 635–641 (1992)

    Article  ADS  CAS  Google Scholar 

  18. Lehman, N. & Joyce, G. F. Evolution in vitro of an RNA enzyme with altered metal dependence. Nature 361, 182–185 (1993)

    Article  ADS  CAS  Google Scholar 

  19. Blake, R. D. & Delcourt, S. G. Thermodynamic effects of formamide on DNA stability. Nucleic Acids Res. 24, 2095–2103 (1996)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  21. Hartl, D. L. & Clark, A. G. Principles of Population Genetics. (Sinauer Associates, 1997)

    Google Scholar 

  22. Hanczyc, M. M. & Dorit, R. L. Experimental evolution of complexity: in vitro emergence of intermolecular ribozyme interactions. RNA 4, 268–275 (1998)

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Lawrence, M. S. & Bartel, D. P. New ligase-derived RNA polymerase ribozymes. RNA 11, 1173–1180 (2005)

    Article  CAS  Google Scholar 

  24. Ouellet, J., Byrne, M. & Lilley, D. M. Formation of an active site in trans by interaction of two complete Varkud Satellite ribozymes. RNA 15, 1822–1826 (2009)

    Article  CAS  Google Scholar 

  25. Kondrashov, F. A. & Kondrashov, A. S. Multidimensional epistasis and the disadvantage of sex. Proc. Natl Acad. Sci. USA 98, 12089–12092 (2001)

    Article  ADS  CAS  Google Scholar 

  26. Wilke, C., Lenski, R. & Adami, C. Compensatory mutations cause excess of antagonistic epistasis in RNA secondary structure folding. BMC Evol. Biol. 3, 3 (2003)

    Article  Google Scholar 

  27. 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 

  28. Hermisson, J. & Wagner, G. P. The population genetic theory of hidden variation and genetic robustness. Genetics 168, 2271–2284 (2004)

    Article  Google Scholar 

  29. Rydzanicz, R., Zhao, X. S. & Johnson, P. E. Assembly PCR oligo maker: a tool for designing oligodeoxynucleotides for constructing long DNA molecules for RNA production. Nucleic Acids Res. 33, W521–W525 (2005)

    Article  CAS  Google Scholar 

  30. Hochberg, Y. & Benjamini, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Stat. Soc. B 57, 289–300 (1995)

    MathSciNet  MATH  Google Scholar 

  31. Cadwell, R. C. & Joyce, G. F. Randomization of genes by PCR mutagenesis. Genome Res. 2, 28–33 (1992)

    Article  CAS  Google Scholar 

  32. Eckert, K. A. & Kunkel, T. A. DNA polymerase fidelity and the polymerase chain reaction. Genome Res. 1, 17–24 (1991)

    Article  CAS  Google Scholar 

  33. Breaker, R. R. & Joyce, G. F. Inventing and improving ribozyme function: Rational design versus iterative selection methods. Trends Biotechnol. 12, 268–275 (1994)

    Article  CAS  Google Scholar 

  34. Needleman, S. B. & Wunsch, C. D. A general method applicable to the search for similarities in the amino acid sequence of two proteins. J. Mol. Biol. 48, 443–453 (1970)

    Article  CAS  Google Scholar 

  35. Yu, W., Rusterholtz, K. J., Krummel, A. T. & Lehman, N. Detection of high levels of recombination generated during PCR amplification of RNA templates. Biotechniques 40, 499–507 (2006)

    Article  CAS  Google Scholar 

  36. Li, W. & Godzik, A. Cd-hit: a fast program for clustering and comparing large sets of protein or nucleotide sequences. Bioinformatics 22, 1658–1659 (2006)

    Article  CAS  Google Scholar 

  37. Guindon, S. & Gascuel, O. A simple, fast, and accurate algorithm to estimate large phylogenies by maximum likelihood. Syst. Biol. 52, 696–704 (2003)

    Article  Google Scholar 

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Acknowledgements

We thank R. Dhar and N. de la Chaux for bioinformatic support. We thank the Functional Genomics Center, Zurich, for collecting sequence data. We acknowledge support from Swiss National Science Foundation grants 315200-116814, 315200-119697 and 315230-129708, from the YeastX program of SystemsX.ch, and from the Research Priority Program in Systems Biology at the University of Zurich.

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Authors and Affiliations

  1. Institute of Evolutionary Biology and Environmental Studies, University of Zurich, 8057 Zurich, Switzerland ,

    Eric J. Hayden, Evandro Ferrada & Andreas Wagner

  2. The Swiss Institute of Bioinformatics, Quartier Sorge-Batiment Genopode, 1015 Lausanne, Switzerland ,

    Eric J. Hayden, Evandro Ferrada & Andreas Wagner

  3. The Santa Fe Institute, 1399 Hyde Park Road, Santa Fe, 87501, New Mexico, USA

    Andreas Wagner

Authors
  1. Eric J. Hayden
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  2. Evandro Ferrada
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  3. Andreas Wagner
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Contributions

E.J.H. and A.W. contributed to the design of the experiments; E.J.H. performed the experiments; E.J.H., E.F., and A.W. all contributed to analysis of the data and co-wrote the paper.

Corresponding author

Correspondence to Andreas Wagner.

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The authors declare no competing financial interests.

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Hayden, E., Ferrada, E. & Wagner, A. Cryptic genetic variation promotes rapid evolutionary adaptation in an RNA enzyme. Nature 474, 92–95 (2011). https://doi.org/10.1038/nature10083

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