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Epigenetic gene silencing alters the mechanisms and rate of evolutionary adaptation

Nature Ecology & Evolution (2019) | Download Citation


Epigenetic, non-DNA sequence-based inheritance can potentially contribute to adaptation but, due to its transient nature and the difficulty involved in uncoupling it from genetic variation, it is unclear whether it has any effect on long-term evolution. However, short-term epigenetic inheritance may interact with genetic change by modifying the rate and type of adaptive mutations. Here, we test this notion in an experimental evolution set-up in yeast. We tune low, intermediate and high levels of heritable silencing of a URA3 reporter under selection by insertion at different positions within silent subtelomeric chromatin in otherwise isogenic Saccharomyces cerevisiae. Heritable silencing does not impact mutation rate but drives population size expansion and rapid epigenetic adaptation. This eventually leads to genetic assimilation of the silent phenotype by mutations that reduce or abolish URA3 expression. Moreover, at intermediate or low levels of heritable silencing we find that populations evolve more rapidly by accumulation of adaptive mutations, in part through acquisition of novel alleles that enhance gene silencing, aiding accelerated adaptation. We provide an experimental proof of concept that defines the impact and mechanisms of how short-term epigenetic inheritance can shape adaptive evolution.

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Data availability

Whole-genome sequence data for all strains listed in Supplementary Fig. 6 are available at the National Center for Biotechnology Information Sequence Read Archive, accession no. SRP129019.

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  1. 1.

    Johannes, F. et al. Assessing the impact of transgenerational epigenetic variation on complex traits. PLoS Genet. 5, e1000530 (2009).

  2. 2.

    Cortijo, S. et al. Mapping the epigenetic basis of complex traits. Science 343, 1145–1148 (2014).

  3. 3.

    Heard, E. & Martienssen, R. A. Transgenerational epigenetic inheritance: myths and mechanisms. Cell 157, 95–109 (2014).

  4. 4.

    Simpson, G. G. The Baldwin effect. Evolution 7, 110 (1953).

  5. 5.

    Waddington, C. H. Canalization of development and genetic assimilation of acquired characters. Nature 183, 1654–1655 (1959).

  6. 6.

    Lande, R. Adaptation to an extraordinary environment by evolution of phenotypic plasticity and genetic assimilation. J. Evol. Biol. 22, 1435–1446 (2009).

  7. 7.

    Cowen, L. E. & Lindquist, S. Hsp90 potentiates the rapid evolution of new traits: drug resistance in diverse fungi. Science 309, 2185–2189 (2005).

  8. 8.

    Jarosz, D. F. & Lindquist, S. Hsp90 and environmental stress transform the adaptive value of natural genetic variation. Science 330, 1820–1824 (2010).

  9. 9.

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

  10. 10.

    Halfmann, R. et al. Prions are a common mechanism for phenotypic inheritance in wild yeasts. Nature 482, 363–368 (2012).

  11. 11.

    Klosin, A., Casas, E., Hidalgo-Carcedo, C., Vavouri, T. & Lehner, B. Transgenerational transmission of environmental information in C. elegans. Science 356, 320–323 (2017).

  12. 12.

    Daxinger, L. & Whitelaw, E. Understanding transgenerational epigenetic inheritance via the gametes in mammals. Nat. Rev. Genet. 13, 153–162 (2012).

  13. 13.

    Bonduriansky, R. & Day, T. Nongenetic inheritance and its evolutionary implications. Annu. Rev. Ecol. Evol. Syst. 40, 103–125 (2009).

  14. 14.

    Klironomos, F. D., Berg, J. & Collins, S. How epigenetic mutations can affect genetic evolution: model and mechanism. Bioessays 35, 571–578 (2013).

  15. 15.

    Kronholm, I. & Collins, S. Epigenetic mutations can both help and hinder adaptive evolution. Mol. Ecol. 25, 1856–1868 (2016).

  16. 16.

    Charlesworth, D., Barton, N. H. & Charlesworth, B. The sources of adaptive variation. Proc. Biol. Sci. 284, 20162864 (2017).

  17. 17.

    Rine, J. & Herskowitz, I. Four genes responsible for a position effect on expression from HML and HMR in Saccharomyces cerevisiae. Genetics 116, 9–22 (1987).

  18. 18.

    Aparicio, O. M., Billington, B. L. & Gottschling, D. E. Modifiers of position effect are shared between telomeric and silent mating-type loci in S. cerevisiae. Cell 66, 1279–1287 (1991).

  19. 19.

    Ivy, J. M., Klar, A. J. & Hicks, J. B. Cloning and characterization of four SIR genes of Saccharomyces cerevisiae. Mol. Cell. Biol. 6, 688–702 (1986).

  20. 20.

    Imai, S., Armstrong, C. M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795–800 (2000).

  21. 21.

    Moazed, D. Mechanisms for the inheritance of chromatin states. Cell 146, 510–518 (2011).

  22. 22.

    Pryde, F. E. & Louis, E. J. Limitations of silencing at native yeast telomeres. EMBO J. 18, 2538–2550 (1999).

  23. 23.

    Jeffery, D. C. B. et al. Analysis of epigenetic stability and conversions in Saccharomyces cerevisiae reveals a novel role of CAF-I in position-effect variegation. Nucleic Acids Res. 41, 8475–8488 (2013).

  24. 24.

    Boeke, J. D., Trueheart, J., Natsoulis, G. & Fink, G. R. 5-Fluoroorotic acid as a selective agent in yeast molecular genetics. Meth. Enzymol. 154, 164–175 (1987).

  25. 25.

    Gottschling, D. E., Aparicio, O. M., Billington, B. L. & Zakian, V. A. Position effect at S. cerevisiae telomeres: reversible repression of Pol II transcription. Cell 63, 751–762 (1990).

  26. 26.

    Ellahi, A., Thurtle, D. M. & Rine, J. The chromatin and transcriptional landscape of native Saccharomyces cerevisiae telomeres and subtelomeric domains. Genetics 200, 505–521 (2015).

  27. 27.

    Gerrish, P. J. & Lenski, R. E. The fate of competing beneficial mutations in an asexual population. Genetica 102-103, 127–144 (1998).

  28. 28.

    Batté, A. et al. Recombination at subtelomeres is regulated by physical distance, double-strand break resection and chromatin status. EMBO J. 36, 2609–2625 (2017).

  29. 29.

    Lang, G. I. & Murray, A. W. Estimating the per-base-pair mutation rate in the yeast Saccharomyces cerevisiae. Genetics 178, 67–82 (2008).

  30. 30.

    Lang, G. I. & Murray, A. W. Mutation rates across budding yeast chromosome VI are correlated with replication timing. Genome Biol. Evol. 3, 799–811 (2011).

  31. 31.

    Ricchetti, M., Dujon, B. & Fairhead, C. Distance from the chromosome end determines the efficiency of double strand break repair in subtelomeres of haploid yeast. J. Mol. Biol. 328, 847–862 (2003).

  32. 32.

    Renauld, H. et al. Silent domains are assembled continuously from the telomere and are defined by promoter distance and strength, and by SIR3 dosage. Genes Dev. 7, 1133–1145 (1993).

  33. 33.

    Aparicio, O. M. & Gottschling, D. E. Overcoming telomeric silencing: a trans-activator competes to establish gene expression in a cell cycle-dependent way. Genes Dev. 8, 1133–1146 (1994).

  34. 34.

    Zhou, J., Zhou, B. O., Lenzmeier, B. A. & Zhou, J.-Q. Histone deacetylase Rpd3 antagonizes Sir2-dependent silent chromatin propagation. Nucleic Acids Res. 37, 3699–3713 (2009).

  35. 35.

    Bitterman, K. J., Anderson, R. M., Cohen, H. Y., Latorre-Esteves, M. & Sinclair, D. A. Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1. J. Biol. Chem. 277, 45099–45107 (2002).

  36. 36.

    Youngson, N. A. & Whitelaw, E. Transgenerational epigenetic effects. Annu. Rev. Genomics Hum. Genet. 9, 233–257 (2008).

  37. 37.

    Mortimer, R. K. & Johnston, J. R. Genealogy of principal strains of the yeast genetic stock center. Genetics 113, 35–43 (1986).

  38. 38.

    Goldstein, A. L. & McCusker, J. H. Three new dominant drug resistance cassettes for gene disruption in Saccharomyces cerevisiae. Yeast 15, 1541–1553 (1999).

  39. 39.

    Deatherage, D. E. & Barrick, J. E. Identification of mutations in laboratory-evolved microbes from next-generation sequencing data using breseq. Methods Mol. Biol. 1151, 165–188 (2014).

  40. 40.

    Rosche, W. A. & Foster, P. L. Determining mutation rates in bacterial populations. Methods 20, 4–17 (2000).

  41. 41.

    R Core Team. R: A Language and Environment for Statistical Computing (R Foundation for Statistical Computing, Vienna, 2013).

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We thank R. Kolodner (University of California, San Diego) and E. Louis (University of Leicester) for strains, and I. Gordo, P. Beldade, C. Bank, M. Ferreira (all Instituto Gulbenkian de Ciência), L.-M. Chevin (Centre National de la Recherche Scientifique, Montpellier) and T. Flatt (University of Fribourg) for helpful comments and suggestions. We acknowledge the Instituto Gulbenkian de Ciência Gene Expression Unit for genome sequencing support. Salary support to D.S. was provided by the Fundação para a Ciência e a Tecnologia fellowship (no. SFRH/BD/52170/2013), and Investigador FCT positions to L.P. and L.E.T.J. This work was supported by the Instituto Gulbenkian de Ciência.

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  1. Instituto Gulbenkian de Ciência, Oeiras, Portugal

    • Dragan Stajic
    • , Lília Perfeito
    •  & Lars E. T. Jansen
  2. Department of Biochemistry, University of Oxford, Oxford, UK

    • Lars E. T. Jansen


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D.S., L.P. and L.J. conceived the study and designed the experiments. D.S. constructed the strains and performed the experiments. D.S., L.P. and L.J. critically analysed the data. D.S. and L.J. created the figures. D.S., L.P. and L.J. wrote the manuscript. L.P. and L.J. provided resources, funding and supervision.

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The authors declare no competing interests.

Corresponding authors

Correspondence to Lília Perfeito or Lars E. T. Jansen.

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