Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Epigenetic gene silencing alters the mechanisms and rate of evolutionary adaptation


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

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.


  1. 1.

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

    Article  Google Scholar 

  2. 2.

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

    CAS  Article  Google Scholar 

  3. 3.

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

    CAS  Article  Google Scholar 

  4. 4.

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

    Article  Google Scholar 

  5. 5.

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

    CAS  Article  Google Scholar 

  6. 6.

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

    Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  8. 8.

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  10. 10.

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  12. 12.

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

    CAS  Article  Google Scholar 

  13. 13.

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

    Article  Google Scholar 

  14. 14.

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

    Article  Google Scholar 

  15. 15.

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

    CAS  Article  Google Scholar 

  16. 16.

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

    Article  Google Scholar 

  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).

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  21. 21.

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

    CAS  Article  Google Scholar 

  22. 22.

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

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  27. 27.

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

    CAS  Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  36. 36.

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

    CAS  Article  Google Scholar 

  37. 37.

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

    CAS  PubMed  PubMed Central  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  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).

    CAS  Article  Google Scholar 

  40. 40.

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

    CAS  Article  Google Scholar 

  41. 41.

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

Download references


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.

Author information




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.

Corresponding authors

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

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Stajic, D., Perfeito, L. & Jansen, L.E.T. Epigenetic gene silencing alters the mechanisms and rate of evolutionary adaptation. Nat Ecol Evol 3, 491–498 (2019).

Download citation

Further reading


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing