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.

Prions are a common mechanism for phenotypic inheritance in wild yeasts


The self-templating conformations of yeast prion proteins act as epigenetic elements of inheritance. Yeast prions might provide a mechanism for generating heritable phenotypic diversity that promotes survival in fluctuating environments and the evolution of new traits. However, this hypothesis is highly controversial. Prions that create new traits have not been found in wild strains, leading to the perception that they are rare ‘diseases’ of laboratory cultivation. Here we biochemically test approximately 700 wild strains of Saccharomyces for [PSI+] or [MOT3+], and find these prions in many. They conferred diverse phenotypes that were frequently beneficial under selective conditions. Simple meiotic re-assortment of the variation harboured within a strain readily fixed one such trait, making it robust and prion-independent. Finally, we genetically screened for unknown prion elements. Fully one-third of wild strains harboured them. These, too, created diverse, often beneficial phenotypes. Thus, prions broadly govern heritable traits in nature, in a manner that could profoundly expand adaptive opportunities.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Figure 1: Identification and verification of prions in wild yeast.
Figure 2: Prion-contingent phenotypes of [ PSI + ] isolates.
Figure 3: Genetic assimilation of the [ PSI + ]-dependent adhesive phenotype in meiotic progeny of UCD978.
Figure 4: Prions of the cell wall-remodelling transcription factor, Mot3, have diverse phenotypic consequences in wild strains.
Figure 5: The curable Hsp104-dependent epigenetic elements in wild yeast can be cytoplasmically transferred.


  1. 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 

  2. Patino, M. M., Liu, J. J., Glover, J. R. & Lindquist, S. Support for the prion hypothesis for inheritance of a phenotypic trait in yeast. Science 273, 622–626 (1996)

    Article  ADS  CAS  Google Scholar 

  3. Chernoff, Y. O., Lindquist, S. L., Ono, B., Inge-Vechtomov, S. G. & Liebman, S. W. Role of the chaperone protein Hsp104 in propagation of the yeast prion-like factor [psi+]. Science 268, 880–884 (1995)

    Article  ADS  CAS  Google Scholar 

  4. Kryndushkin, D. S., Alexandrov, I. M., Ter-Avanesyan, M. D. & Kushnirov, V. V. Yeast [PSI+] prion aggregates are formed by small Sup35 polymers fragmented by Hsp104. J. Biol. Chem. 278, 49636–49643 (2003)

    Article  CAS  Google Scholar 

  5. Chernoff, Y. O., Newnam, G. P., Kumar, J., Allen, K. & Zink, A. D. Evidence for a protein mutator in yeast: role of the Hsp70-related chaperone Ssb in formation, stability, and toxicity of the [PSI] prion. Mol. Cell. Biol. 19, 8103–8112 (1999)

    Article  CAS  Google Scholar 

  6. Lancaster, A. K., Bardill, J. P., True, H. L. & Masel, J. The spontaneous appearance rate of the yeast prion [PSI+] and its implications for the evolution of the evolvability properties of the [PSI+] system. Genetics 184, 393–400 (2010)

    Article  CAS  Google Scholar 

  7. True, H. L., Berlin, I. & Lindquist, S. L. Epigenetic regulation of translation reveals hidden genetic variation to produce complex traits. Nature 431, 184–187 (2004)

    Article  ADS  CAS  Google Scholar 

  8. Griswold, C. K. & Masel, J. Complex adaptations can drive the evolution of the capacitor [PSI+], even with realistic rates of yeast sex. PLoS Genet. 5, e1000517 (2009)

    Article  Google Scholar 

  9. Lancaster, A. K. & Masel, J. The evolution of reversible switches in the presence of irreversible mimics. Evolution 63, 2350–2362 (2009)

    Article  Google Scholar 

  10. Tyedmers, J., Madariaga, M. L. & Lindquist, S. Prion switching in response to environmental stress. PLoS Biol. 6, e294 (2008)

    Article  Google Scholar 

  11. Halfmann, R., Alberti, S. & Lindquist, S. Prions, protein homeostasis, and phenotypic diversity. Trends Cell Biol. 20, 125–133 (2010)

    Article  CAS  Google Scholar 

  12. Morimoto, R. I. Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging. Genes Dev. 22, 1427–1438 (2008)

    Article  CAS  Google Scholar 

  13. Masel, J. & Bergman, A. The evolution of the evolvability properties of the yeast prion [PSI+]. Evolution 57, 1498–1512 (2003)

    Article  Google Scholar 

  14. Alberti, S., Halfmann, R., King, O., Kapila, A. & Lindquist, S. A systematic survey identifies prions and illuminates sequence features of prionogenic proteins. Cell 137, 146–158 (2009)

    Article  CAS  Google Scholar 

  15. Crow, E. T. & Li, L. Newly identified prions in budding yeast, and their possible functions. 22, 452–459 Semin. Cell Dev. Biol. (2011)

  16. Halfmann, R. & Lindquist, S. Epigenetics in the extreme: prions and the inheritance of environmentally acquired traits. Science 330, 629–632 (2010)

    Article  ADS  CAS  Google Scholar 

  17. McGlinchey, R. P., Kryndushkin, D. & Wickner, R. B. Suicidal [PSI+] is a lethal yeast prion. Proc. Natl Acad. Sci. USA 108, 5337–5341 (2011)

    Article  ADS  CAS  Google Scholar 

  18. Nakayashiki, T., Kurtzman, C. P., Edskes, H. K. & Wickner, R. B. Yeast prions [URE3] and [PSI+] are diseases. Proc. Natl Acad. Sci. USA 102, 10575–10580 (2005)

    Article  ADS  CAS  Google Scholar 

  19. Wickner, R. B. et al. Prion diseases of yeast: amyloid structure and biology. 22, 469–475 Semin. Cell Dev. Biol. (2011)

    Article  CAS  Google Scholar 

  20. Giudici, P. & Kunkee, R. E. The effect of nitrogen deficiency and sulfur containing amino acids on the reduction of sulfate to hydrogen sulfide by wine yeasts. Am. J. Enol. Vitic. 45, 107–112 (1994)

    CAS  Google Scholar 

  21. Derkatch, I. L. et al. Dependence and independence of [PSI+] and [PIN+]: a two-prion system in yeast? EMBO J. 19, 1942–1952 (2000)

    Article  CAS  Google Scholar 

  22. Sondheimer, N. & Lindquist, S. Rnq1: an epigenetic modifier of protein function in yeast. Mol. Cell 5, 163–172 (2000)

    Article  CAS  Google Scholar 

  23. Resende, C. G., Outeiro, T. F., Sands, L., Lindquist, S. & Tuite, M. F. Prion protein gene polymorphisms in Saccharomyces cerevisiae. Mol. Microbiol. 49, 1005–1017 (2003)

    Article  CAS  Google Scholar 

  24. Chernoff, Y. O. et al. Evolutionary conservation of prion-forming abilities of the yeast Sup35 protein. Mol. Microbiol. 35, 865–876 (2000)

    Article  CAS  Google Scholar 

  25. Liti, G. et al. Population genomics of domestic and wild yeasts. Nature 458, 337–341 (2009)

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  27. Chien, P., Weissman, J. S. & DePace, A. H. Emerging principles of conformation-based prion inheritance. Annu. Rev. Biochem. 73, 617–656 (2004)

    Article  CAS  Google Scholar 

  28. Wickner, R. B., Edskes, H. K., Shewmaker, F. & Nakayashiki, T. Prions of fungi: inherited structures and biological roles. Nature Rev. Microbiol. 5, 611–618 (2007)

    Article  CAS  Google Scholar 

  29. Sharma, S. V. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69–80 (2010)

    Article  CAS  Google Scholar 

  30. Feinberg, A. P. & Irizarry, R. A. Evolution in health and medicine Sackler colloquium: Stochastic epigenetic variation as a driving force of development, evolutionary adaptation, and disease. Proc. Natl Acad. Sci. USA 107 (suppl. 1). 1757–1764 (2010)

    Article  ADS  CAS  Google Scholar 

  31. Song, Y. et al. Role for Hsp70 chaperone in Saccharomyces cerevisiae prion seed replication. Eukaryot. Cell 4, 289–297 (2005)

    Article  CAS  Google Scholar 

  32. Newnam, G. P., Wegrzyn, R. D., Lindquist, S. L. & Chernoff, Y. O. Antagonistic interactions between yeast chaperones Hsp104 and Hsp70 in prion curing. Mol. Cell. Biol. 19, 1325–1333 (1999)

    Article  CAS  Google Scholar 

  33. Chernoff, Y. O. Stress and prions: lessons from the yeast model. FEBS Lett. 581, 3695–3701 (2007)

    Article  CAS  Google Scholar 

  34. Chernova, T. A. et al. Prion induction by the short-lived, stress-induced protein Lsb2 is regulated by ubiquitination and association with the actin cytoskeleton. Mol. Cell 43, 242–252 (2011)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  36. Koonin, E. V. & Wolf, Y. I. Is evolution Darwinian or/and Lamarckian? Biol. Direct 4, 42 (2009)

    Article  Google Scholar 

  37. Halfmann, R. & Lindquist, S. Screening for amyloid aggregation by semi-denaturing detergent-agarose gel electrophoresis. J. Visualized Exp. 17, e838 (2008)

    Google Scholar 

  38. Schacherer, J., Shapiro, J. A., Ruderfer, D. M. & Kruglyak, L. Comprehensive polymorphism survey elucidates population structure of Saccharomyces cerevisiae. Nature 458, 342–345 (2009)

    Article  ADS  CAS  Google Scholar 

  39. Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics 25, 1754–1760 (2009)

    Article  CAS  Google Scholar 

  40. Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009)

    Article  Google Scholar 

  41. DePristo, M. A. et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nature Genet. 43, 491–498 (2011)

    Article  CAS  Google Scholar 

  42. Paradis, E., Claude, J. & Strimmer, K. APE: Analyses of Phylogenetics and Evolution in R language. Bioinformatics 20, 289–290 (2004)

    Article  CAS  Google Scholar 

  43. Alberti, S., Gitler, A. D. & Lindquist, S. A suite of Gateway cloning vectors for high-throughput genetic analysis in Saccharomyces cerevisiae. Yeast 24, 913–919 (2007)

    Article  CAS  Google Scholar 

  44. Gietz, D., St Jean, A., Woods, R. A. & Schiestl, R. H. Improved method for high efficiency transformation of intact yeast cells. Nucleic Acids Res. 20, 1425 (1992)

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  46. Haase, S. B. & Reed, S. I. Improved flow cytometric analysis of the budding yeast cell cycle. Cell Cycle 1, 117–121 (2002)

    Article  Google Scholar 

  47. Diezmann, S. & Dietrich, F. S. Saccharomyces cerevisiae: population divergence and resistance to oxidative stress in clinical, domesticated and wild isolates. PLoS ONE 4, e5317 (2009)

    Article  ADS  Google Scholar 

Download references


We are grateful to L. Bisson and L. Joseph, who provided the Department of Viticulture and Enology yeast collection from the University of California, Davis, USA. We also received strains from G. Fink, E. Louis, F. Dietrich and S. Dietzmann, and L. Kruglyak. We thank M. Taipale, K. Allendoerfer, K. Matlack, L. Pepper, V. Khurana, G. Fink, L. Joseph, A. Hochwagen and G. Walker for materials, discussions, and/or critical reading of the manuscript. N. Azubuine and T. Nanchung provided a constant supply of plates and media. S.L. is a Howard Hughes Medical Institute (HHMI) investigator. This work was supported by grants from the G. Harold and Leila Y. Mathers Foundation and HHMI. D.F.J. was supported as an HHMI fellow of the Damon Runyon Cancer Research Foundation (DRG-1964-08) and by an NIH Pathway to independence award (K99 GM098600). S.K.J. was supported as a summer research student by the Howard Hughes Medical Institute (HHMI) Exceptional Research Opportunities Program (EXROP).

Author information

Authors and Affiliations



R.H., D.F.J., A.K.L. and S.L. designed the experiments. R.H. performed SDD–AGE analyses. R.H., D.F.J., S.K.J. and A.C. carried out phenotyping experiments. D.F.J. analysed high-throughput phenotyping data. D.F.J. and A.K.L. analysed whole-genome sequence data. D.F.J. and A.C. performed cytoductions. R.H., D.F.J. and S.L. wrote the paper.

Corresponding author

Correspondence to Susan Lindquist.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains a Supplementary Discussion, Supplementary References and Supplementary Figures 1-4 with legends. (PDF 1979 kb)

Supplementary Tables

This file contains Supplementary Tables 1-3. (PDF 1591 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


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