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Epigenetic regulation of translation reveals hidden genetic variation to produce complex traits


Phenotypic plasticity and the exposure of hidden genetic variation both affect the survival and evolution of new traits1,2,3, but their contributing molecular mechanisms are largely unknown. A single factor, the yeast prion [PSI+], may exert a profound effect on both4. [PSI+] is a conserved, protein-based genetic element that is formed by a change in the conformation and function of the translation termination factor Sup35p5, and is transmitted from mother to progeny. Curing cells of [PSI+] alters their survival in different growth conditions and produces a spectrum of phenotypes in different genetic backgrounds4. Here we show, by examining three plausible explanations for this phenotypic diversity, that all traits tested involved [PSI+]-mediated read-through of nonsense codons. Notably, the phenotypes analysed were genetically complex, and genetic re-assortment frequently converted [PSI+]-dependent phenotypes to stable traits that persisted in the absence of [PSI+]. Thus, [PSI+] provides a temporary survival advantage under diverse conditions, increasing the likelihood that new traits will become fixed by subsequent genetic change. As an epigenetic mechanism that globally affects the relationship between genotype and phenotype, [PSI+] expands the conceptual framework for phenotypic plasticity, provides a one-step mechanism for the acquisition of complex traits and affords a route to the genetic assimilation of initially transient epigenetic traits.

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Figure 1: [PSI+]-related phenotypes are dependent on read-through.
Figure 2: Variable strength phenotypes are observed with progeny from outcrosses.
Figure 3: Progeny from an outcross of 5V-H19 show [PSI+]-independent caffeine resistance.


  1. Agrawal, A. A. Phenotypic plasticity in the interactions and evolution of species. Science 294, 321–326 (2001)

    Article  ADS  CAS  Google Scholar 

  2. Behera, N. & Nanjundiah, V. Phenotypic plasticity can potentiate rapid evolutionary change. J. Theor. Biol. 226, 177–184 (2004)

    Article  MathSciNet  Google Scholar 

  3. Pigliucci, M. & Murren, C. J. Perspective: Genetic assimilation and a possible evolutionary paradox: can macroevolution sometimes be so fast as to pass us by? Evolution Int. J. Org. Evolution 57, 1455–1464 (2003)

    Article  Google Scholar 

  4. 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 

  5. Uptain, S. M. & Lindquist, S. Prions as protein-based genetic elements. Annu. Rev. Microbiol. 56, 703–741 (2002)

    Article  CAS  Google Scholar 

  6. Michelitsch, M. D. & Weissman, J. S. A census of glutamine/asparagine-rich regions: implications for their conserved function and the prediction of novel prions. Proc. Natl Acad. Sci. USA 97, 11910–11915 (2000)

    Article  ADS  CAS  Google Scholar 

  7. Harrison, P. M. & Gerstein, M. A method to assess compositional bias in biological sequences and its application to prion-like glutamine/asparagine-rich domains in eukaryotic proteomes. Genome Biol. 4, R40 (2003)

    Article  Google Scholar 

  8. Harrison, P. et al. A small reservoir of disabled ORFs in the yeast genome and its implications for the dynamics of proteome evolution. J. Mol. Biol. 316, 409–419 (2002)

    Article  CAS  Google Scholar 

  9. Namy, O., Duchateau-Nguyen, G. & Rousset, J. P. Translational readthrough of the PDE2 stop codon modulates cAMP levels in Saccharomyces cerevisiae. Mol. Microbiol. 43, 641–652 (2002)

    Article  CAS  Google Scholar 

  10. Namy, O. et al. Identification of stop codon readthrough genes in Saccharomyces cerevisiae. Nucleic Acids Res. 31, 2289–2296 (2003)

    Article  CAS  Google Scholar 

  11. Sherman, M. Y. & Goldberg, A. L. Cellular defenses against unfolded proteins: a cell biologist thinks about neurodegenerative diseases. Neuron 29, 15–32 (2001)

    Article  CAS  Google Scholar 

  12. Ter-Avanesyan, M. D. et al. Deletion analysis of the SUP35 gene of the yeast Saccharomyces cerevisiae reveals two non-overlapping functional regions in the encoded protein. Mol. Microbiol. 7, 683–692 (1993)

    Article  CAS  Google Scholar 

  13. Liu, J. J. & Lindquist, S. Oligopeptide-repeat expansions modulate ‘protein-only’ inheritance in yeast. Nature 400, 573–576 (1999)

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  15. Chernoff, Y. O., Newnam, G. P. & Liebman, S. W. The translational function of nucleotide C1054 in the small subunit rRNA is conserved throughout evolution: genetic evidence in yeast. Proc. Natl Acad. Sci. USA 93, 2517–2522 (1996)

    Article  ADS  CAS  Google Scholar 

  16. Bradley, M. E., Bagriantsev, S., Vishveshwara, N. & Liebman, S. W. Guanidine reduces stop codon read-through caused by missense mutations in SUP35 or SUP45. Yeast 20, 625–632 (2003)

    Article  CAS  Google Scholar 

  17. Leeds, P., Peltz, S. W., Jacobson, A. & Culbertson, M. R. The product of the yeast UPF1 gene is required for rapid turnover of mRNAs containing a premature translational termination codon. Genes Dev. 5, 2303–2314 (1991)

    Article  CAS  Google Scholar 

  18. Frischmeyer, P. A. et al. An mRNA surveillance mechanism that eliminates transcripts lacking termination codons. Science 295, 2258–2261 (2002)

    Article  ADS  CAS  Google Scholar 

  19. DePace, A. H., Santoso, A., Hillner, P. & Weissman, J. S. A critical role for amino-terminal glutamine/asparagine repeats in the formation and propagation of a yeast prion. Cell 93, 1241–1252 (1998)

    Article  CAS  Google Scholar 

  20. Firoozan, M., Grant, C. M., Duarte, J. A. & Tuite, M. F. Quantitation of readthrough of termination codons in yeast using a novel gene fusion assay. Yeast 7, 173–183 (1991)

    Article  CAS  Google Scholar 

  21. Lund, P. M. & Cox, B. S. Reversion analysis of [psi-] mutations in Saccharomyces cerevisiae. Genet. Res. 37, 173–182 (1981)

    Article  CAS  Google Scholar 

  22. Eaglestone, S. S., Cox, B. S. & Tuite, M. F. Translation termination efficiency can be regulated in Saccharomyces cerevisiae by environmental stress through a prion-mediated mechanism. EMBO J. 18, 1974–1981 (1999)

    Article  CAS  Google Scholar 

  23. 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 

  24. Kushnirov, V. V., Kochneva-Pervukhova, N. V., Chechenova, M. B., Frolova, N. S. & Ter-Avanesyan, M. D. Prion properties of the Sup35 protein of yeast Pichia methanolica. EMBO J. 19, 324–331 (2000)

    Article  CAS  Google Scholar 

  25. Nakayashiki, T., Ebihara, K., Bannai, H. & Nakamura, Y. Yeast [PSI+] “prions” that are crosstransmissible and susceptible beyond a species barrier through a quasi-prion state. Mol. Cell 7, 1121–1130 (2001)

    Article  CAS  Google Scholar 

  26. Santoso, A., Chien, P., Osherovich, L. Z. & Weissman, J. S. Molecular basis of a yeast prion species barrier. Cell 100, 277–288 (2000)

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  29. Queitsch, C., Sangster, T. A. & Lindquist, S. Hsp90 as a capacitor of phenotypic variation. Nature 417, 618–624 (2002)

    Article  ADS  CAS  Google Scholar 

  30. Guthrie, C. & Fink, G. (eds) Guide to Yeast Genetics and Molecular Biology (Academic Press, San Diego, 1991)

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We thank members of the Lindquist lab, the True lab, R. Parker and J. Masel for discussions and comments on experiments and the manuscript. We thank J. Weissman, S. Liebman and their lab members for plasmids and strains. This research was supported by the National Institutes of Health.

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Correspondence to Susan L. Lindquist.

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

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