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A yeast prion provides a mechanism for genetic variation and phenotypic diversity

Nature volume 407, pages 477–483 (2000)Cite this article

Abstract

A major enigma in evolutionary biology is that new forms or functions often require the concerted effects of several independent genetic changes. It is unclear how such changes might accumulate when they are likely to be deleterious individually and be lost by selective pressure. The Saccharomyces cerevisiae prion [PSI+] is an epigenetic modifier of the fidelity of translation termination, but its impact on yeast biology has been unclear. Here we show that [PSI+] provides the means to uncover hidden genetic variation and produce new heritable phenotypes. Moreover, in each of the seven genetic backgrounds tested, the constellation of phenotypes produced was unique. We propose that the epigenetic and metastable nature of [PSI+] inheritance allows yeast cells to exploit pre-existing genetic variation to thrive in fluctuating environments. Further, the capacity of [PSI+] to convert previously neutral genetic variation to a non-neutral state may facilitate the evolution of new traits.

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Figure 1: [PSI+] does not alter growth on standard rich media (YPD, pH 6.8), but causes strain-specific changes at pH 6.0.
Figure 2: [PSI+] affects growth in different ways in different genetic backgrounds.
Figure 3: Colony morphology changes produced by [PSI+] in strain 5V-H19.
Figure 4: Stress tolerance in [PSI+] and [psi-] derivatives.
Figure 5: [PSI+] negatively affects the growth of all seven strain backgrounds in the presence of 5mM ZnCl2.

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References

  1. Koch, A. L. Enzyme evolution. I. The importance of untranslatable intermediates. Genetics 72, 297–316 ( 1972).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Ohno, S. Evolution by Gene Duplication (Springer, New York, 1970).

    Google Scholar 

  3. Ohta, T. Simulating evolution by gene duplication. Genetics 115, 207–213 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Walsh, J. B. How often do duplicated genes evolve new functions? Genetics 139, 421–428 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Nadeau, J. H. & Sankoff, D. Comparable rates of gene loss and functional divergence after genome duplications early in vertebrate evolution. Genetics 147, 1259–1266 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Hall, B. G., Yokoyama, S. & Calhoun, D. H. Role of cryptic genes in microbial evolution. Mol. Biol. Evol. 1, 109–124 (1983).

    CAS  PubMed  Google Scholar 

  7. Cox, B. [PSI], a cytoplasmic suppressor of super-suppression in yeast. Heredity 20, 505–521 ( 1965).

    Google Scholar 

  8. Liebman, S. W. & Sherman, F. Extrachromosomal psi+ determinant suppresses nonsense mutations in yeast. J. Bact. 139 , 1068–1071 (1979).

    CAS  PubMed  Google Scholar 

  9. 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).

    CAS  PubMed  Google Scholar 

  10. Serio, T. R. & Lindquist, S. L. [PSI+]: an epigenetic modulator of translation termination efficiency. Annu. Rev. Cell Dev. Biol. 15, 661–703 ( 1999).

    CAS  PubMed  Google Scholar 

  11. Stansfield, I. et al. The products of the SUP45 (eRF1) and SUP35 genes interact to mediate translation termination in Saccharomyces cerevisiae. EMBO J. 14, 4365–4373 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhouravleva, G. et al. Termination of translation in eukaryotes is governed by two interacting polypeptide chain release factors, eRF1 and eRF3. EMBO J. 14, 4065–4072 ( 1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 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).

    ADS  CAS  PubMed  Google Scholar 

  14. Paushkin, S. V., Kushnirov, V. V., Smirnov, V. N. & Ter-Avanesyan, M. D. Propagation of the yeast prion-like [psi+] determinant is mediated by oligomerization of the SUP35-encoded polypeptide chain release factor. EMBO J. 15, 3127–3134 ( 1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Kikuchi, Y. & Kikuchi, A. in Gene Expression and Regulation: the Legacy of Luigi Gorini (eds Bissell, M., Deho, G., Sironi, G. & Torriani, A.) 257–264 (Elsevier, Amsterdam, 1988).

    Google Scholar 

  16. Kushnirov, V. V. et al. Nucleotide sequence of the SUP2 (SUP35) gene of Saccharomyces cerevisiae. Gene 66, 45– 54 (1988).

    CAS  PubMed  Google Scholar 

  17. Wilson, P. G. & Culbertson, M. R. SUF12 suppressor protein of yeast. A fusion protein related to the EF-1 family of elongation factors. J. Mol. Biol. 199, 559– 573 (1988).

    CAS  PubMed  Google Scholar 

  18. Ter-Avanesyan, M. D., Dagkesamanskaya, A. R., Kushnirov, V. V. & Smirnov, V. N. The SUP35 omnipotent suppressor gene is involved in the maintenance of the non-Mendelian determinant [psi+] in the yeast Saccharomyces cerevisiae . Genetics 137, 671– 676 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    ADS  CAS  PubMed  Google Scholar 

  20. Kushnirov, V. V. et al. Divergence and conservation of SUP2 (SUP35) gene of yeast Pichia pinus and Saccharomyces cerevisiae. Yeast 6, 461–472 ( 1990).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  23. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Tuite, M. F., Mundy, C. R. & Cox, B. S. Agents that cause a high frequency of genetic change from [psi+] to [psi-] in Saccharomyces cerevisiae. Genetics 98, 691–711 ( 1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Adams, A., Gottschling, D. E., Kaiser, C. A., Stearns, T. Methods in Yeast Genetics (Cold Spring Harbor Laboratory Press, Plainview, 1997).

    Google Scholar 

  26. Hampsey, M. A review of phenotypes in Saccharomyces cerevisiae. Yeast 13, 1099–1133 ( 1997).

    CAS  PubMed  Google Scholar 

  27. Rieger, K. J. et al. Large-scale phenotypic analysis—the pilot project on yeast chromosome III. Yeast 13, 1547– 1562 (1997).

    CAS  PubMed  Google Scholar 

  28. Budavari, S. (ed.) The Merck Index (Merck and Company, Rahway, New Jersey, 1989).

    Google Scholar 

  29. Roncero, C., Valdivieso, M. H., Ribas, J. C. & Duran, A. Isolation and characterization of Saccharomyces cerevisiae mutants resistant to Calcofluor white. J. Bacteriol. 170, 1950–1954 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  31. Derkatch, I. L., Bradley, M. E., Zhou, P., Chernoff, Y. O. & Liebman, S. W. Genetic and environmental factors affecting the de novo appearance of the [PSI+] prion in Saccharomyces cerevisiae. Genetics 147, 507–519 ( 1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Grant, C. M., Firoozan, M. & Tuite, M. F. Mistranslation induces the heat-shock response in the yeast Saccharomyces cerevisiae. Mol. Microbiol. 3, 215–220 (1989).

    CAS  PubMed  Google Scholar 

  34. Parsell, D. A. & Lindquist, S. The function of heat-shock proteins in stress tolerance: degradation and reactivation of damaged proteins. Annu. Rev. Genet. 27, 437–496 (1993).

    CAS  PubMed  Google Scholar 

  35. Bailleul, P. A., Newnam, G. P., Steenbergen, J. N. & Chernoff, Y. O. Genetic study of interactions between the cytoskeletal assembly protein sla1 and prion-forming domain of the release factor sup35 (eRF3) in Saccharomyces cerevisiae. Genetics 153, 81– 94 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Tikhomirova, V. L. & Inge-Vechtomov, S. G. Sensitivity of sup35 and sup45 suppressor mutants in Saccharomyces cerevisiae to the anti-microtubule drug benomyl. Curr. Genet. 30, 44–49 (1996).

    CAS  PubMed  Google Scholar 

  37. Liebman, S. W. & Derkatch, I. L. The yeast [PSI+] prion: making sense of nonsense. J. Biol. Chem. 274, 1181–1184 (1999).

    CAS  PubMed  Google Scholar 

  38. Seoighe, C. & Wolfe, K. H. Updated map of duplicated regions in the yeast genome. Gene 238, 253– 261 (1999).

    CAS  PubMed  Google Scholar 

  39. Olson, M. V. When less is more: gene loss as an engine of evolutionary change. Am. J. Hum. Genet. 64, 18–23 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Levitt, R. C. Polymorphisms in the transcribed 3′ untranslated region of eukaryotic genes. Genomics 11, 484– 489 (1991).

    CAS  PubMed  Google Scholar 

  41. Czaplinski, K. et al. The surveillance complex interacts with the translation release factors to enhance termination and degrade aberrant mRNAs. Genes Dev. 12, 1665–1677 ( 1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Mewes, H. W. et al. Overview of the yeast genome. Nature 387, 7–65 (1997).

    PubMed  Google Scholar 

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

    ADS  CAS  PubMed  Google Scholar 

  44. 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).

    ADS  CAS  PubMed  Google Scholar 

  45. Chernoff, Y. O. et al. Conservative system for dosage-dependent modulation of translational fidelity in eukaryotes. Biochimie 74, 455 –461 (1992).

    CAS  PubMed  Google Scholar 

  46. Zhou, P. et al. The yeast non-Mendelian factor [ETA+] is a variant of [PSI+], a prion- like form of release factor eRF3. EMBO J. 18, 1182–1191 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Eustice, D. C., Wakem, L. P., Wilhelm, J. M. & Sherman, F. Altered 40S ribosomal subunits in omnipotent suppressors of yeast. J. Mol. Biol. 188, 207–214 (1986).

    CAS  PubMed  Google Scholar 

  48. Wakem, L. P. & Sherman, F. Isolation and characterization of omnipotent suppressors in the yeast Saccharomyces cerevisiae. Genetics 124, 515–522 ( 1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 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).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank members of the Lindquist lab and M. Jensen for discussion and comments on the manuscript, and V. Iyer, P.O. Brown, J. Henikoff and S. Henikoff for collaborative efforts and for allowing us to cite unpublished work. This research was supported by the Jane Coffin Childs Memorial Fund for Medical Research (H.L.T.), the National Institutes of Health and the Howard Hughes Medical Institute.

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  1. Department of Molecular Genetics and Cell Biology, Howard Hughes Medical Institute, The University of Chicago, Chicago, 60637, Illinois, USA

    Heather L. True & Susan L. Lindquist

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True, H., Lindquist, S. A yeast prion provides a mechanism for genetic variation and phenotypic diversity. Nature 407, 477–483 (2000). https://doi.org/10.1038/35035005

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