Academic journal article Genetics

The Spontaneous Appearance Rate of the Yeast Prion [PSI+] and Its Implications for the Evolution of the Evolvability Properties of the [PSI+] System

Academic journal article Genetics

The Spontaneous Appearance Rate of the Yeast Prion [PSI+] and Its Implications for the Evolution of the Evolvability Properties of the [PSI+] System

Article excerpt

ABSTRACT

Epigenetically inherited aggregates of the yeast prion [PSI+] cause genomewide readthrough translation that sometimes increases evolvability in certain harsh environments. The effects of natural selection on modifiers of [PSI+] appearance have been the subject of much debate. It seems likely that [PSI+] would be at least mildly deleterious in most environments, but this may be counteracted by its evolvability properties on rare occasions. Indirect selection on modifiers of [PSI+] is predicted to depend primarily on the spontaneous [PSI+] appearance rate, but this critical parameter has not previously been adequately measured. Here we measure this epimutation rate accurately and precisely as 5.8 × 10^sup -7^ per generation, using a fluctuation test. We also determine that genetic "mimics" of [PSI+] account for up to 80% of all phenotypes involving general nonsense suppression. Using previously developed mathematical models, we can now infer that even in the absence of opportunities for adaptation, modifiers of [PSI+] are only weakly deleterious relative to genetic drift. If we assume that the spontaneous [PSI+] appearance rate is at its evolutionary optimum, then opportunities for adaptation are inferred to be rare, such that the [PSI+] system is favored only very weakly overall. But when we account for the observed increase in the [PSI+] appearance rate in response to stress, we infer much higher overall selection in favor of [PSI+] modifiers, suggesting that [PSI+]-forming ability may be a consequence of selection for evolvability.

THE yeast phenotype [PSI+] is characterized by prion aggregates of the protein Sup35. Cells are in either a [psi-] (normal) or [PSI+] state, depending on the absence or presence of the prion aggregates (Figure 1, a and b). Sup35 prion aggregates replicate in a similar fashion to mammalian prions but are cytoplasmic and, as such, the prion state is cytoplasmically inherited (Wickner et al. 1995).

When not part of an aggregate, Sup35 helps mediate translation termination in yeast (Stansfield et al. 1995b; Zhouravleva et al. 1995). Sup35 molecules that are incorporated into nonfunctional prion aggregates are presumably not available for translation termination, which can lead to the translation of stop codons by nearcognate tRNAs (Figure 1b) (Tuite and Mclaughlin 1982; Pure et al. 1985; Lin et al. 1986). This partial loss of Sup35 function leads to an increased frequency of readthrough translation of 3'-untranslated regions (3'-UTR) across all genes (Figure 1b). This increase is modest in wild-type yeast, from an average readthrough rate of 0.3% in [psi-] cells up to 1% in [PSI+] cells (Firoozan et al. 1991). Some [PSI+] yeast strains grow faster than [psi-] controls in certain harsh environments, suggesting that readthrough translation of some 3'-UTRs may be adaptive in certain conditions (True and Lindquist 2000; Joseph and Kirkpatrick 2008). This directly shows that [PSI+]-mediated capacitance may increase evolvability in the laboratory. [PSI+]- mediated phenotypes have a complex genetic basis, involving multiple loci (True et al. 2004).

As an epigenetically inherited protein aggregate, [PSI+] can easily be lost after some generations (Cox et al. 1980). This returns the lineage to its normal [psi-] state and restores translation fidelity. If a subset of revealed phenotypic variation is adaptive, it may have lost its dependence on [PSI+] by this time (True et al. 2004). This process of genetic assimilation may, for example, involve one or more point mutations in stop codons, increasing readthrough up to 100% (Figure 1e) (Griswold and Masel 2009). This leaves the yeast with a new adaptive trait and with no permanent load of other, deleterious variation.

In general, stop codons can be lost either directly through point mutations or indirectly through upstream indels. This leads to novel coding sequence coming from in-frame and out-of-frame 3'-UTRs, respectively. …

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