The spontaneous appearance rate of the yeast prion [PSI+] and its implications for the evolution of the evolvability properties of the [PSI+] system - PubMed (original) (raw)

The spontaneous appearance rate of the yeast prion [PSI+] and its implications for the evolution of the evolvability properties of the [PSI+] system

Alex K Lancaster et al. Genetics. 2010 Feb.

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 x 10(-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.

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Figures

Figure 1.—

Comparison between the three possible modes ([PSI+], genetic mimic, point mutation revertant) of the expression of 3′-UTR sequences in yeast. (a) The normal [_psi_−] phenotypic state; (b) the [PSI+] prion causes readthrough and low-level expression of 3′-UTRs across multiple genes, appearing at rate mPSI; (c) a genetic mimic of [PSI+] such as the sal3-4 mutant of Sup35 (E

aglestone

et al. 1999) appearing at rate _m_mimic not reversible by the application of guanidine hydrochloride; (d) a point mutation in a single stop codon at rate μpoint, leading to incorporation of formerly 3′-UTR into a single coding sequence. (e) [PSI+] can act as a “stop-gap” mechanism, buying a lineage more time to acquire one or more adaptive stop codon readthrough point mutations. When this genetic assimilation is complete, [PSI+] can revert to [_psi_−] (M

asel

and B

ergman

2003; G

riswold

and M

asel

2009).

Figure 2.—

The model of L

ancaster

and M

asel

(2009) predicts the parameter range (shaded) for which mPSI (expressed as a function of the elevation from the unstressed baseline observed value of 5.8 × 10−7) is compatible with both a 95% C.I. of _m_mimic of (2.04–2.77) × 10−6 and _N_e = (3–6) × 106. The upper bound is given by the combination {_m_mimic = 2.04 × 10−6, _N_e = 6 × 106} and the lower bound by {_m_mimic = 2.77 × 10−6, _N_e = 3 × 106}.

Figure 3.—

Sensitivity of our inference to the effective population size, _N_e. For _N_e ∼ 5 × 106, as estimated for Saccharomyces, we infer a role for natural selection in favoring [PSI+]-mediated evolvability if and only if mPSI is elevated by stress, as has been observed. (a) For _N_e ≲ 105 we would not infer evolvability, even with realistically elevated switching rates. (b) Selection for evolvability would be inferred even in the absence of stress-mediated induction for _N_e ≳ 4 × 107. Higher values of _N_e are not shown because their computation requires excessive memory, but the result is still clear.

Figure 3.—

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The spontaneous appearance rate of the yeast prion [PSI+] and its implications for the evolution of the evolvability properties of the [PSI+] system - PubMed (original) (raw)