Genetic variation and phenotypic plasticity are key to the evolution of new traits. A recent study by Susan Lindquist and colleagues provides insights into the molecular mechanisms that underlie phenotypic plasticity and shows how the yeast prion [PSI+] enables cells to tap into their existing genetic variation to acquire complex traits in a single step.

[PSI+] is formed as a result of a conformational change in the translation termination factor Sup35p. 'Curing' Saccharomyces cerevisiae cells of the prion, which involves growing them in the presence of guanidine hydrochloride and which stabilizes the wild-type Sup35p protein, alters their survival in different growth conditions and results in a range of phenotypes, depending on the genetic background. Lindquist and co-workers asked how this genetic diversity is brought about.

They identified three possible explanations. First, curing cells of [PSI+] also cures them of all other prions, so the phenotypic diversity could result from different strains losing different prions. Second, termination of translation is less efficient in strains that carry [PSI+], so readthrough of stop codons might be more frequent in these strains, leading to, for example, translation of pseudogenes or 3′UTRs, which freely acquire genetic variation. Third, protein aggregation, which accompanies [PSI+] formation, could affect protein homeostasis.

To test each hypothesis in turn, the authors created yeast strains in which the effects of other prions, translational readthrough and protein aggregation were uncoupled from one another. The results were clear — most of the phenotypic diversity arises as a result of [PSI+]-mediated nonsense suppression.

Outcrossing the [PSI+] strains to different genetic backgrounds revealed that the newly acquired traits are complex. These heritable complex traits, which can be acquired or lost in as little as a single generation by losing [PSI+], can be fixed and maintained even in the absence of the prion. Moreover, a single trait can be fixed in many ways, by reassortment of other genetic polymorphisms or by new mutation, or by a combination of the two.

As the authors say, “conceptually, [PSI+] presents a new framework for phenotypic plasticity”. The [PSI+]-based mechanism means that organisms need not 'wait' for suitable mutations to occur when the environment changes; instead, they can draw on already exisiting, hitherto silent, genetic variation. Taken together with the authors' previous findings that heat-shock proteins can also reveal hidden genetic variation, Lindquist and colleagues prompt us to re-examine protein folding mechanisms, for they could be unexpectedly important in translating genotypes into phenotypes.