The yeast prion [PSI+] is a wonderful model system for studying evolutionary capacitance, since the relevant molecular biology is well understood. Genetic variation beyond stop codons is subject to little selective pressure. The [PSI+] prion is an epigenetically inherited aggregate of the Sup35 protein, which is a release factor required for translation to terminate at stop codons. When [PSI+] appears, elevated readthrough occurs at every gene in the genome, and a range of pre-existing cryptic genetic variation is phenotypically revealed. As an epigenetically inherited protein aggregate, [PSI+] can easily be lost after some generations. 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. This process of genetic assimilation may, for example, involve one or more point mutations in stop codons. This leaves the yeast with a new adaptive trait and with no permanent load of other, deleterious variation.
A great advantage of this system is that we can use the rich resource of fully sequenced, closely related Saccharomyces species. We classified events in which 3′UTR was incorporated into coding regions, both in Saccharomyces and in rodents. Based on mutational bias, most such events are expected to result from indels occurring shortly before the stop codon and knocking it out of frame. This leads to the inclusion of frameshifted 3′UTR in the new allele, and this is indeed what we found in most cases in rodents. In contrast, in Saccharomyces a high proportion of 3′UTR incorporation events led to the inclusion of inframe 3′UTR through precise mutation of the stop codon. This is compatible with the genetic assimilation of inframe readthrough products produced by [PSI+] (Giacomelli et al. 2007).
Another project we are pursuing is to test whether sequences beyond stop codons are preadapted. Theory tells us that this will be the case so long as there is little, but still some selection on readthrough products (Masel 2006). We are currently searching for evidence of such selection pressure.
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