Sunday, January 30, 2011

Why only hungry K.lactis have sex?

One of my professors at the Univeristy of Valencia used to tell us that a Yeast's life was "mainly driven by food and sex", referring to the relevance and impact in this single-cell organisms of the signalling pathways in response to starvation, presence of nutrients or pheromones. One particular species of yeast, the diary yeast Kluyveromyces lactis, seemed to have combined both stimuli into a single pathway, requiring both starvation and pheromone signals to mate. Although this was known for decades, the specific mechanism and how it had evolved remained a mystery.

In a recent paper by the group of Alexander Johnson (UCSF), the origin of such phenotype has been established, by comparing regulation of mating genes in K. lactis, Saccharomyces cerevisiae, and Candida albicans. The evolutionary mechanism involved is that of a transcriptional rewiring, in which the core mating genes have been put under the control of the gene responsible for signalling starvation (RME1), which in turn is now also controlled by the mating factors (a/alpha). This intercalation of a new step within the mating signalling pathway effectively results in both stimuli being necessary for mating.

How could this happen? the implied scenario involves the acquisition of regulation by mating factors for RME1, at least four core mating genes loosing their reponsive elements to the mating factors - rather than change of the binding site of the factor, which was found to be similar to that in the other yeasts-, and the same genes acquiring responsive elements to RME1. 9 transitions in total. The first one (RME1 under control of mating) also occurs in S. cerevisiae, so it seems to have pre-dated the re-programming of the core mating genes control, effectively paving the way for the final rewiring. To unveil the order of the  other 8 transitions, one would need to find intermediate states in other yeasts. Given the potential deleterious effects of a mating gene loosing pheromone control, and the low probability of loosing one binding factor while acquiring the other one in four genes, I envision an intermediary state where the genes where responding to both RME1/mating factors. Then, the lost in a single core mating gene of the direct response to mating factors would render the pheromone-responsive elements in the other core genes non-functional (three of this core genes encode proteins that should be combined into a heterotrimer to function), thus leaving the only functional route that passing through RME1. Accumulating mutations would have then simply removed the pheromone-response site.

An interesting story of how regulation can effectively be altered by evolution in small steps.  Another important connection is that of the fact that for many fungi, most particularly pathogens such as Candida glabrata, we lack direct observation of the mating cycle although they conserve intact the mating genes and for some we have indirect evidence that they mate. Perhaps it all comes down to very specific requirements for mating, achieved by intercalating layers of regulation of mating genes as that found in K. lactis.

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