Under stress, yeast cells can unleash a remarkable mechanism based on protein-misfolding that gives them new characteristics without requiring genetic mutations.
Researchers in Whitehead Member Susan Lindquist's lab now have shown that this mechanism is triggered much more often as the cells undergo stress, suggesting that it is tailored to play exactly this role in evolution.
The mechanism is based on a prion-a protein misfolded into an unusual configuration that can change its function within a cell.
"When things are hunky-dory, only one in a million yeast cells flips into the prion state," observes Susan Lindquist. "But under stress, the organism isn't maintaining its protein as well, so it's more likely that it will flip into that state. The more it is stressed, the more it is likely to change to that state."
In yeast, the [PSI+] prion is a misfolded version of the Sup35 protein, which plays a key role in how cells translate their messenger RNA molecules into proteins. Earlier studies showed that [PSI+] changes how messenger RNA translation ends, thus uncovering hidden genetic variations by creating altered proteins that change the cell.
Most of the resulting phenotypes (variants of the organism) have no effect on cell survival or make things worse. "But about a quarter of the time, the phenotypes are good," says Lindquist, who is also a Howard Hughes Medical Institute investigator and a professor of biology at Massachusetts Institute of Technology. "Sometimes the yeast can grow on energy sources it couldn't grow on before, or withstand antibiotics it couldn't withstand."
But was it just a coincidence, as some biologists have maintained, that yeast cells have maintained this mechanism for hundreds of millions of years? Or has it actually evolved as a way for yeast to evolve more quickly?
Since the change it induces is more commonly detrimental than beneficial, if this mechanism is really meant to accelerate evolution, it should become more common under conditions that are stressful for the cell-environments that are not suited to the cell's current phenotype. That is, Lindquist says, in situations where it is worth taking a chance.
To test this hypothesis, the scientists first examined what genes might help to induce the prion state, plowing through the entire genome of Saccharomyces cerevisiae , the common baker's yeast that biologists have studied intensively for many years. Jens Tyedmers, a lead author on the paper published in PLoS Biology on November 25, tested 4700 yeast strains that each lacked one of the genes in the yeast genome, and then tested each strain's ability to create the prion.
Among the strains most successful at generating prions, "we found many genes that are basically involved in regulating the response of a cell to stress," reports Tyedmers, formerly a postdoc in the Lindquist lab and now a research project leader at the Center for Molecular Biology in Heidelberg, Germany.
With that encouragement, Maria Lucia Madariaga, another lead author on the paper, went on to do stress tests on the yeast.
"We wanted to use some conditions you would find in nature," notes Madariaga, formerly a graduate student in the Lindquist lab and now an MD candidate at Harvard Medical School. "Yeast hanging out in a vineyard are subject to heat, salt and other stresses."