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Prions act as stepping stones in evolution

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When a protein misfolds, the results can be disastrous. An incorrect change in the molecule's shape can lead to diseases including Alzheimer's and Huntington's. But scientists have discovered that misfolded proteins can have a positive side in yeast, helping cells navigate the dicey current of natural selection by expressing a variety of hidden genetic traits.

What's more, at the center of this process is a prion, a protein that changes shape in a self-perpetuating way--much like the prion in mammals that is responsible for certain neurological conditions such as Mad Cow disease.

"This is the first time we've seen a prion affect a cell in a beneficial way that can determine the evolution of an organism," said Heather True, lead author of a paper about the work, which will appear Aug. 15 in the online edition of the journal Nature.

Previously, True and Susan Lindquist, director of the Whitehead Institute and professor of biology at the Massachusetts Institute of Technology, reported that a particular yeast protein called Sup35 somehow altered the metabolic properties--or phenotype--of the cell when it misfolded into a prion state. Sup35 helps guide the process by which cells manufacture protein molecules. However, when Sup35 misfolds into its prion state, it forms amyloid fibers similar to those found in Alzheimer's patients and causes the cell's protein-producing machinery to go awry.

More often than not, this is deleterious to the cell. But in about 20 percent of the cases tested, the Whitehead team discovered that these new phenotypes afford the yeast cell a survival advantage.

"We still didn't know the molecular mechanisms behind this," said True, a former postdoctoral researcher in the Lindquist lab, and now an assistant professor at Washington University in St. Louis. "How exactly did the prion change the appearance of the cell?"

The answer revealed a twist in the traditional understanding of how traits are inherited.

In order for Sup35 to ensure that the cell properly reads the protein recipes contained in genes, it focuses on what are called "stop codons"--sections of DNA that indicate exactly where in the gene a particular protein recipe ends. Sup35 ensures that the cell only translates material prior to these designated codons.

But when it misfolds into a prion conformation, Sup35 gets sloppy, and the cell reads beyond the stop codons, translating genetic information that previously had been dormant. As a result, the cell's phenotype changes.

And here's where evolution comes in.

On those rare occasions when, due to a particular environment, the altered properties of the cell provide it with a survival advantage, the cell passes that trait on to its progeny. But when the daughter cells are mated and genetic reassortment takes place, they can subsequently pass along this same trait without the prion. That is, the trait becomes fixed in the cell's lineage and no longer depends on the prion state. "We don't know yet exactly how the daughter cells do this, but they do it quickly, often after a single mating," said Lindquist.

The prion thus appears to function as an evolutionary stepping stone, affording the population of cells a chance to survive in a new environment where they need a different phenotype until they can acquire the genetic changes that produce the same effect.

These new traits are genetically complex. When Sup35 misfolds into a prion form, it affects a number of genes in one fell swoop.

"This prion has a capacity to hide and release genetic information throughout the entire genome that can contribute to new traits in a complex way," explained Lindquist.

This research was supported by the National Institutes of Health.

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