News Release

Prions may play crucial role in evolution.

Peer-Reviewed Publication

University of Chicago Medical Center



Prions, abnormally folded proteins associated with several bizarre human diseases, may hold the key to a major mystery in evolution: how survival skills that require multiple genetic changes arise all at once when each genetic change by itself would be unsuccessful and even harmful.

In a study in the September 28, 2000, issue of Nature researchers at the Howard Hughes Institute at the University of Chicago describe a prion-dependent mechanism that seems perfectly suited to solving this dilemma, at least for yeast. It allows yeast to stockpile an arsenal of genetic variation and then release it to express a host of novel characteristics, including the ability to grow well in altered environments.

"We found that a heritable genetic element based on protein folding, not encoded in DNA or RNA, allows yeast to acquire many silent changes in their genome and suddenly reveal them," said Susan Lindquist, Ph.D., professor of molecular genetics and cell biology at the University of Chicago, Howard Hughes Investigator and principal author of the study.

There are thousands of proteins in every cell and each one has to fold into just the right shape in order to function. In prion diseases, which include mad cow disease and Creutzfeldt-Jakob disease, a normal cell protein, PrP, assumes an abnormal shape.

Mis-folded proteins are usually just degraded, but the prion protein causes other PrP proteins to mis-fold, too, creating a protein-folding chain reaction. Thus, they act as infectious agents. As more and more of the proteins fold into the prion shape, they form inactive aggregates which lead to dysfunction and disease.

A few years ago geneticists made the startling discovery that yeast, the organism found in bread and beer, has prions, too. Yeast prions are unrelated to the mammalian prions, and don’t harm humans or yeast. They do, however, have the unusual property of mis-folding in the same peculiar way and spreading their change in shape from one protein to another. Mother cells pass these proteins to their daughters, so the change, once it occurs, is inherited from generation to generation.

Because yeast prions act much like mammalian prions and are easier to study, scientists hope they will offer clues about how these mis-folding chain reactions get started and how they might be stopped.

But the real puzzle is why these things exist in yeast cells in the first place. University of Chicago researchers appear to have found the answer, and it has broad and unexpected implications: the yeast prion seems to play an adaptive role and may greatly influence evolutionary processes.

The prion protein they studied is called Sup35. It normally ensures that yeast faithfully translate the genetic code. Specifically, Sup35 recognizes special signals that tell the entire protein production machinery to stop when it is supposed to stop.

Sup35 doesn't function in its prion state. As a result, the protein production machinery runs right through the "stop signs." This means that usually silent regions of the genetic code are suddenly expressed. Because these regions are normally not expressed, they don't face selective pressures that prevent mutations from accumulating. The prion therefore uncovers, all at once, a wealth of previously hidden genetic mutations and creates a completely new set of growth properties. Suddenly cells change the kind of food they eat, change their resistance to antibiotics and even grow colonies with completely different shapes.

In some cases the prion may simply cause the protein production machinery to read through the "stop sign" at the end of a normal gene. This would create a protein whose function is altered by the addition of a new tail.

In other cases the cell machinery may produce a completely new protein from a mutated gene that is not ordinarily translated because it contains a stop signal.

The key to its effect is the stable inheritance of the prion state and the normal state. A spontaneous switch between the two states occurs approximately once in a million generations. Because a yeast colony produces a new generation every two hours, in a short time a colony will produce some members that have switched their state.

"It’s an ‘all or nothing’ switch, with the changes immediately inherited by all the progeny," said Lindquist. "But because the cell maintains the ability to switch back, the prion switch allows cells to occupy a new niche without losing their capacity to occupy the old."

The researchers exposed seven distinct genetic strains of yeast in their prion and non-prion states to 150 different growth conditions. The prion-positive state had a substantial effect on the growth of the yeast in nearly half of the conditions tested. In more than 25 percent of these cases its effects were positive. The incredible diversity of the advantages conveyed by the prions indicated that each strain had different novel genes turned on in its prion-positive state.

This prion switch is conserved in yeast across very distantly related genetic strains. Though the switch may have evolved as an accidental consequence of a shape change in an unimportant functioning part of the Sup35, its conservation suggests an evolutionary advantage.

"It may be that the prion switch offers yeast a way to respond to commonly fluctuating environments," said Lindquist. "During its evolution S. cerevisiae (brewers’ yeast) must have met with such erratic environments that it needed to maintain a global mechanism for exploiting genome-wide variation."

By providing yeast with a way to respond to fluctuating environments, the prion switch may offer a significant evolutionary advantage.

"Though we haven’t shown it yet, selective pressure should operate to ‘fix’ the advantageous genes, which could then be read and translated at all times," said Lindquist.

Prion mechanisms could be more common than previously suspected and exert an important influence on the rates and mechanisms of evolutionary change.

"We need to expand our understanding of inheritance," said Lindquist. "It involves much more than a certain nucleic acid sequence of DNA."

###

Susan L. Lindquist is the Albert D. Lasker Professor of Medical Sciences, Department of Molecular Genetics & Cell Biology at the University of Chicago and a Howard Hughes Medical Institute Investigator. Her co-author is Heather L. True, a Fellow in the Department of Molecular Genetics & Cell Biology at the University of Chicago.


Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.