Scientists Find Protein at the Intersection of Genetics, Development and the Environment

CAMBRIDGE, Mass. — Environmental stress can reveal hidden genetic variation in plants, resulting in novel traits that might provide an alternative to genetic modification of crops, researchers report in the journal Nature. They have linked this phenomenon to the actions of a particular molecule, the heat stress protein Hsp90. These findings place Hsp90 at the interface of environment and genetics and potentially provide an explanation for a long-standing evolutionary puzzle: how do large changes in form and function requiring the synchronous alteration of several features occur during evolution?

The scientists—from the Whitehead Institute in Cambridge, Mass., and the University of Chicago—knew that Hsp90 helps other proteins fold properly. They found that it acts like a buffer for naturally occurring subtle mutations, allowing them to accumulate without visible effect. Then when stress compromises the ability of Hsp90 to fold its critical target proteins, these variations are revealed – in other words, they lie dormant until a stress event, and then are exposed all at once. Most of these changes will be harmful. But a few unusual combinations could produce valuable new traits, spurring the pace of evolution.

This mechanism might be harnessed to create better crop plants by conventional breeding methods, without the need for transgenic manipulations of crops, said team leader Susan Lindquist, director of the Whitehead Institute for Biomedical Research and senior author on the study. This would circumvent the public controversy surrounding genetically modified organisms, which derive their traits from exotic genes transplanted into them. Manipulating the Hsp90 buffer may identify useful naturally-occurring variants, such as plants which grow better in poor soil or have increased pest resistance. "Our data suggests that there may be a wealth of genetic variation out there right now that we can’t see because the plants haven’t been grown in the right conditions," Lindquist explained.

Chaperone Proteins

Hsp90 is part of a family of proteins known as "chaperones," which are solely dedicated to helping other proteins fold and assume their proper functions. Like simple sheets of paper that fold into origami figures, proteins fold into a vast array of complex shapes. Cells are vigilant about getting these folds right because misfolded proteins will affect the well-being of the cell. Among the chaperone proteins, Hsp90 is particularly interesting because its activities are focused on proteins that play key regulatory roles in growth and development. Under normal conditions, Hsp90 stabilizes a wide range of proteins.

Christine Queitsch and Todd Sangster, graduate students in the Lindquist lab and co-authors on the paper, investigated the effects of lowering Hsp90 function in the plant Arabidopsis thaliana using strains that differed subtly in their genetic makeup. They either exposed the plants to the drug geldanamycin or increased temperatures. Both conditions perturb Hsp90 buffering and both released a hidden world of genetic mutations. For instance, plants grew leaves with new shapes, had different pigmentation, or hairy roots. Traits observed in one plant were generally shared with offspring that had the same genetic blueprint. But plants with different blueprints produced a wild profusion of different traits.

Common to Plants and Animals

These results mirror the Lindquist group’s earlier research on the fruit fly Drosophila. Thus, Hsp90’s role in buffering genetic variation appears to be conserved between the plant and animal kingdoms. This strengthens an earlier suggestion that the ability of Hsp90 to buffer and release hidden variation could influence the rate and nature of evolution.

In fruit flies, the traits uncovered by Hsp90 were shown to be due to many small hidden genetic changes. Remarkably, several generations of selective breeding concentrated these genetic changes to the point at which the new traits remained even when Hsp90 activity was restored.

Plants showing desirable traits when Hsp90 function is reduced might also be bred to enrich the underlying genetic variation. This could increase the pace at which plant breeders can work to improve crop species. "While there are other mechanisms that can hide genetic variation, the Hsp90 buffering system is directly linked to the environment and to many different traits. This distinguishes it from the others," says Queitsch. "The Hsp90 buffer offers a powerful tool for harnessing natural variation to create desirable traits in plants. It also provides a way to better understand the interplay between genetics and environment in the determination of physical characteristics."

Some genetically identical plants had striking differences in appearance when Hsp90 activity was lowered. Since they were raised in identical conditions and had the same genes, these differences had to be due to chance events. Such events–also called developmental noise–are intrinsic to all developmental processes. For example, people carry many mutations that increase susceptibility to diseases, such as breast cancer or schizophrenia. Some get the disease and others don't. In some cases this is due to the presence of other genetic factors, in others to chance events or "developmental noise." The authors show that, at least in plants, Hsp90 decreases developmental noise, promoting normal development. This work provides the first hint that a single molecule influences stability in a whole host of developmental processes.

"The process of protein folding interacts with our biology and our environment in so many ways. We've just begun to grasp it. It’s like holding a tiger by the tail," Lindquist said.

Citation

Queitsch, C., Sangster, T. A., & Lindquist, S. (2002). Hsp90 as a capacitor of phenotypic variation. Nature, 417(6889), 618-624.