Weizmann Insitute scientists show how proteins beat the evolutionary stakes

Evolution is something of a gamble: in order to stay a step ahead of a shifting environment, organisms must change or risk extinction. Yet the instrument of this change, mutation, carries a serious threat: mutations are hundreds of times more likely to be harmful to the organism than advantageous. Now, in a paper published online Nov. 28 in Nature Genetics, a team of scientists at the Weizmann Institute of Science has shown one way that evolving organisms may be hedging their bets.

Dr. Dan Tawfik, who headed the team from the Biological Chemistry Department, believes that proteins with so-called promiscuous or moonlighting activities can provide nature with ready-made starting points for the evolution of new functions. Proteins that have evolved to perform a given function often have the ability to take on other, often completely unrelated tasks as well. For example, one of the enzymes studied by the group, PON1, is known to remove cholesterol from artery walls, as well as to break up a certain chemicals used as pesticides.

Yet its main function is to act as a catalyst for the removal of a class of compounds called lactones that have no connection at all to the other two.

To investigate what kind of evolutionary advantage promiscuity offers, the team created a speeded-up version of evolution in the lab. Mutations were introduced into the genes coding for various proteins in a completely random manner. Evolutionary pressure was then simulated by selecting those mutants with higher levels of activity in one of the promiscuous traits.

After several rounds of mutation and selection, the scientists looked at their enzymes to see what had changed. As expected, they had managed to increase the activity they were selecting for by as much as a hundredfold and more. But how did increasing one skill affect the others?

Interestingly, the levels of the other promiscuous activities also underwent drastic changes. In most cases, the levels dropped dramatically, though in some there was a significant increase. However, the primary function of the enzymes, the one for which they had originally evolved, changed hardly at all. “This is particularly surprising when you consider that all of these activities take place at the exact same site on the enzyme,” says Tawfik.

This phenomenon makes sense when viewed in evolutionary terms. “Two contradictory things are necessary for the survival of organisms,” he says. “First of all, an organism needs to be robust in the face of mutation – it needs to undergo as little change as possible in its functioning in spite of mutations. But, evolutionary adaptation requires some mutations to induce new traits. It appears that the organism can have it both ways: the main function remains robust while the promiscuous functions are extremely responsive to mutation.”

The scientists believe that promiscuity may be an intermediate phase for some evolving proteins. In the face of further evolutionary pressure, the protein line could split, diverging into two distinct genes. This multi-tasking may also partly explain another phenomenon that has been puzzling biologists: rapidly emerging drug and antibiotic resistance, and enzymes that have adapted to break down man-made chemicals that have only been around for 50 years. Natural evolution, according to standard theory, should take thousands and hundreds of thousands of years to work. The key may be in promiscuous functions that have never been under selection pressure. These latent “underground” skills may provide the evolutionary shortcut needed for rapid adaptation.

Dr. Dan Tawfik’s research is supported by the Y. Leon Benoziyo Institute for Molecular Medicine, the Dolfi and Lola Ebner Center for Biomedical Research, the Estelle Funk Foundation, the Dr. Ernst Nathan Fund for Biomedical Research, the Henry S. and Anne Reich Family Foundation, The Harry and Jeanette Weinberg Fund for Molecular Genetics of Cancer and the Eugene & Delores Zemsky Charitable Foundation Inc.

Dr. Tawfik is the incumbent of the Elaine Blond Career Development Chair.