Seemingly Unimportant Mutations Can Foster Disease

Initially innocuous genetic changes known as neutral mutations may play a role in disorders ranging from the flu and bacterial infections to schizophrenia

Rutherford and Lindquist first demonstrated what Hsp90 does in fruit flies. When they depleted the protein by exposing flies to heat or chemicals, the insects grew up with all sorts of weird features, from subtle, unimportant things like extra hairs to severe deformities like misshapen eyes. None of these changes were caused by fresh mutations but rather by existing dormant ones that had been hidden by Hsp90 and unmasked by its absence. For good reason, Lindquist has described Hsp90 as an evolutionary “capacitor,” after the devices that store electrical charge and release it when needed. It stores cryptic variation, unleashing it in demanding environments, just when it is most needed.

Hsp90 is ancient and found in plants and fungi as well as animals—signs that it is one of life’s critical molecules.One of Lindquist’s lab members, Daniel Jarosz, discovered that a fifth of all the variation in the yeast genome is concealed by Hsp90—a huge reservoir just waiting to be released. By exposing so much variation in one fell swoop, Hsp90’s behavior provides a possible answer to one of evolution’s most puzzling questions—the origin of complex combinations of traits.

“Sometimes it’s hard to envision how new forms or functions could emerge if they require multiple mutations, none of which are individually beneficial. The frequency of it should be exceedingly rare,” Jarosz says. It is a dilemma that opponents of evolutionary theory often seize on. But heat-shock proteins, and cryptic variation more broadly, provide a possible solution. When environments change, they allow organisms to make use of mutations that were sitting quietly in the wings but that in combination suddenly offer a solution to some challenge to survival. They act as evolutionary rocket fuel. “Hsp90 can help us to understand how complex traits could ever be achieved in very rapid fashion,” Jarosz says. For those in the field, it is an exciting time. “We’re really at the cusp of making big discoveries in the most fundamental question in evolutionary biology: ‘How does life bring about new things?’” Wagner says.

The disease connection
Beyond offering new insight into the underpinnings of evolution, research into cryptic mutations is suggesting new ways to look at and combat disease. It has been very hard to decipher the genetic underpinnings of many human traits or diseases, from height to schizophrenia. Even though they run strongly in families, scientists have found only a small number of genes associated with them. Plotkin wonders if cryptic variation might help to solve the puzzle of this “missing heritability.” Perhaps we should be looking for mutations that have no effect on their own but rather influence the risk of diseases in combination. “This is just wild speculation on my part, but it sounds reasonable to me,” he says.

The same thinking is being applied to other disorders. We continually provide bacteria, fungi and viruses with new challenges by attacking them with our immune system or hitting them with waves of toxic drugs. One of their chief defences is the ability to evolve resistance, and cryptic variation helps them to do this faster. Lindquist, for example, has shown that Candida albicans, the fungus responsible for thrush, needs lots of Hsp90 to evolve resistance to antifungal drugs. When she blocked Hsp90, the fungi stayed vulnerable. Cancer cells also benefit from Hsp90, because they need help in folding their wide array of unstable mutant proteins. Many scientists are now testing chemicals that block Hsp90 as potential treatments for cancer or ways of preventing fungi and bacteria from developing drug-resistance.

Others are trying to predict how cryptic variation fuels the evolution of viruses. Plotkin and Bloom are focusing on influenza. “The flu virus is evolving all the time to escape all the antibodies that it has stimulated in the human population,” Plotkin says. “This is why we have to update the vaccine every year.” Last year he analyzed the genomes of flu viruses collected over four decades. He found hundreds of pairs of mutations, where one swiftly appeared after the other. In many cases the first of the pair was neutral—it did nothing except to pave the way for the second mutation. By identifying these hidden mutations, which predate more serious ones, we could find strains that are primed for resistance and cut them off with the right vaccines. “We could, to some extent, predict the evolution of flu,” Plotkin says.

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