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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

Some cryptic mutations can also prove useful on their own, essentially keeping quiet until circumstances arise where they come in handy. And, by building up a lot of cryptic variation, organisms can increase their ability to adapt. Imagine that something goes badly wrong in your house. If you have a bunch of tools you never needed before stashed away in a cupboard, one of them might end up being good for the job or could be modified. In the same way, a storehouse of cryptic variation increases the chances that living things will be preadapted to cope with new challenges.

These ideas fit well with Darwin’s theory of natural selection, in which beneficial traits that boost an organism’s reproductive success are passed down to future generations, or “selected” to continue on. Biologists, however, are increasingly realizing that some mutations are important not because they provide immediate benefits but because they enable adaptations to occur in the future. These mutations can build up because natural selection does not remove genetic alterations that have no obvious effects on our proteins, cells or bodies.

The notion that cryptic mutations can be useful has a long history. In the 1930s Sewall Wright, one of the founding fathers of evolutionary theory, recognized that initially unimportant genetic changes could later give rise to valuable ones. Theodosius Dobzhansky, another central figure, said that species need to have “a store of concealed, potential, variability.” Even so, until very recently scientists managed to document only a few arcane examples of hidden mutations affecting the wings or hairs of flies without any proof these changes benefited the animals. “We didn’t have the tools to take it further, and the topic languished,” says Joanna Masel from the University of Arizona in Tucson. With powerful sequencing technology and mathematical models on hand, scientists have now been able to show that cryptic variation is a powerful and widespread force in evolution. In everything from flu viruses to flowers to fungi, they have found tangible case studies where useful adaptations arose from seemingly neutral mutations.

Evidence
One of the clearest examples comes from Andreas Wagner at the University of Zurich and involves molecules called ribozymes, which consist of RNA (genetic material related to DNA) and function in the body as catalysts. They speed up chemical reactions involving other RNA molecules but are picky about the ones they interact with. To react with a new target, they need to alter their shapes. And to do that, they need the sequence of their building blocks to change. In test-tube studies Wagner found that ribozymes could adapt to deal with a new target six times faster if they had previously built up lots of cryptic variation. Just as in the Tamiflu-resistant flu viruses, these mutations made no difference on their own; they merely brought some of the ribozymes a step closer to achieving the changes they needed. “They had a leg up in the evolutionary process,” Wagner says.

Another example comes from studies of heat-shock proteins, which help nascent proteins to fold properly into their functional forms and also protect them from losing their function in response to various stresses, such as excess heat. In 1998 Suzanne Rutherford and Susan Lindquist from the Massachusetts Institute of Technology showed that a heat-shock protein called Hsp90 can both hide cryptic variation and unleash it, depending on circumstances.

By helping proteins to fold correctly, Hsp90 allows them to tolerate genetic mutations that might otherwise catastrophically distort their shapes. It can thus allow proteins to build up such mutations, along with neutral ones. If conditions become more challenging—such as a significant rise in temperature—the Hsp90 molecules may be in such demand that they cannot aid all the proteins that need them. Suddenly, proteins have to fold without Hsp90’s help, and all their cryptic mutations become exposed to natural selection. Some of these mutations would have beneficial effects in the challenging conditions and would thus pass to the next generation.

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