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

CDC/Dr. William Kaplan

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When Jesse Bloom heard in 2009 that Tamiflu, once the world’s best treatment for flu, had inexplicably lost its punch, he thought he knew why. Sitting in his lab at the California Institute of Technology, the biologist listened to a spokesperson from the World Health Organization recount the tale of the drug’s fall from grace. Introduced in 1999, the compound was the first line of defense against the various strains of flu virus that circulate around the world every year. It did not just treat symptoms; it slowed the replication of the virus in the body, and it did its job well for a time. But in 2007 strains worldwide started shrugging off the drug. Within a year Tamiflu was almost completely useless against seasonal influenza.

The WHO spokesperson explained that the sweeping resistance came about through the tiniest of changes in the flu’s genetic material. All flu viruses have a protein on their surface called neuraminidase—the “N” in such designations as H1N1—which helps the viruses to break out of one cell and infect another. Tamiflu is meant to stick to this protein and gum it up, trapping the viruses and curtailing their spread. But flu viruses can escape the drug’s attention through a single change in the gene encoding the neuraminidase protein. A mutation called H274Y subtly alters neuraminidase’s shape and prevents Tamiflu from sticking to it.

Most public health experts had assumed that flu viruses would eventually evolve resistance to Tamiflu. But no one anticipated it would happen via H274Y, a mutation first identified in 1999 and originally thought to be of little concern. Although it allows flu viruses to evade Tamiflu, it also hampers their ability to infect other cells. Based on studies in mice and ferrets, scientists concluded that the mutation was “unlikely to be of clinical consequence.” They were very wrong. The global spread of viruses bearing H274Y proved as much.

That spread “sounded alarm bells to me,” Bloom says. Something else had changed to let the virus use the mutant neuraminidase without losing the ability to spread efficiently. He soon found that certain strains of H1N1 had two other mutations that compensated for H274Y’s debilitating effects on the virus’s ability to spread from cell to cell. Neither of the pair had any effect on their own. In the lingo of biologists they were “neutral.” But viruses that carried both of them could pick up H274Y, gaining resistance to Tamiflu without losing their infectivity. Both mutations looked innocuous individually, but together they made the virus more adaptable in the face of a challenge. To put it another way, they made it better at evolving.

Such neutral mutations are also known collectively as hidden or cryptic variation. They were long ignored by most researchers, but thanks to technological advances, scientists are starting to see that they are a major driving force in evolution—including the evolution of microorganisms that make us sick. By studying cryptic variation, scientists are finding new ways of safeguarding our health and discovering fuller answers to one of evolution's most fundamental questions: Where do new adaptive traits come from? As Joshua Plotkin from the University of Pennsylvania puts it: “This is the forefront of modern evolutionary biology.”

How it works
As the flu example shows, one way that cryptic mutations can enhance adaptation is by collaborating with other mutations to produce a whole that is greater than the sum of its parts. Imagine that someone gave you a triangular metal frame or a pair of wheels. Both parts would be useless on their own, but put them together and you get a working bicycle. If you have either component, you have nothing immediately useful but you are primed to reap the benefits of the second one. In the same way cryptic variation can lay the groundwork for future adaptations.

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