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The Power of Hidden Mutations, or Why I Wish I Bought a Fan

England is currently in the middle of a heatwave (if you’re from a tropical country, try not to laugh). The air is hot, still and oppressive, and I feel like I’m stuck in a Tennessee Williams play. I wish I had a fan but, of course, all of the shops are out of fans. The smart move would have been to buy a fan in the middle of winter, when they were readily available. The fan would have been useless for months, neither giving me benefits not inconveniencing me. But when the environment changed and a cooling device suddenly became useful, I’d be laughing.

A lot of evolutionary biologists are coming round to the same idea. We’re used to the idea that living things pick up changes (mutations) in their genes. Some of these benefit their owners and spread through the population thanks to natural selection; others are harmful, and get weeded out. But many mutations don’t seem to do anything at all. They don’t change any proteins. They don’t influence the success of their owners. They’re called “neutral”.

But these neutral mutations might not be so innocuous after all. Some, like my imagined fan, suddenly become useful when the environment changes. Others lay the groundwork for further mutations that would otherwise do nothing (or be harmful) on their own—in other words, they make organisms better at evolving.

These “cryptic mutations” turn out to be a powerful force in evolution. They’ve been discussed since the 1930s, when eminent biologists talked about unimportant genetic changes that could later give rise to valuable ones, or stores of “concealed potential variability.” But it’s only now that we have the tools and techniques to find concrete and convincing case studies.

I’ve written about these discoveries in a new feature for Scientific American. The lead story is one of the best examples of how important cryptic mutations can be, and how they are relevant to our health.  But do head over there for the full story.

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.

6 thoughts on “The Power of Hidden Mutations, or Why I Wish I Bought a Fan

  1. That is very interesting. But there is one thing I may not have understood well. Once you see that both mutations in the influenza virus have an instant benefit as a combination, then it’s not like that fan you’ve bought in January. It wasn’t a (double) mutation stored for a rainy day, rather it had an instant effect. Tamiflu was introduced in the late 1990ies, right?
    When first reading about Darwins’ finches, I wondered wether one of the benefits of having a beak rather than teeth was it’s evolutionary plasticity – or if a body part could be of evolutionary advantage not by what it is or can do right now, but rather by how easily it transforms into something well adapted if and when that is called for. I couldn’t ever work out for myself wether such an “adaptability benefit” would work within the theory of evolution.

  2. Not to go off topic Ed, but calling it a heatwave in the UK made me laugh.

    Over here in Arizona we regularly have temperatures of between 100 F and 116 F (thats 37.77 C to 46.6 C) for the better part of 8 months. Usually with NO cloud cover or wind so it can feel much hotter than it is.

    Without AC in Arizona, you can actually die in your own house.

    Lastly there is one very small mistake (its a very small mistake that almost everyone makes). Look at the last sentence “…myself wether such…”

    Wether is spelt wrong, it should be “whether”.

    Either way this was a good article that made for a good read.

  3. The SciAm version of the article mentioned that flu mutations often come in pairs, with the first being innocuous and the second activating the problem. It speculates that identifying the first, cryptic, mutation can help us prepare for the second.

    I suspect that this is simply a factor of the speed with which single-stranded viruses mutate, and the number of virus copies produced. I bet we’d find that there are zillions of “first” mutations happening all the time, and it’s only in hindsight that we can tell which one paired with the “second” mutation.

    Things would be different in double-stranded organisms with longer generations and fewer offspring. There, mutations would be more rare, and there might be some actual link between a paired “first” and “second” mutation. But in flu, I suspect the numbers will show that independent double mutations are simply the way evolution happens, and there’s no particular reason for the first mutation to be cryptic… except that if it were not cryptic, we would consider it to be the second mutation.

  4. I’m reminded of being in Perthshire in Scotland in August 1977. The Perth newspaper one day had a headline that screamed across page 1 – “Scorching heat wave to continue – high of 72 today”
    72 F = 20 C.

    Scorching heatwave. Right.

  5. Not strictly on topic, but it can be the case that mutations labeled “neutral” are simply ones which have not had their harmful effects clearly associated, or perhaps triggered by some specific factor.

  6. I’ve always been suspicious of how scientist have always referred to large pieces of dna as ‘junk’. I think maybe that despite all of the knowledge we’ve gained in understanding dna, many of the theories swirling around it’s operation are still junk. Scientist have always had a habit of short-changing the complexities of the universe and all of the structures within it.

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