If mutations can go viral, adaptationism is less annoying.

Feb. 9, 2016: I have edited the paragraph beginning with "Exciting..." to remove details of mutation rates because my initial posting was probably wrong about coding vs. non-coding mutation rates. To fix that requires much more nuance than is relevant for the point I'm making in that paragraph, not to mention much more nuance than I'm capable of grasping immediately! Cheers and thanks to Daniel and Ken in comments below and to everyone who chimed in on Twitter. 

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I always account for virally-induced mutation when I imagine the evolution of our genome. That's because I'll never forget this quote. Who could?

“Our genome is littered with the rotting carcasses of these little viruses that have made their home in our genome for millions of years.” - David Haussler in 2008 

Or this...

"Retroviruses are the only group of viruses known to have left a fossil record, in the form of endogenous proviruses, and approximately 8% of the human genome is made up of these elements." (source and see this)

Exciting virus discoveries aside, we're constantly mutating with each new addition to the human lineage. Thanks to whole genome sequencing, the rate of new mutation between human parent and offspring is becoming better known than ever before. We each have new single nucleotide mutations in the stretches of our DNA that are known to be functional (very little of the entire genome) and that are not (the majority of the genome). These are variants not present in our parents’ codes (for example, we might have a ‘T’ where there is a ‘A’ in our mother’s code). And there are also deletions and duplications of strings of letters in the code, sometimes very long ones. Estimates vary on parent-offspring mutation rate and that's because there are different sorts of mutations and individuals vary, even as they age, as to how many mutations they pass along, for example. Still, without any hard numbers (which I've left out purposefully to avoid the mutation rate debate), knowing that there is constant mutation is helpful for imagining how evolution works. And it also helps us understand how mutations even in coding regions aren't necessarily good nor bad. Most mutations in our genome are just riding along in our mutation-tolerant codes—where they will begin and where they will go no one knows!

And it's with that appreciation for constant, unpredictable, but tolerated mutation—of evolution's momentum, of a lineage's perpetual change, selection or not—on top of a general understanding of population genetics that just makes adaptation seem astounding. It makes it difficult to believe that adaptation is as common as the myriad adaptive hypotheses for myriad traits suggest.

That's because this new raw material for adaptation, this perpetual mutation, really is only a tiny fragment of everything that can be passed on. But, what's more, each of those itty bitty changes could be stopped in its tracks before going anywhere.

The good, the bad, and the neutral, they all need luck to pass them onto the next generation. That's right. Even the good mutations have it rough. Even the winners can be losers! Here are the ways a mutation can live or die in you or me:

The Brief or Wondrous Life of Mutations, Wow.

This view of mutation fits into that slow and stately process that Darwin described, despite his imagination chugging away before he had much understanding of genetics.

Of course, bottlenecks or being part small populations would certainly help our rogue underdogs proliferate, and swiftlier so, in future generations.

Still, trying to imagine how any of my mutations, including any that might be adaptive, could become fixed in a population is enough to make me throw Origin of Species across the room.

By "adaptive," I'm talking about "better" or "advantageous" traits and their inherited basis ... that ever-popular take on the classic Darwinian idea of natural selection and competition.

For many with a view of mutation like I spelled out above, it's much easier to conceptualize adaptation as the result of negative selection, stabilizing selection, and tolerant or weak selection than it is to accept stories of full-blown positive selection, which is what "Darwinian" usually describes (whether or not that was Darwin's intention). One little error in one dude's DNA plus deep time goes all the way to fixed in the entire species because those who were lucky enough to inherit the error passed it on more frequently, because they had that error, than anyone passed on the old version of that code? I guess what I'm saying is, it's not entirely satisfying.

But what if a mutation could be less pitiful, less lonely, less vulnerable to immediate extinction? Instead, what if a mutation could arise in many people simultaneously? What if a mutation didn't have to start out as 1/10,000? What if it began as 1,000/10,000?

That would certainly up its chances of increasing in frequency over time, and quickly, relative to the rogue underdog way that I hashed out in the figure above. And that means that if there was a mutation that did increase survival and reproduction relative to the status quo, it would have a better chance to actually take over as an adaptation. This would be aided, especially, if there was non-random mating, like assortative mating, creating a population rife with this beneficial mutation in the geologic blink of an eye.

But how could such a widespread mutation arise? This sounds so heartless to put it like this, but thanks to the Zika virus, it seems to me that viruses could do the trick.

Electron micrograph of Zika virus. (wikipedia)

I'd been trapped in thinking that viruses cause unique mutations in our genomes the way that copy errors do. But why should they? If they infect me and you, they could leave the same signatures in our genomes. And the number of infected/mutated could increase if the virus is transmitted via multiple species (e.g. mosquito and human, like Zika). If scientists figure out that the rampant microcephaly associated with the Zika virus is congenital, wouldn't this be an example* of the kind of large-scale mutation that I'm talking about? 

*albeit a horrifying one, and unlikely to get passed on because of its effects, so it's not adaptive whatsoever.

If viral mutations get into our gametes or into the stem cells of our developing embryos, then we've got germ-line mutation and we could have the same germ-line mutation in the many many genomes of those infected with the virus. As long as we survive the virus, and we reproduce, then we'll have these mutant babies who don't just have their own unique mutations, but they also have these new but shared mutations and the shared new phenotypes associated with them, simultaneously.

Why not? Well, not if there are no viruses that ever work like this.

We need some examples. The mammalian placenta, and its subsequent diversity, is said to have begun virally, but I can't find any writing that assumes anything other than a little snowflake mutation-that-could.

Anything else? Any traits that "make us human"? Any traits that are pegged as convergences but could be due to the mutual hosting of the same virus exacting the same kind of mutation with the same phenotypic result in separate lineages?

I've always had a soft spot for underdogs. And I've always given the one-off mutation concept the benefit of the doubt because I know that my imagination struggles to appreciate deep time. What choice do you have when you think evolutionarily? However, just the possibility that viruses can mutate us at this larger scale, even though I know of no examples, is already bringing me a little bit of hope and peace, and also some much needed patience for adaptationism.

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Update: I just saw this published today, asking whether microcephaly and other virus-induced birth defects are congenital. Answer = no one knows yet: http://www.nytimes.com/2016/02/09/science/zika-virus-microcephaly-birth-defects-rubella-cytomegalovirus.html?partner=IFTTT&_r=1

Good crud -- antivirals

The development of antiviral agents to combat viral infections from the common cold to HIV, hepatitis, SARS, Ebola, and other lethal diseases has proven to be elusive to date.  Such an agent would be an invaluable contribution to the world's armamentarium against disease.  And now it may be that the world is on the verge of getting such an agent.  Last year, Leo James, an immunologist at Cambridge reported in PNAS that his lab had found that antibodies can make their way into cells and destroy the virus before it harms the cell or causes illness.  This was treated as great news for the possible development of antivirals, though it was early days, and of course much more work is needed.

Then, Todd Rider, at MIT, published a paper in PLoS One in July that reported progress on a treatment that takes advantage of the double stranded nature of RNA viruses, and the ability of cells to kill themselves when they detect that they've been infected by a virus.

We have developed a new broad-spectrum antiviral approach, dubbed Double-stranded RNA (dsRNA) Activated CaspaseOligomerizer (DRACO) that selectively induces apoptosis in cells containing viral dsRNA, rapidly killing infected cells without harming uninfected cells. We have created DRACOs and shown that they are nontoxic in 11 mammalian cell types and effective against 15 different viruses, including dengue flavivirus, Amapari and Tacaribe arenaviruses, Guama bunyavirus, and H1N1 influenza. We have also demonstrated that DRACOs can rescue mice challenged with H1N1 influenza. DRACOs have the potential to be effective therapeutics or prophylactics for numerous clinical and priority viruses, due to the broad-spectrum sensitivity of the dsRNA detection domain, the potent activity of the apoptosis induction domain, and the novel direct linkage between the two which viruses have never encountered.

Why this was published in PLoS One, which is in many senses not really a fully peer reviewed journal, if it is so important isn't clear.  Maybe it was rejected by more noted journals, or maybe the authors believe in the public library concept, or they want quick publication without the usual delays and hassles with nit-picking referees.  In any case, why is the BBC just getting around to reporting this now?  Because they've just done a radio segment on the development of antivirals, including an interview with Rider, highlighting his work.

Viruses are difficult to stop because they are complete parasites, and so much of how they work is identical to how our own cells work.  Bacteria are easier targets because they are so different from ourselves, and so destroying them doesn't pose the same kind of risk to our own cells that targeting viruses does.

A number of labs are currently working on antivirals, from somewhat different angles. Peter Palese at Mt Sinai has found a compound which is active at least against influenza, and perhaps other respiratory viruses, though in principle, the list could be longer.  Every cell needs pyrimidines to make nucleic acids -- if you reduce the pool of pyrimidines, viruses won't be able to replicate.  Palese has identified a compound that acts to reduce that pool, which results in a lower viral load and absence of clinical disease, at least for the flu.  Why that wouldn't harm the host cells for the same reason isn't clear (to us, who aren't experts in this area by any means).

A different agent looks to be effective against a large number of viruses.  Benhur Lee at UCLA has identified a compound that seemed to be effective against poxes, RNA viruses, DNA viruses, and many others.  These are lipid envelope viruses; Lee's agent attacks the viral lipid membrane, disarming at least (or only, it's not yet clear) this type of virus.

But Todd Rider suggests that his drug, or DRACO (yes, you are supposed to think of "draconian") will be able to treat all viral infections, without harming uninfected cells.  Cells have enzymes that can detect long dsRNA -- when they detect it, they fight the virus off.  But, some viruses can outsmart that system, so Rider has wired together the protein that recognizes dsRNA with a caspase, a protein that triggers apoptosis, or cell suicide.  When it finds the dsRNA, it will activate the caspase, causing the infected cell to destroy itself.

Will this method become clinically useful?  Other immunologists caution that success in the laboratory is a far cry from success in infected humans.  Rider recognizes that he has a lot more work to do, but he says that so far no one has offered a reason why his antiviral approach isn't going to work.  The potential seems to be there.  Of course, side effects, both foreseen and unforeseen, are a potential risk, as with any new way we find to mess with biology, but this all sounds like progress on an important scale.

If one or more antiviral agent is on the horizon, it is in part due to increased understanding of viruses at the genetic level.  This we would say is a laudable use of genetic knowledge and technology.  It may be that 90% of the work will turn out to be crud, but this is the kind of generation of crud that seems to us to be justified.  And the ubiquity and importance to humans and our pets and food sources, of better control of viruses means this kind of work could be as important as most of us (vainly) claim their (our) work to be.