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

Imagine no mutation.

Imagine no mutation.
I wonder if you can.
No means for new variation.
A creationist's view of Man.
Imagine all the people
learning it this way.

Boo-hoo, ewww.

I found out this semester that although most of my students in "Human Origins" had learned about natural selection, that relatively few of them had learned about mutation. 

Huh? Are people still stuck on Darwin? Apparently. 

Mutation requires a little bit of genetics to understand, but c'mon! Natural selection makes no sense without it. None.

And what's more, natural selection cannot be the all-powerful force that popular culture might have us believe when mutation is accounted for. Evolution is so much more fascinating with even a basic understanding of mutation. In this molecular-clock, whole-genome-sequencing era, how can anyone teaching and learning evolution not have at least a basic understanding of chance, perpetual accumulation of mutations?

We've all, each and every one of us, got many de novo mutations. So our genomes are distinct from our parents' and siblings', not just because of genetic recombination of our grandparents' genomes when our parents' eggs and sperms were built, but because of unique mutations that occurred while making those germ cells or in the early stages after their union.

That this constant change in lineages is occurring with each reproductive event is proof that natural selection is a largely tolerant process, perpetually allowing perpetual evolution by mutation.

(And, maybe natural selection has much less, and mutation has much more, to do with speciation than many have assumed.)

What happens to each and every one of our unique mutations, whether or not they live on in our offspring, whether or not they play a role in adaptation, depends on quite a bit of luck, partly because of the "Law of Segregation":

A Mutation's Future
Click to enlarge. Email me for original file that you can modify: holly_dunsworth@uri.edu

For a description of evolution that incorporates perpetual mutation, check out "Evolution is the only natural explanation. And it's all we need."

Novel mutations = novel conclusions?

As reported in the NYT, the results of three new studies, published (here, here, and here) this week in Nature on the genetics of autism has found novel gene mutations that might explain risk as well as evidence that risk increases with the age of the father.  From the Sanders et al. paper:

Here we show, using whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, that highly disruptive (nonsense and splice-site) de novo mutations in brain-expressed genes are associated with autism spectrum disorders and carry large effects. On the basis of mutation rates in unaffected individuals, we demonstrate that multiple independent de novo single nucleotide variants in the same gene among unrelated probands reliably identifies risk alleles, providing a clear path forward for gene discovery. Among a total of 279 identified de novo coding mutations, there is a single instance in probands, and none in siblings, in which two independent nonsense variants disrupt the same gene, SCN2A (sodium channel, voltage-gated, type II, α subunit), a result that is highly unlikely by chance.

It explains risk in only a very small fraction of cases.  Though, Sander et al. suggest that the model may well be useful for explaining many more. As the Times story says:

Experts said the new research gave scientists something they had not had: a clear strategy for building some understanding of the disease’s biological basis.

And,

An intensified search for rare mutations could turn up enough of these to account for 15 percent to 20 percent of all autism cases, some experts say, and allow researchers a chance to see patterns and some possible mechanisms to explain what goes awry. 

This would be great, of course.  Any clues to the bigger picture could be extremely helpful.  However, if autism is like every other complex disorder, a finding that's true at one extreme of the distribution of the phenotype will not necessarily apply to any other part of the distribution.  There are high shared fractions of the genome among relatives, usually many coding changes, too.  So it is going to be difficult to 'prove' that the change observed really is causal. Exome sequence assumes coding changes and in a way is vulnerable to identifying a coding change and assuming it's causal, when regulatory changes are not in the search space; is this the drunk looking for his keys under the lamplight?

Indeed, as O'Roak et al. conclude,

Although there is no one major genetic lesion responsible for ASD, it is still largely unknown whether there are subsets of individuals with a common or strongly related molecular aetiology and how large these subsets are likely to be.

O'Roak et al. identified novel mutations in sporadic, non-familial cases, and characterized them as to their severity and type, and they also identified pathways that the affected genes might share.  They conclude that there are likely to be from hundreds to over a thousand genes associated with autism: "Our analysis predicts extreme locus heterogeneity underlying the genetic aetiology of autism."

Of course there must be 'networks', and all of this kind of rhetoric sounds impressive but really is post-facto and in a sense superficial.  Genes interact with other genes, not just in terms of protein-protein interactions but also related to expression level (not assayable by exome sequencing).  So saying that there are hundreds of genes in networks is to some extent big-words to acknowledge that we may find this or that component, but this trait is simply not simple.

Neale et al. report, "Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold."  Again, other functional elements in DNA that greatly outnumber the protein-coding parts, are likely to be at least as important.  Indeed, there are findings that 1% or more of autism is due to copy number variation, which may overall swamp the rare variants in importance, if the results hold up.

Each of these studies looked at a subset of the study population -- because autism is such a wide spectrum of disorders, it's important to reduce possible genetic heterogeneity by narrowing the phenotype in any study -- and found novel, or sporadic mutations to be associated with risk.  Because the idea that new mutations, which we all carry a substantial number of, might be causative can't help predict who is at risk, the hope is that if these mutations are indeed associated with risk, they might give some clues as to which developmental pathways are affected in this disorder.  The hope has been for years that genes for autism will be identified. Now that it's looking like this is a polygenic disorder, if indeed genes are a primary cause, and that sporadic mutations might be significant, it's looking more and more likely that those who have long said that major genes that can predict the disorder will not be found have been right.

The Times quotes a well-known population geneticist on this work:

“This is a great beginning, and I’m impressed with the work, but we don’t know the cause of these rare mutations, or even their levels in the general population,” said Dr. Aravinda Chakravarti of the Institute of Genetic Medicine at the Johns Hopkins University Medical School, who was not involved in the studies. “I’m not saying it’s not worth it to follow up these findings, but I am saying it’s going to be a hard slog.”

If these new results can in fact lead to understanding what goes awry in the developing brain to lead to autism, great.  Whether this will ever be clinically significant is another matter.  And one needs to remember that autism is by far mainly environmentally caused!  The report last week that its prevalence has increased by 78% in the past decade alone shows that this is about environments (that increase is unlikely to all be due to changing definitions of the disorder, or changes in diagnostic practices).  Well, a determined geneticist will argue that rapid environmental change could, in principle, have led to higher disease risk by triggering big responses in a few common genetic variants interacting with the environment.  Not so! We've had he environmental change (whatever it is), and ASD is clearly not due to one or two major genes responding to that change.

The same arguments apply to excessively exuberant claims implying simple genetic adaptation due to natural selection, and for the same reasons.

If biomedical research is about doing something about autism, rather than about forcing genetic thinking onto the problem, we're looking under the wrong lamp-post!