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Darwin the Newtonian. Part V. A spectrum, not a dogma

Our previous installments on genetic drift (a form of chance) vs natural selection (a deterministic force-like phenomenon) and the degree to which evolution is due to each (part 1 here) lead to a few questions that we thought we'd address to end this series.

First, there is no sense in which we are suggesting that complex traits arise out of nowhere, by 'chance' alone.  There is no sense in which we are suggesting that screening for viability or utility does not occur as a regular part of evolution.  But we are asking what the nature of that screening is, and what a basically deterministic, Newtonian view of natural selection, that is we believe widely if often tacitly held, implies and how accurate it may be.

It's also important here to point out something that is obvious.  The dynamics of evolution from both trait and genome level comprise a spectrum of processes, not a single one that should be taken as dogma.  A spectrum means that there is a range of relative roles of what can be viewed as determinism and chance that the two are not as distinct as may seem, and that even identifying, much less proving what is going on in a given situation is often dicey.  Some instances of strong selection, like some of chance seem reasonably clear and those concepts are apt.  But much, perhaps most, of evolution is a more subtle mix of phenomena and that is what we are concerned with.

Secondly, we have discussed our view of natural selection before, in various ways.  In particular, we cite our series on what we called the 'mythology' of selection, a term we used to be provocative in the sense of hopefully stimulating readers to think about what many seem to take for granted.  Yes, we're repeating ourselves some, but think the issues are important and our ideas haven't been refuted in any serious way so we think they're worth repeating.

A friend and former collaborator took exception to our assumption that people still believe that what we see today is what was the case in the past.  He felt we were setting up a straw man. The answer is somewhat subjective, but we believe that if you read many, many descriptions of current function and their evolution, you'll see that they are often if not usually just equated de facto with being 'adaptations', and that means that doing what they do now came about because it was favored by the force of selection in the past.  We think it's not a straw man at all, but a description of what is being said by many people much of the time: very superficial, dogmatic assumptions both of determinative selection and that we can infer the functional reason.

Of course everyone acknowledges that earlier states had their own functions and today's came from earlier, and that functions change (bat wings used to be forelegs, e.g.), but the idea is that bat flight is here because the way bats fly was selected for.  One common metaphor going back to an article by Lewontin and Gould is that evolution works via 'spandrels', traits evolved for one purpose or incidentally part of some adaptation, that are then usable by evolution to serve some new function. Yes, evolution works through changing traits, but how often are they 'steps' in this sense or is the process more like a rather erratic escalator, if we need a metaphor?

There are ways for adaptive traits to arise that have nothing to do with Darwinian competition for limited resources, and are perfectly compatible with a materialist view.  Organismal selection occurs when organisms who 'like' a particular part of their environment, tend to hang out there.  They'll meet and mate with others who are there as well.  If the choice has to do with their traits--ability to function at high altitude, or whatever--then over time this trait will become more common in this niche compared to their peers elsewhere, and eventually mating barriers may arise, and a new species with what appears to be a selected adaptation. But no differential reproduction is required--no natural selection.  It's natural assortment instead.

All aspects of our structure and function depend on interaction among molecules.  If two molecules must interact for some function to occur, then mutant versions may not serve that purpose and the organism may perish. This would seem most important during embryonic development.  An individual with incompatible molecular interactions (due to genetic mutation) would simply not survive.  This leaves the population with those whose molecules do interact, but there is no competition involved--no natural selection.  It's natural screening instead.

Natural selection of the good ol' Darwinian kind can occur, leading to complex adaptations in just the way Darwin said 150+ years ago.  But if the trait is the result of very many genes, the individual variants that contribute may be invisible to selection, and hence come and go essentially by chance. This is what we have called phenogenetic drift.  Do you doubt that?  If so, then why is it that most complex traits that are mapped can take on similar values in individuals with very different genotypes?  This is, if anything, the main bottom line finding of countless very large and extensive mapping studies, in humans and even bacteria.  This is basically what Andreas Wagner's work, that we referred to earlier in the series, is about.   It rather obviously implies that which of equivalent variants proliferates is the result of chance.  There's nothing non-Darwinian about this.  It's just what you'd expect instead.

We'd expect this because the many factors with which any species must deal will challenge each of its biological systems. That means many screening factors (better we think than calling them selection 'pressures' as would usually be done).  Most of these are affected by multiple genes.  Genes vary within a population.  If any given factor's effects were too strong, it would threaten the species' existence.  At least, most must be relatively weak at any given time, even if persisting over very long time periods.  Multiple traits, multiple contributing genes in this situation means that relative to any one trait or gene, the screening must be rather weak.  That in turn means that chance affects which variant proliferates.  There's nothing non-Darwinian about this.  It's essentially why he stressed the glacial slowness of evolution.

There is, however, the obvious fact that known functional parts of DNA are far less variable than regions with no known function.  This can be, and usually is assumed to be, the expected evidence of Darwinian natural selection.  But factors like organismal dispersion or functional (embryonic) adequacy can account for at least some of this.  Longer-standing genes and genetic systems would be expected to be more entrenched because they can acquire fewer differences before they won't work with other elements in the organism.  This is at least compatible with the view we've expressed, and there could be some ways of testing the explanation.

This view means we need not worry about whether a variant is 'truly' neutral in the face of environmental screening.  We could even agree that there's no testable sense in which a variant evolves by 'pure' chance. Even very tiny differences in real function can evolve in a way that is statistically 'neutral'.  Again, this can be the case even if the trait to which such variants contribute is subject to clear natural or other forms of selection.

This view is also wholly compatible with the findings of GWAS, the evidence that every trait is affected by genetic variation to some extent, the fact that organisms are adapted to their environment in many ways and the fact that prediction based on genotyping is often a problematic false promise.  And because this is a spectrum, randomly generated by mutation, some variants and or traits they affect will be very harmful or helpful--and will look like strong, force-like natural selection.  These variants and traits led to Mendel, and led to the default if often tacit assumption that natural selection is the force that explains everything in life.

Further, it is important for all the same sorts of reasons that the shape of the spectrum--the relative amount of a given level of complexity--is not based on any distribution we know of and hence is not predictable, generally because it is the result of a long history of random and local context and contingencies, of various unknown strength and frequency (about the past, we can estimate a distribution but that doesn't mean we understand any real underlying probabilistic process that caused what we see).  This is interesting, because many aspects of genetic variation (and of the tree of life) can be fitted to a reasonable extent to various probability distributions (see Gene Koonin's paper or his book The Logic of Chance).  But these really aren't causal parametric 'laws' in the usual sense, but descriptions after the fact without rigorous causal characteristics.  Generally, prediction of the future will be weak and problematic.

In the view of life we've presented, evolution will have characteristics that are weak or unpredictable directional tendencies, and the same for genetic specificities (and hence predictive power). It is the trait that is in a sense predictable, not the effects of individual genes.

We think this view of evolution is compatible with the observed facts but not with many of the simplified ideas that are driving life sciences at present.

Our viewpoint is that the swarm of factors environmental and genomic means that chance is a major component even of functional adaptations, in the biodesic paths of life.

Darwin the Newtonian. Part IV. What is 'natural selection'?

If, as I suggested yesterday, genetic drift is a rather unprovable or even metaphysical notion, then what is the epistemological standing of its opposite: not-drift?  That concept implies that the reproductive success of the alternative genotypes under consideration is not equal. But since we saw yesterday that showing that two things are exactly equal is something of a non-starter, how different is its negation?  

Before considering this, we might note that to most biologists, those who think and those who just invoke explanations, non-drift means natural selection.  That is what textbooks teach, even in biology departments (and in schools 
of medicine and public health, where simple-Simon is alive and well). But natural selection implies systematic, consistent favoring of one variant over others, and for the same reason.  That is by far the main rationale for the routine if unstated assumption that today's functions or adaptations are due to past selection for those same functions: we observe today and retroactively extrapolate to the past.  It's understandable that we do that, and it was a major indirect way (along with artificial selection) in which Darwin was able to reconstruct an evolutionary theory that didn't require divine ad hoc creation events.   But there are problems with this sort of thinking--and some of them have long been known, even if essentially stifled by what amounts to a selectionist ideology, that is, a rather unquestioning belief in a kind of single-cause worldview.

What does exactly not-zero mean?
I suggested yesterday that drift, meaning exactly no systematic difference between states (like genotypes) was so illusive as to be essentially philosophical.  But zero-difference is a very specific value and may thus be especially hard to prove.  But non-zero is essentially an open-ended concept and might thus be trivially easy to show.  But it's not!

One alternative to two things being not zero is simply that they have some difference.  But need that difference be specifiable or of a fixed amount?  Need it be constant or similar over instances of time and place?  If not, we are again in rather spooky territory, because not being identical is not much if any help in understanding.  One wants to know by how much, and why--and if it's consistent or a fluke of sample or local circumstance.  But this is not a fixed set of things to check.

Instead of just 'they're different', what is usually implicitly implied is that the genotypes being compared have some particular, specific fitness difference amount, not just that they differ. That is what asserting different functional effects of the variants largely implies, because otherwise one is left asserting that they are different....sort of, sometimes, and this isn't very satisfying or useful.  It would be normal, and sensible, to argue that the difference need not be precisely, deterministically constant, because there's always a luck component, and ecological conditions change.  But if the difference varies widely among circumstances, it is far more difficult to make persuasive 'why' explanations. For example, small differences favoring variant A over variant B in one sample or setting might actually favor B over A in other times or places.  Then selection is a kind of willy-nilly affair--which probably is true!--but much more difficult to infer in a neat way, because it really is not different from being zero on average (though 'on average' is also easier to say than to account for causally).  If a difference is 'not zero', there are an infinity of ways that might be so, especially if it is acknowledged to be variable, as every sensible evolutionary biologist would probably agree is the case.

But then looking for causes becomes very difficult because among all the variants in a population, and all the variation in individual organisms' experience means that there may be an open-ended  number of explanations one would have to test to account for an observed small fitness difference between A and B.  And that leads to serious issues about statistical 'significance' and inference criteria.  That's because most alleged fitness differences are essentially local and comparative.  In turn that means the variant is not inherently selected but is context-dependent: fitness doesn't have a universal value, like, say, G, the universal Newtonian gravitational constant in physics, and to me that means that even an implicitly Newtonian view of natural selection is mistaken as a generality about life. 

If selection were really force-like in that sense, rather than an ephemeral, context-specific statistical estimate, its amount (favoring A over B) should approach the force's parameter, analogous to G, asymptotically: the bigger the sample and greater the number of samples analyzed the closer the estimated value would get to the true value.  Clearly that is not the way life is, even in most well-controlled experimental settings.  Indeed, even Darwin's idea of a constant struggle for existence is incompatible with that idea.

There are clearly many instances in which selective explanations of the classical sort seem specifically or even generally credible.  Infectious disease and the evolution of resistance is an obvious example.  Parallel evolution, such as independent evolution of, say, flight or similar dog-like animals in Australia and Africa, may be taken to prove the general theory of adaptation to environments.  But what about all the not dogs in these places?  We are largely in ad hoc explanatory territory, and the best of evolutionary theory clearly recognizes that.

So, in what sense does natural selection actually exist?  Or neutrality?  If they are purely comparative, local, ad hoc phenomena largely demonstrable only by subjective statistical criteria, we have trouble asserting causation beyond constructing Just-So stories.  Even with a plausible mechanism, this will often be the case, because plausibility is not the same as necessity.  Just-So stories can, of course, be true....but usually hard to prove in any serious sense.

Additionally, in regard to adaptive traits within or between populations or species, if genetic causation is due to contributions of many genes, as typically seems to be the case, there is phenogenetic drift, so that even with natural selection working force-like on a trait, there may be little if any selection on specific variants in that mix: even if the trait is under selection, a given allelic variant may not be.

Some other slippery issues
Natural selection is somewhat strange.  It is conceptually a passive screen of variation, but often treated as if an inherent property of a genotype (or an allele), whose value is determined on what else is in the same locus in the population.  Yet it's also treated as if this is inherent and unchanging property of the genotype...until any competing genotypes disappear.  As the favored allele becomes more common, its amount of advantage will increasingly vary because, due to recombination and mutation, the many individuals carrying the variant will also vary in the rest of their genomes, which will introduce differences in fitness among them (likewise, early on most carriers of the favored 'A' variant will be heterozygotes, but later on more and more will be homozygotes).  When the A variant becomes very common in the population, its advantage will hardly be detectable since almost all its peers fellws will have the same genotype at that site.  Continued adaptation will have to shift to other genes, where there still is a difference.  Some AA carriers will have detrimental variants at another gene, say B, and hence reduced fitness. Relatively speaking, some A's, or eventually maybe all A's, will have become harmful, because even in classical Darwinian terms selection is only relative and local.  So, selection even in the force-like sense, is very non-Newtonian, because it is so thoroughly context-dependent.  

Another issue is somatic mutation.  The genotypes that survive to be transmitted to the next generation are in the germ line.  But every cell division induces some mutations, and depending on when and where during development or later life a mutation occurs, it could affect the traits of the individual.  Even if selection were a deterministic force, it screens on individuals and hence that includes any effects of somatic mutation in those individuals.  But somatic mutations aren't inherited, so even if the mechanism is genetic their effects will appear as drift in evolutionary terms.  

Most models of adaptive selection are trait-specific.  But species do not evolve one trait at a time, except perhaps occasionally when a really major stressor sweeps through (like an epidemic).  Generally, a population is always subject to a huge diversity of threats and opportunities, contexts and changes.  Every one of our biological systems is always being tested, of in many ways at once. Traits are also often correlated with one another, so pushing on one may be pulling on another.  That means that even if each trait were being screened for separate reasons, the net effect on any one of the must typically be very very small, even if it is Newtonian in its force-like nature.  

The result is something like a Japanese pachinko machine.  Pachinko is popular type of gambling in Japan. A flurry of small metal balls bounces down from the top more or less randomly through a jungle of pins and little wheels, before finally arriving at the bottom.  The balls bounce off each other on the way in basically random collisions. The payoff (we could say it's analogous to fitness) is based on the balls that, after all this apparent chaos, end up in a particular pocket at the bottom.  In biological analogy, each ball can represent a different trait or perhaps individuals in a population. They bounce around rather randomly, constrained only by the walls and objects there--nothing steers them specifically. What's in the pocket is the evolutionary result. 

Pachinko machine (from Google images)
 (you can easily find YouTube videos showing pachinkos in action)

All similes limp, and these collisions are probably in truth deterministic, even if far too too complex to predict the outcome.  Nonetheless, this sort of dynamics among individuals with their differing genes of varying and context-specific effects, in diverse and complex environments, suggests why in this dynamic complex, change related to a given trait will be a lot like drift; there are so many that if each were too strongly force-like extinction would be more likely the result.  Further, since most traits are affected by many parts of the genome, the intensity of selection on any one of them must be reduced to be close to the expectations of drift. Adaptive complexity is another reason to think that adaptive change must be glacially slow, as Darwin stressed many times, but also that selection is much less force-like, as a rule.  After the fact, seeing what managed to survive, it looks compatible with force-like, straight-line selection.

Here, the process seems to rest heavily on chance.  But as we discussed in a post in 2014 in a series on the modes and nature of natural selection, we likened the course that species take through time to the geodesic paths that objects take through spacetime, that is determined (and there it really does seem to be 'determined') by the splattered matter and energy in any point it passes through.

An overall view
This leaves us in something of a quandary.  We can easily construct criteria for making some inferences, in the stronger cases, and testing them in some experimental settings.  We can proffer imaginative scenarios to account for the presence of organized traits and adaptations.  But evolutionary explanations are often largely or wholly speculative.  This applies comparably to natural selection and to genetic drift as well, and these are not new discoveries although they seem to be in few peoples' interest to acknowledge them fully.

Darwin wanted to show by plausibility argument that life on earth was the result of natural processes, not ad hoc divine creation events.  He had scant concepts of chance or genetic drift, because his ideas of the mechanism of inheritance were totally wrong.  Concepts of probabilism and statistical testing and the like were still rather new and only in restricted use.  Darwin would have no trouble acknowledging a role for drift.  How he would respond to the elusiveness of these factors, and that they really are not 'forces', is hard to say--but he probably would vigorously try to defend systematic selection by arguing that what is must have gotten here by selection as a force. 

The causal explanation of life's diversity still falls far short of the kind of mathematical or deterministic rigor of the core physical sciences, and even of more historical physical sciences like geology, oceanography, and meteorology.  Until someone finds better ways (if they indeed are there to be found), much of evolutionary biology verges on metaphysical philosophy for reasons we've tried to argue in this series.  We should be honest about that fact, and clearly acknowledge it.

One can say that small values are at least real values, or that you can ignore small values, as in genetic drift.  Likewise one can say that small selective effects will vary from sample to sample because of chance and so on.  But such acknowledgments undermine the kinds of smooth inferences we naturally hunger for.  The assumption that what we see today is what was the case in the past is usually little more than an assumption. This is a main issue we should confront in trying to understand evolution--and it applies as well to the promises being made of 'precision' prediction of genomic causation in health and medicine.  The moving tide of innumerable genotypic ways to get similar traits, at any time, within or between populations, and over evolutionary time, needs to be taken seriously. 

It may be sufficient and correct to say, almost tautologically, that today's function evolved somehow, and we can certainly infer that it got here by some mix of evolutionary factors.  Our ancestors and their traits clearly were evolutionarily viable or we wouldn't be here.  So even if we can't really trace the history in specifics, we can usually be happy to say that, clearly, whales evolved to be able to live in the ocean.  Nobody can question that.  But the points I've tried to make in this series are serious ones worth thinking seriously about, if we really want to understand evolution, and the genetic causal mechanisms that it has produced.

Darwin the Newtonian. Part III. In what sense does genetic drift 'exist'?

It has been about 50 years since Motoo Kimora and King and Jukes proposed that a substantial fraction of genetic variation can be selectively neutral, meaning that the frequency of such an allele (sequence variant) in a population or among species changes by chance--genetic drift--and, furthermore, that selectively 'neutral' variation and its dynamics are a widespread characteristic of evolution (see Wikipedia: Neutral theory of molecular evolution). Because Darwin had been so influential with his Newtonian-like deterministic theory of natural selection, natural evolution was and still is referred to as 'non-Darwinian' evolution. That's somewhat misleading, if convenient as a catch-phrase, and often used to denigrate the idea of neutral evolution, because even Darwin knew there were changes in life that were not due to selection (e.g., gradual loss of traits no longer useful, chance events affecting fitness).

First, of course, is the 'blind watchmaker' argument.  How else can one explain the highly organized functionally intricate traits of organisms, from the smallest microbe to the largest animals and plants?  No one can argue that such traits could plausibly just arise 'by chance'!

But beyond that, the reasoning basically coincides with what Darwin asserted.  It takes a basically thermodynamic belief and applies it to life.  Mother Nature can detect even the smallest difference between bearers of alternative genotypes, and in her Newtonian force-like way, will proffer better success on the better genotype.  If we're material scientists, not religious or other mystics, then it is almost axiomatic that since a mutation changes the nature of the molecule, if for no other reason that it requires the use of a different nucleotide and hence the use and or production of at least slightly different molecules and at least slightly different amounts of energy.

The difference might be very tiny in a given cell, but an organism has countless cells--many many billions in a human, and what about a whale or tree! Every nonessential nucleotide has to be provided for each of the billions of cells, renewed each time any cell divides.  A mutation that deleted something with no important function would make the bearer more economical in terms of its need for food and energy. The difference might be small, but those who then don't waste energy on something nonessential must on average do better: they'll have to find less food, for example, meaning spend less time out scouting and hence exposed to predators, etc.  In short, even such a trivial change will confer at least a tiny advantage, and as Darwin said many times to describe natural selection, nature detects the smallest grain in the balance (scale) of the struggle for life.  So even if there is no direct 'function,' every nucleotide functions in the sense of needing to be maintained in every cell, creating a thermodynamic or energy demand.  In this Newtonian view, which some evolutionary biologists hold or invoke quite strongly, there simply cannot be true selective neutrality--no genetic drift!


The relative success of any two genotypes in a population sample will almost never be exactly the same, and how could one ever claim that there is no functional reason for this difference?  Just because a statistical test doesn't find 'significant' differences in the probabilistic sense that it's not particularly unusual if nothing is going on, tiny differences nonetheless obviously can be real.  For example, a die that's biased in favor of 6 can, by chance, come up 3 or some other number more often in an experiment of just a few rolls. Significance cutoff values are, after all, nothing more than subjective criteria that we have chosen as conventions for making pragmatic decisions (the reason for dice being this way is interesting, but beyond our point here).

But what about the lightning strikes?  They are fortuitous events that, obviously, work randomly against individuals in a population in a way unrelated to their genotypes, thus adding some 'noise' to their relative reproductive success and hence of allele (genetic variant) frequencies in the population over time.  That noise would also be a form of true genetic drift, because it would be due to a cause unrelated to any function of the affected variants, whose frequencies would change, at least to some extent, by chance alone. A common, and not unreasonable selectionist response to that is to acknowledge that, OK! there's a minor role for chance, but nonetheless, on average, over time, the more efficient version must still win out in the end: 'must', for purely physical/chemical energetics if no other reasons.  That is, there can be no such thing as genetic drift on average, over the long haul.  Of course, 'overall' and 'in the end' have many unstated assumptions.  Among the most problematic is that sample sizes will eventually be sufficiently great for the underlying physical, deterministic truth to win out over the functionally unrelated lightning-strike types of factors.

On the other hand, the neutralists argue in essence that such minuscule energetic and many other differences are simply too weak to be detected by natural selection--that is, to affect the fitness of their bearers.  Our survival and reproduction are so heavily affected by those genotypes that really do affect them, that the remaining variants simply are not detectable by selection in life's real, finite daily hurly-burly competition. Their frequencies will evolve just by chance, even if the physical and energetic facts are real in molecular terms.

But to say that variants that are chemically or physically different do not affect fitness is actually a rather strong assertion! It is at best a very vague 'theory', and a very strong assumption of Newtonian (classical physics) deterministic principles. It is by no means obvious how one could ever prove that two variants have no effect.


So we have two contending viewpoints.  Everyone accepts that there is a chance component in survival and reproduction, but the selectionist view sees that component as trivial in the face of basic physical facts that two things that are different really are different and hence must be detectable by selection, and the other view that true equivalence is not only possible but widespread in life.

When you think about it, both views are so vague and dogmatic that they become largely philosophical rather than actual scientific views.  That's not good, if we fancy that we are actually trying to understand the real world.  What is the problem with these assertions?

Can drift be proved?
Maybe the simplest thing in an empirical setting would just be to rule out genetic drift, and show that even if the differences between two genotypes are small in terms of fitness there is always at least some difference.  But it might be easier to take the opposite approach, and prove that genetic drift exists.  To that, one must compare carriers of the different genotypes and show that in a real population context (because that's where evolution occurs) there is no, that is zero difference in their fitness. But to prove that something has a value of exactly zero is essentially impossible!


Is each outcome equally likely?  How to tell?


Again to a dice-rolling analogy, a truly unbiased die can still come up 6 a different number of times than 1/6th of the number of rolls: try any number of rolls not divisible by 6!  In the absence of any true theory of causation, or perhaps to contravene the pure thermodynamic consideration that different things really are different, we have to rely on statistical comparisons among samples of individuals with the different competing genotypes.  Since there is the lightning-strike source of at least some irrelevant chance effects and no way to know all the possible ways the genotypes' effects might differ truly but only slightly, we are stuck making comparisons of the realized fitness (e.g., number of surviving offspring) of the two groups.  That is what evolution does, after all.  But for us to make inferences we must apply some sort of statistical criteria, like a significance cut-off value ('p-value') to decide. We may judge the result to be 'not different from chance', but that is an arbitrary and subjective criterion.  Indeed, in the context of these contending views, it is also an emotional criterion.  Really proving that a fitness difference is exactly zero without any real external theory to guide us, is essentially impossible.

All we can really hope to do without better biological theory (if such were to exist) is to show that the fitness difference is very small.  But if there is even a small difference, if it is systematic it is the very definition of natural selection!  Showing that the difference is 'systematic' is easier to say than do, because there is no limit to the causal ideas we might hypothesize.  We cannot repeat the study exactly, and statistical tests relate to repeatable events.

There's another element making a test of real neutrality almost impossible.  We cannot sample groups of individuals who have this or that variant and who do not differ in anything else.  Every organism is different, and so are the details of their environment and lifestyle experiences.  So we really cannot ever prove that specific variants have no selective effect, except by this sort of weak statistical test averaging over non-replicable other effects that we assume are randomly distributed in our sample.  There are so many ways that selection might operate, that one cannot itemize them in a study and rule out all such things.  Again, selectionists can simply smile and be happy that their view is in a sense irrefutable.

A neutralist riposte to this smugness would be to say that, while it's literally true that we can't prove a variant to confer exactly zero effect, we can say that it has a trivially small effect--that it is effectively neutral.  But there is trouble with that argument, besides its subjectivity, which is the idea that the variant in question may in other times and genomic or environmental contexts have some stronger effect, and not be effectively neutral.


A related problem comes from the neutralists' own idea that by far most sequence variants seem to have no statistically discernible function or effect.  That is not the same as no effect.  Genomes are loaded with nearly or essentially neutral variants by the usual sampling strategies used in bioinformatic computing, such as that neutral sites have greater variation in populations or between species than is found in clearly functional elements.  But this in no way rules out the possibility that combinations of these do-almost-nothings might together have a substantial or even predominant effect on a trait and the carriers' fitness.


After all, is not that just what have countless very large-scale GWAS studies shown? Such studies repeatedly, and with great fanfare, report that there are tens, hundreds, or even thousands of genome sites that have very small but statistically identifiable individual effects but that even these together still account for only a minority of the heritability, the estimate of the overall amount of contribution that genetic variation makes to the trait's variation.  That is, it is likely that many variants that individually are not detectably different from being neutral may contribute to the trait, and thus potentially to its fitness value, in a functional sense.


This is one of the serious and I think deeply misperceived implications of the very high levels of complexity that are clearly and consistently observed, which raises questions about whether the concept of neutrality makes any empirical sense, and remains rather a metaphysical or philosophical idea.  This is related to the concepts of phenogenetic drift that we discussed in Part II of this series, in which the same phenotype with its particular fitness can be produced by a multitude of different genotypes--the underlying alleles being exchangeable.  So are they neutral or not?

In the end, we must acknowledge that selective neutrality cannot be proved, and that there can always be some, even if slight, selective difference at work.  Drift is apparently a mythical or even mystical, or at least metaphoric concept.  We live in a selection-driven world, just as Darwin said more than a century ago.  Or do we?  Tune in tomorrow.

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. 
***
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 codeswhere they will begin and where they will go no one knows!

And it's with that appreciation for constant, unpredictable, but tolerated mutationof evolution's momentum, of a lineage's perpetual change, selection or noton 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.

***
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

Rare Disease Day and the promises of personalized medicine

O ur daughter Ellen wrote the post that I republish below 3 years ago, and we've reposted it in commemoration of Rare Disease Day, Febru...