I don’t know who the New York Review of Books is getting to vet its biology articles, but this one below (free access) is really confusing. One reason may be that the authors have no particular expertise in evolution. Israel Rosenfeld is an MD with training in neuroscience, while Edward Ziff is a professor at NYU who works on neural transmission. I’ve never heard of either of them, which doesn’t rule them out as being able to say anything useful about evolution, but I usually am familiar with people who write about evolution for the NYRB, and they always had a name in evolutionary biology (viz., my student Allen Orr).  Anyway, here’s the article (click on screenshot to see it).

The problem with this article is that it’s deeply confused, conflating gene regulation within the lifetime of an individual (which can be achieved by “epigenetically” attaching or detaching methyl groups to genes to turn them on or off) with environmentally induced modification of the DNA that is inherited over several generations, causing a form of “non-Darwinian” evolution.

The former is not problematic; we’ve long known that genes can be regulated by environmental factors; that’s what Jacob and Monod got their Nobel Prizes for. We’ve learned more recently that this regulation can also be programmed to cause methylation: genes are adaptively activated and deactivated by the attachment of methyl groups (or small RNA molecules) to segments of genes. But even that adaptive regulation is coded for by DNA. That is, there are genes which are programmed to turn other genes on or off by adding small molecules to them. That’s the way cells differentiated so that even though all cells have the DNA, some become liver cells, others brain cells or blood cells, and so on. That is permanent changes in gene regulation occurring largely by methylation, and over generations of cells, but not over generations of individuals. Such differentiation within an individual still evolved in a Darwinian way, it’s just that natural selection favored particular ways to adaptively activate or inactivate genes.

However, a vocal group of biologists maintain that evolution can also occur when the environment rather than DNA (extrinsic factors like cold or starvation) can methylate genes too, and that methylation can be inherited. The problem with this, as I’ve emphasized repeatedly, is twofold. First those environmental changes are nearly always nonadaptive or maladaptive—they’re more like random screwups—and so can’t be the basis of adaptive evolution.

Second, environmentally induced changes in DNA are nearly always wiped out during gamete formation, and so those changes cannot be the basis of long-term evolution or adaptation. There are a few exceptions, but I don’t know of any such modifications that can last longer than three generations. The fact that this form of “Lamarckian” inheritance isn’t pervasive is also shown by the numerous adaptations that have been dissected genetically: all of them are based on changes in the DNA sequence rather than attachment of methyl groups induced by the environment.

Rosenfield and Ziff conflate the programmed regulation of genes by other genes that induce methylation with the “Lamarckian” changes in DNA sequence. That’s clear when they say stuff like this:

Until the mid-1970s, no one suspected that the way in which the DNA was “read” could be altered by environmental factors, or that the nervous systems of people who grew up in stress-free environments would develop differently from those of people who did not. One’s development, it was thought, was guided only by one’s genetic makeup. As a result of epigenesis, a child deprived of nourishment may continue to crave and consume large amounts of food as an adult, even when he or she is being properly nourished, leading to obesity and diabetes. A child who loses a parent or is neglected or abused may have a genetic basis for experiencing anxiety and depression and possibly schizophrenia. Formerly, it had been widely believed that Darwinian evolutionary mechanisms—variation and natural selection—were the only means for introducing such long-lasting changes in brain function, a process that took place over generations. We now know that epigenetic mechanisms can do so as well, within the lifetime of a single person.

This is deeply confusing, for it conflates gene regulation within an individual with evolutionary changes that evolve over many generations. In fact, the epigenetic regulation mentioned by Rosenfield and Ziff did evolve over generations by natural selection. They are saying that two things are distinct and contradictory when in fact they are the same thing. It’s no surprise that this article (which is largely written in technical jargon) would confuse the layperson.

Likewise, single-generation screwups induced by the environment in adults that affect their children have nothing to do with natural selection or evolution (note that “evolution” is in the article’s title). Even if those changes induce modification of their children’s DNA, this one-generation effect does not persist after that, and has nothing to do with evolution:

The most revealing instances for studies of intergenerational transmission have been natural disasters, famines, and atrocities of war, during which large groups have undergone trauma at the same time. These studies have shown that when women are exposed to stress in the early stages of pregnancy, they give birth to children whose stress-response systems malfunction. Among the most widely studied of such traumatic events is the Dutch Hunger Winter. In 1944 the Germans prevented any food from entering the parts of Holland that were still occupied. The Dutch resorted to eating tulip bulbs to overcome their stomach pains. Women who were pregnant during this period, Carey notes, gave birth to a higher proportion of obese and schizophrenic children than one would normally expect. These children also exhibited epigenetic changes not observed in similar children, such as siblings, who had not experienced famine at the prenatal stage.

During the Great Chinese Famine (1958–1961), millions of people died, and children born to young women who experienced the famine were more likely to become schizophrenic, to have impaired cognitive function, and to suffer from diabetes and hypertension as adults. Similar studies of the 1932–1933 Ukrainian famine, in which many millions died, revealed an elevated risk of type II diabetes in people who were in the prenatal stage of development at the time. Although prenatal and early-childhood stress both induce epigenetic effects and adult illnesses, it is not known if the mechanism is the same in both cases.

Whether epigenetic effects of stress can be transmitted over generations needs more research, both in humans and in laboratory animals. But recent comprehensive studies by several groups using advanced genetic techniques have indicated that epigenetic modifications are not restricted to the glucocorticoid receptor gene. They are much more extensive than had been realized, and their consequences for our development, health, and behavior may also be great.

First, “intergenerational transmission” of this sort has been known for a while: smoking, alcohol, thalidomide, and now famine, can screw up the health of the next generation. But those changes disappear after that. They are not, as the authors admit in the last paragraph, something that’s “transmitted over generations.” But they must be transmitted over generations if they’re to cause evolution.

The authors are a bit weaselly here in saying “whether epigenetic effects can be transmitted over generations needs more research”, when we already know from many studies that they’re almost always never transmitted over generations. Why didn’t they admit that? I presume because they have a bill to sell.

To complete the confusion (I doubt that many NYRB readers have even gotten to this point), Rosenfield and Ziff imply that adaptive epigenetic modification of genes is something distinct from Darwinian natural selection. But, as I’ve said, it is Darwinian natural selection that molds the adaptive regulation of genes: genes tell other genes when and how to be regulated. So read the following paragraph and see if you can make out what the authors are trying to say:

It is as though nature employs epigenesis to make long-lasting adjustments to an individual’s genetic program to suit his or her personal circumstances, much as in Lamarck’s notion of “striving for perfection.” In this view, the ill health arising from famine or other forms of chronic, extreme stress would constitute an epigenetic miscalculation on the part of the nervous system. Because the brain prepares us for adult adversity that matches the level of stress we suffer in early life, psychological disease and ill health persist even when we move to an environment with a lower stress level.

It is not “nature” that employs epigenesis, but genes that have resulted from natural selection. What do they mean, exactly, by “nature.”  I’ve read that paragraph several times, and I still can’t figure out what the authors are trying to say, especially in the last sentence. It seems to imply that ill health of children induced by parental environments that persists in low-stress situations is a byproduct of natural selection that adapted us for adversity as adults, and that it has to be that way.  But it doesn’t. The paragraph is gobbledy-gook, and an example of bad and confused writing.

This wouldn’t have happened had this piece been edited by the venerable Bob Silvers, the longtime NYRB editor, famous for his punctilious editing, who died last year. There’s a new editor now, and he’s pretty tetchy when criticized, so I’ll expect I’ll get some flak for criticizing this piece. But read it for yourself, and see if, as a non-biologist, you can make sense of it. I am a biologist, and am deeply confused by it.

There’s no excuse for popular science writing that is this bad and confusing. I’d suggest to the new editor, Ian Buruma, that he choose his science writers more carefully. Epigenetics simply has not caused a “revolution in evolution.”

Here’s an evolutionary geneticist, and a really good one, who also read the piece:

What utter of nonsense; manages to confuse all sorts of evolutionary, genetic, & developmental issues https://t.co/a9m2TtQNPn pic.twitter.com/ZAFxirCnHw

— Graham Coop (@Graham_Coop) May 24, 2018

There’s an interesting new paper out on the genetic basis of eye loss in cave fish, reported in a manuscript in biorxiv (not yet peer reviewed) by Aniket Gore et al. (reference and free download at bottom. ) It’s also summarized by New Scientist in the online article below (click on screenshot to go to article), as well as in a copy of the magazine’s paper issue, which I saw in Cambridge.  I’ll briefly summarize the paper, but what interested me at first was how New Scientist dealt with it.

The original title in the paper journal was “Blind cavefish’s strange evolution”, but now it’s this online (click on screenshot to go there):

That’s not much of a difference. What is different is how they sell the result in the paper version versus the online version, which I suspect came later (or was revised).  The paper version says this (h/t to Andrew Berry for the screenshot):

So that makes you think that the researchers found something that may lead to revising the “standard view of evolution.” But the first paragraph of the online version is nowhere near as strong:

We’ve found out why a Mexican cavefish has no eyes – and the surprising answer is likely to be seized upon by those who think the standard view of evolution needs revising.

To me that’s a big difference, for the striking result is now one that “some people who already think the standard view of evolution needs revising” will “seize upon.” And that online version is more correct, for there’s simply nothing in the paper that would lead us to call for a revision—or even a reexamination” of the standard Darwinian theory. The paragraph has changed from touting the result as a potential kink in evolutionary theory to a finding that those who already don’t like that theory could use as ammunition against it. But those people are, as we’ll see, wrong.

So what was found? We know that Mexican tetra, Astyanax mexicanus, has some blind forms that have lost their eyes after invading caves. In the blind tetras, eye development starts normally, but then the incipient eyes start to regress (that’s evidence for evolution, by the way), and they’re left with eyes of variable size—or none at all. There are some three dozen different blind forms in different caves, and many of these developed independently from the normally-eyed surface-dwelling form. The blind versus sighted forms aren’t regarded as two species because they can all mate with each other, and because the blind forms are no more closely related to each other than to some sighted forms. They’re better regarded as “ecotypes” or “morphs” then species.

Here are the two forms, sighted on top and blind at bottom:

Why did these fish, as do many animals that invade and evolve in caves, lose their eyes? We’re not sure, but there are several theories. If you have eyes that you don’t need, because it’s dark (these fish get around using their lateral lines), then you might get a reproductive advantage by diverting the metabolic energy needed to produce eyes into other features that enhance reproduction, like gonads or eggs. Or, eye loss may be advantageous because besides eyes being useless in caves, they’re easily damaged or infected, and thus losing them may enhance your survival and reproduction. Alternatively, mutations that lead to eye loss, normally weeded out in surface populations, might accumulate over time in caves, so that the eyes would eventually disappear over generations. Or several of these factors, and others I haven’t mentioned, could operate together. We don’t know for sure, but one can think of ways to test these ideas.

What these researchers found, and what got the editors all excited about revising evolution, was that the genes that normally form eyes appear to have been inactivated not by changes in their own DNA sequence by mutation, but by “methylation”: epigenetic changes in which methyl groups are stuck on the DNA bases of eye-making genes, presumably inactivating them. As the authors note, ““Although a central role for DNA methylation in development and disease has been well-documented, our results suggest that epigenetic processes can play an equally important role in adaptive evolution.”

Well, we already know that epigenetic processes have played a role in adaptive evolution, for the way development proceeds—the way cells become different from one another as they develop from a single fertilized egg—is largely through the acquisition of methylated groups that can be inherited within a body as a cell divides. That is, the position of and influences on a cell can cause it to acquire methylation marks that turn it into difference courses of development: a liver cell, a kidney cell, a bone cell, and so on. But these changes, all inherited among cells in a single body, have resulted from natural selection: they’re adaptive because having different kinds of cells and tissues is adaptive.  What has happened is that the DNA program itself, within the egg, contains information that says “methylate cell X at genes Y and Z if it experiences condition C”, and so on. Although development involves more than simply differential turning on and off of genes by methylation, this is an important way that development proceeds in multicellular organisms.

The thing is, this is not a violation of evolutionary theory in any sense. The commands for methylation under certain conditions, and the results of a gene being methylated, have evolved by changes in regular DNA sequences that control the methylation of other DNA sequences. It’s just an evolved way to regulate genes.

What has likely happened in these cave fish, then, is that other, “regulatory” genes have changed in the cave forms that provide instructions sort of like this: “hey, gene Y: at a certain point, you attach methyl groups to other genes for eye formation, shutting down those genes and causing the eyes to degenerate.” That could easily evolve by conventional natural selection.

(Since there appear to be no changes in the DNA sequences of eye-forming genes themselves, it’s not likely that they themselves have evolved direct sensitivity to environmental conditions and so can turn themselves off in the dark. Blind cave fish raised in the light, as many hobbyists do, don’t develop eyes. There is some evolved change somewhere in the cave fish genome that simply turns the eyes off regardless of the environment, and it does so by methylation.)

Thus we have no challenge here to conventional evolutionary theory. In fact, the New Scientist piece, to its credit, quotes scientists who say that:

“This is a most interesting paper,” says evolutionary biologist Douglas Futuyma of Stony Brook University in New York. But he doesn’t think it poses any challenge to standard evolutionary theory as the epigenetic change is itself most likely a result of a genetic change.

Gore’s team shows that the silencing of the eye genes is due to the increased activity of a specific gene involved in methylation, Futuyma points out. So the question then is, what is making this gene more active?

“I think it likely that there has been an alteration in DNA sequence of that gene,” he says.

I agree. Yet Eva Jablonka, always a big proponent of “neo-Darwinism is wrong”, thinks that something more is going on: that the cue to methylate the genes producing eyelessness doesn’t come from other genes, but from the environment itself! That is, somehow the presence of darkness is an environmental effect that methylates the eye-forming genes in adaptive ways, making the eyes disappear.

That would be the kind of environmental epigenetics that truly is non-Darwinian, for it would be “Lamarckian” inheritance in which an environmentally acquired change somehow becomes adaptively incorporated into the DNA and is inherited from then on. As I’ve said repeatedly, we have no examples of such acquired methylation lasting more than two or three generations, so there’s no evidence that it could serve as a stable basis of inheritance, much less of adaptation.

Nevertheless, Jablonka persists:

However, Jablonka thinks that heritable epigenetic changes alone could explain the loss of eyes. What is more, she even thinks it possible that the epigenetic changes were somehow triggered by the cave environment in the first place. That would be a form of Lamarckian evolution: the idea that characteristics acquired during an individual’s lifetime can be passed on to descendants.

Absent any evidence that such acquired methylations are stable over generations, this is not credible. (Note that the paper’s authors make no such claim.) And that’s why the more rational evolutionists aren’t going to accept such Lamarckian evolution until we find some good cases.

The article concludes with more doubts:

David Shuker at the University of Edinburgh, UK, is unconvinced by this or any of the other proposed examples of evolution via epigenetic mechanisms.

There is no doubt that some animals respond to the environment via epigenetic mechanisms, he says, but these mechanisms have evolved via genetic changes. “It goes through genetically built systems,” Shuker says.

So, like Futuyma, he thinks standard evolutionary processes such as mutation and natural selection still explain all we have discovered.

“We are always finding new ways in which these processes manifest themselves,” says Shuker. “We have found lots of amazing things.” But the basic principles remain valid, he says.

Shuker is suspicious of some efforts to promote the idea of an “extended evolutionary synthesis”. He thinks some people are trying sneak religious ideas back into evolutionary theory.

“They are trying to allow organisms to have agency not controlled by genes,” he says.

I don’t know Dr. Shuker (Futuyma is my pal), but I like him already! At any rate, the editors’ realization that only Jablonka (and perhaps a few other outlier evolutionists) push this kind of inheritance as something requiring us to revise evolutionary theory, may be one reason why New Scientist dialed back the enthusiasm of its first paragraph. It’s interesting enough to find out that fish’s “eye genes” have lost their expression via methylation induced by other genes; we don’t need to go hog wild and start postulating new theories of evolution.

________

A. V. Gore et al. 2017. An epigenetic mechanism for cavefish eye degeneration. Biorxiv, online.

UPDATE:  As reader Michael found out and reveals in a comment below, Skinner is well funded by Templeton. It crossed my mind, but I thought, “naaaah. . .” and couldn’t be arsed to look it up. But yes, Skinner is eating well from the Templeton trough. It’s pretty clear that Templeton is deeply invested in showing that the “conventional” view of evolution and genetics is wrong, for they’ve also put millions into other researchers to that end. I’m not quite sure why they’re doing this, but the money would be more widely invested in other research not explictly designed to bust a paradigm.

__________

I’m not sure what’s with the website Aeon, as it seems to publish some good stuff, but their science sometimes seems wonky.  Such is the case with an article published by Michael Skinner last November but just called to my attention by reader Rodney, “Unified theory of epigenetics“, which bears the subtitle “Darwin’s theory that natural selection drives evolution is incomplete without input from evolution’s anti-hero: Lamarck.” Lamarck, of course, was the French biologist and polymath who proposed that animals could stably inherit modifications of their body, behavior, and physiology that were imposed by the environment. The classic example is the giraffe’s long neck “evolving” over generations by giraffes stretching their necks ever further to reach leaves higher on the trees. Each stretch would somehow feed back into the DNA, so straining giraffes would have offspring with longer necks.

The problem with this idea, and why Lamarck hasn’t become any kind of evolutionary hero, is that it doesn’t work. While the environment can play a role in sorting out those genes that their carriers leave more offspring, there’s no good way for environmental information to somehow become directly encoded in the genome. For that would require a kind of reversal of the “central dogma” of biology, stated by Francis Crick like this:

The central dogma of molecular biology deals with the detailed residue-by-residue transfer of sequential information. It states that such information cannot be transferred back from protein to either protein or nucleic acid.

Now there are some exceptions to this, and we’ll mention one of them here, but by and large this is correct, especially in its implication that information from the environment cannot change the sequence of DNA or the proteins that DNA produces through RNA intermediates. If this were possible, and you lifted weights before your kid was born, that kid would either be born with bigger muscles or would be more prone to develop them than the children of non-lifters.

Of course the environment can act to turn genes on and off. The classic example is the presence of lactose in the environment, which activates genes in E. coli that can metabolize that sugar: that was the classic Nobel-winning work of Jacob and Monod on gene regulation. But lactose does not change the structure of DNA or protein, but rather acts, in an evolved system, to turn on genes helping the bacterium use a sugar not normally present in the environment.

One exception to the central dogma is “epigenetic” modification of DNA and the histone proteins used in packaging DNA. Some environmental factors can act to modify the DNA, usually by attaching methyl groups to its bases, and these modifications can not only change gene action, but can be inherited—but only for a couple of generations. The fact that these epigenetic markers are usually erased from the DNA during sperm and egg formation, and none have been found to be permanent, mean that environmentally-induced epigenetic change cannot be an important part of evolutionary change, which requires permanent alterations of genes (invariably by mutations).  Some epigenetic modifications, however, can play a role in evolution: these are markers coded by the genes themselves, like gene X coding for instructions to “put a methyl group at position Y on gene Z”. These changes, however, are coded in the DNA, arose by mutation, and were not induced by the environment.

On this site I’ve repeatedly discussed the problem with seeing environmentally-induced epigenetic changes in DNA as a neglected and important aspect of evolutionary biology, and what I’ve written above is somewhat of a refresher. You can search on this site here for the many pieces I’ve written about it, including critiques of Siddhartha Mukherjee’s misleading article touting epigenetics in The New Yorker.

Skinner, a professor of biological science at Washington State University and somewhat of an epigenetic evangelist, ignores the many criticisms of epigenetics that have been made, still maintaining that it’s so important that it mandates a paradigm shift in evolution. He claims, for instance, that “regular” genetic variation in DNA caused by mutations is insufficient to fuel adaptation, and thus we need “something else”—that something else being epigenetic “mutations” caused by the environment. This claim has been refuted by, among others, Deborah Charlesworth and her coauthors in a paper I’ve highlighted before. (The pdf is here.)

In the rest of the essay, Skinner gives several examples of environmentally induced changes in the DNA that can be passed to offspring. The problem is that none of the changes are passed on for more than a few generations, and thus cannot be a meaningful scaffold for evolutionary change. (Skinner’s example of the environmentally-induced flowering trait found by Linnaeus and being transmitted for over 100 generations is wrong.) I’ll just give two of Skinner’s examples quoted from his Aeon piece:

One example that we studied in our lab involved the impact of environmental chemical exposure on trait variation and disease. In our study, we set out to investigate the ability of an environmental toxicant – vinclozolin, the most commonly used fungicide in agriculture today – to alter traits through epigenetic change. First, we briefly exposed a gestating female rat to the fungicide; then we bred her progeny for three generations, to great-grand-offspring, in the absence of any continued exposures. For nearly all males down through the lineage, we observed a decrease in the number and viability of sperm and an associated incidence of infertility with age. And we observed a variety of other disease conditions in both males and females three generations removed from the direct exposure, including abnormalities in the testis, ovaries, kidneys, prostate, mammary glands and brain. Corresponding epigenetic alterations in the sperm involve changes in DNA methylation and non-coding RNA expression.

What we see here is an epigenetic change that is not adaptive (it reduces fertility) induced by a toxin. The important thing is that it was observed to last for only three generations. This is not something that can support the possibility of adaptive evolutionary change—or any evolutionary change—and certainly doesn’t buttress the paper’s conclusion that the results “have significant implications for evolutionary biology.”

Here’s another example (there are several, but all suffer from the same problem of transitory change):

Our research showed that ancestral exposure to the toxicant vinclozolin also affected sexual selection in animals three generations down the lineage. Considered a major force in evolution since Darwin first posed his theory, sexual selection – also known as mate preference – was assessed by allowing females from other litters to choose between either descendants of exposed or unexposed males. Females overwhelmingly selected those who lacked the transgenerational epigenetic alterations and whose ancestors had not been exposed. In conclusion, exposure to the fungicide permanently altered the descendant’s sperm epigenetics; that, in turn, led to inheritance of sexual selection characteristics known to reduce the frequency with which their genes might propagate in the broader population and directly influence evolution on a micro-evolutionary scale.

Here we have exposure to another toxin, with the result that female rats preferentially chose males who hadn’t been exposed to the toxin (those males, being poisoned, may have lacked vigor). It is true that if there is genetic variation in female preference for males not exposed to the toxin, this could cause an increase in the frequency of genes for that preference—but for only three generations. There would be very short-term evolution, but it would be halted when the epigenetic markers disappeared, for then there would be no selective pressure on the females because there would no longer be epigenetic markers differentiating the males.

And so the long essay goes on, concluding, with the merest evidence, that neo-Darwinism needs a big reboot (my emphasis):

Despite the pushback [JAC: he means the arguments from people who have pointed out the weaknesses of the epigenetic model], I’m convinced that we have reached the point where a paradigm shift is due. Accepting that epigenetics plays a role in evolution does not topple the science of genetics; embracing neo-Lamarckian ideas does nothing to challenge classic neo-Darwinian theory. The accepted sciences are essential and accurate, but part of a bigger, more nuanced story that expands our understanding and integrates all our observations into a cohesive whole. The unified theory explains how the environment can both act to directly influence phenotypic variation and directly facilitate natural selection, as shown in the diagram above.

With a growing number of evolutionary biologists developing an interest in the role of epigenetics, there are now some mathematical models that integrate genetics and epigenetics into a system, and the work has paid off. Consideration of epigenetics as an additional molecular mechanism has assisted in understanding genetic drift; genetic assimilation (when a trait produced in response to the environment ultimately becomes encoded in the genes); and even the theory of neutral evolution, whereby most change happens not in response to natural selection, but by chance. By providing an expanded molecular mechanism for what biologists observe, the new models provide a deeper, more nuanced and more precise roadmap to evolution at large.

Taken together, these findings demand that we hold the old standard, genetic determinism, up to the light to find the gaps. It was Thomas Kuhn who in 1962 suggested that when a current paradigm reveals anomalies then new science needs to be considered – that is how scientific revolutions are born.

A unified theory of evolution should combine both neo-Lamarckian and neo-Darwinian aspects to expand our understanding of how environment impacts evolution. The contributions of Lamarck more than 200 years ago should not be discounted because of Darwin, but instead integrated to generate a more impactful and insightful theory. Likewise, genetics and epigenetics must not be seen as conflicting areas, but instead, integrated to provide a broader repertoire of molecular factors to explain how life is controlled.

This is a call to revolution that is way too early, for there are no good data calling for such a change, much less for even a minor evolutionary role of environmental epigenetic changes in DNA. I’m not sure why people drag in Kuhn when the current paradigm is still satisfactory (see the Charlesworth et al. paper), but of course one makes one’s name in science not by buttressing a well-established paradigm, but by overturning it. Neither Skinner nor anyone else has yet done that to the neo-Darwinian theory of evolution. Those of us who continue to adhere to it do so not out of loyalty or stubborness, but because there aren’t good data showing that the theory is wrong.

Epigenetic modification remains an important discovery, and has implications for gene regulation, cell differentiation, disease, and the evolution of genetic conflict between males and females, but the evolutionarily important modifications are those  instilled into the genome by natural selection, not by abrupt intrusions from the environment.