A good piece by Razib Khan on epigenetics

December 20, 2022 • 11:45 am

I guess I’ve banged on about epigenetics for quite a few years here, and if there’s any lesson you should have learned, it’s that while epigenetics is of vital importance during the development of an organism, it’s vastly overrated as a cause of “intergenerational inheritance”.  What mean by “epigenesis” or “epigenetics” is the attachment of methyl and acetyl  groups to DNA and to the proteins (“histones”) that shepherd the DNA as it operates to create organisms. The attachment of these small molecules to DNA and proteins is in fact a major determinant of how development works—how a single, undifferentiated zygote (fertilized egg) develops into the hundreds of different types of tissues that we have.

And this epigenetic change is in fact programmed into the DNA as a way of producing this essential differentiation. There will be, say, a gene that says, “if environmental factor X is present, put a methyl group on the DNA at position Y.” Genes can do that, you know. And the position where these groups are attached either expresses genes or shut them down, which is why our tissues and cells differ in how they look and behave. They all have the same genes—it’s just that they’re differentially activated and repressed at different times and places. Epigenetics is a vital part of this gene regulation.

We’ve known this for a while, and it’s uncontroversial. What is not uncontroversial is the recent notion of “intergenerational epigenetics”: that environmental changes affecting a behavior or trait in one generation (famine or other traumas are often implicated) can be passed on not from one cell generation to another, but from one human or organismal generation to another. It’s said, for instance, that the Dutch famine during 1944 raised the death toll of offspring in the next generation. (That’s not surprising given that maternal effects in utero can affect offspring.)  But it’s often said that this kind of environmental influence can be inherited across multiple generations, forming a kind of evolutionary change—almost Lamarckian in its scope. And this “transgenerational inheritance is supposed to be fairly common too.

Well it isn’t, nor is it an important “alternative” to neo-Darwinian evolutionary change. The article below by Razib Khan on his Substack site is the best discussion I know about the good and the bad stuff about the popular view of epigenetics, and is well worth reading. It explains what epigenesis is, why it’s so important in the development of organisms, and why it’s so overblown in the popular press, which loves to print stuff that smells like “Darwin was WRONG.”

Click to read:

I’m not going to summarize this except to emphasize Razib’s discussion of the problems with intergenerational (two generations) and transgeneration (three generations or more) epigenetic change. The reason why transgenerational epigenesis can’t really work is that the epigenetic marks are wiped off genes and histones during gamete formation, so induced epigenetic changes can’t be passed on. (What can be passed on is DNA that specifies that, to react to certain environmental stimuli like heat, epigenetic marks will be placed at positions X, Y, and Z.) Since female babies are born with their eggs already in place, their gametic marks aren’t wiped off until the next generation: the third.

And what about the Dutch and all that other stuff in the press about “non-Darwinian inheritance”? Well, some of it may be true (especially in plants), but Razib notes that there’s a publication bias towards positive results, which makes the probability values of the stuff that does get published dubious.  Let me quote him:

How then to explain results like those from Sweden where grandfathers’ and grandmothers’ food deprivation was correlated with increased mortality of grandsons and granddaughters respectively? The p-values in these studies were below 0.05, so they were statistically significant (in other words, even if the default hypothesis is true, the probability is less than 5% that you’d get that result, so perhaps consider the alternative). Studies like this can see print because the design and results fall within scientific guidelines, so they technically meet a journal’s gatekeeping standards. But at this point, as most readers are aware, just because a study is statistically significant does not mean it will stand the test of time or its results be broadly replicable; the p-value tells you only the probability of the given outcome assuming a certain model, and sometimes unlikely things do happen. But it doesn’t tell you anything about all the comparable studies that never saw print because the statistics didn’t cooperate, nor does it reveal all the datasets selectively discarded because they turned out to be junk. A study, or studies, may show something, but the truth of a matter is established through many replications, ideally with controls for confounding variables that may be driving some of the intergenerational associations (obviously, more than genes are transmitted within families; folkways, customs and habits are acquired through imitation).

In addition, trite though the chestnut that correlation does not equal causation might be, in the case of transgenerational epigenetic transmission it cannot be avoided. Extraordinary claims contradicting over a century of established Mendelian genetics and seventy years of scientifically validated molecular biology require extraordinary evidence. In humans, many roadblocks remain to establishing that inherited characteristics in subsequent generations are due to environmental shocks in prior ones, not least that you cannot perform randomized controlled experiments. Inferences must be from observation studies, correlational or indirect (“natural experiments” like famines). Deeper digging reliability shows that cases where epigenetic marks seem to have been inherited transgenerationally actually turn out to be conditional on the existence of a conventional DNA mutation being passed on within the family. These mutations may induce a byproduct of distinctive epigenetic marks, so they are caused every generation by variants natural selection or drift favors. The causal role of the epigenetic variant in a trait may hold, but its transmission across generations due to the epigenetic mark is a mirage. Epigenetics in this case is downstream of conventional Mendelism. It is like some fine print addendum automatically regenerated anew by a DNA mutation every generation. A mere footnote to a well-characterized classical genetic process of inheritance.

In plain English, any case for the mechanism required to posit the inheritance of human epigenetic variation is a royal mess. That doesn’t mean that transgenerational epigenetic transmission doesn’t happen; it is well documented in plants and C. elegans (“worms”). A small body of candidate studies in humans also require further follow-up, but even these remain the object of strong skepticism from most biologists. Contrary to what headline writers and pop psychotherapists might like you to believe, thus far, epigenetics is terribly implausible as a factor in theories of human intergenerational trauma.

And a short summary explaining why epigenesis can’t be both important and ubiquitous:

Finally, even if transgenerational epigenetic transmission does occur, it has to be vanishingly rare and not very impactful in any studied organisms. Why? Simply because, for a century, conventional geneticists, using Mendel’s framework of mutations passed onward through pedigrees, have studied how characteristics are transmitted in the real world. If many traits were strongly dependent on (previously unnoticed) epigenetic insults in the few most recent generations, that would distort these results, and the deviations would emerge rapidly, as particularly well-studied organisms with distinctive traits might change after every novel shock. The existence of the entire field of transmission genetics negates the idea that epigenetic effects passed through families could ever be common, even in the case of plants where this is a well-known phenomenon. If epigenetic transmission was ubiquitous, then the textbooks of Mendelian genetics could never have been written. And stepping beyond basic science, applied fields like plant and animal breeding are underpinned by the Mendelian framework; epigenetic interruptions transmitted across generations could be economically disastrous, as farmers’ breeding projects would no longer yield the desired traits valuable to them.

But there are even deeper evolutionary biological reasons to be skeptical of epigenetic transmission. The persistence of fixed epigenetic marks across generations would undermine the plasticity and flexibility that epigenetics enables in individuals on a molecular scale. As a molecular mechanism, epigenetics grants cells and organisms the flexibility to adapt to short-term changed conditions and stressors; a high level of fidelity in future generations would verge on epigenetic determinism. If the duplication and passing on of DNA to future generations should be a high-fidelity process that maintains the characteristics natural selection has preferred, epigenetics should be a local adaptation mechanism that allows organisms to track environmental volatility without locking in one generation’s adaptations in perpetuity.

The excellent piece is written for the intelligent and scientifically inquisitive layperson, and you should read it to understand why epigenetic is so vital during the development of organisms, and yet so unimportant as a means of passing environmentally-induced changes across generations.

9 thoughts on “A good piece by Razib Khan on epigenetics

  1. An amusing historical-scientific connection with regard to parsimony :

    https://en.m.wikipedia.org/wiki/Deferent_and_epicycle

    ” “Adding epicycles” has come to be used as a derogatory comment in modern scientific discussion. The term might be used, for example, to describe continuing to try to adjust a theory to make its predictions match the facts.”

    … I’m not arguing here, I’m just saying the parallel is amusing, maybe.

    But parsimony is important.

  2. I took what I consider to be a great course in epigenetics a few years ago (having no prior knowledge of the subject) on Coursera called “Epigenetic Control of Gene Expression” taught by Dr. Marnie Blewitt. I learned a lot (did all the homework and took the tests) and really liked her as an instructor. I believe this and other courses on Coursera can still be audited for free or taken for credit for a relatively low cost (I haven’t looked at their policy recently).

  3. Ag, no man, aren’t we epi-geneticists not even allowed 2 generations? A tiny, itsy bitsy small second one? 🙁

  4. I’m glad you bang away and have kept at it.

    Epigenetics is deceptively attractive, loved by media-types. It may be believed but many forget to bother with evidence or think about how one would acquire evidence in-support/non-support. Or talk about the limitations of their evidence.

    What a site!

  5. It took a while for me to read through Khan’s article. It’s very good! The fundamental point is that epigenetics is a phenomenon (almost exclusively) limited to cell lines within an organism. The slate is wiped clean between generations. I have to admit, being out of professional science since 1996, that I was somewhat confused by all the talk in the popular press—the “Darwin was wrong” stuff. What I read *seemed* overblown and naive, but I wasn’t sure. Khan’s article and this discussion helped a great deal.

    1. thanks. basically i am aiming to the general public, but i wanted it to be exhaustive/thorough enough ppl could still kind of use it as a ‘reference’.

      jerry gave a little post-publish feedback and i appreciate it. i hope to never spend so much time reviewing review articles on epigenetics in the near future 🙂

      1. I want to chime in and tell you how helpful this was to me, a layman when it comes to subjects like evolution and epigenetics. I’ve bookmarked your article for future reference, which I only do when a page does a really phenomenal job at explaining something I didn’t know or cannot adequately explain myself. Thank you for this public service to science!

      2. Thank you for going to that effort – the result is very helpful. My wife is a child psychiatrist and rather drawn in by the fanciful ‘science-y’ explanations of the non-medical professionals who surround her at work (psychologists, social workers and therapists). I shall encourage her to read it.

  6. I subscribe to Razib Khan’s substack and you should too….as a paying subscriber!

    Fantastic articles on biology and also history. Better, I think, than what you would get in the New York Times……let’s not mention the dolorous Sci American.

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