A good piece by Razib Khan on epigenetics

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.