Transgenerational Epigenetic Inheritance: the story of learned avoidance
elifesciences.org
elifesciences.org
(As if first time mothers didn’t have enough to worry about - stop stressing so much, it could lead to long-lasting irreversible changes to your fetus!)
* Standard biology disclaimers: this is not the only way this happens, this varies across species and time, nature has no master plan. “Some of the time some genes have some amount of their expression modified somewhat by some mechanisms that are somewhat responsive to some part of the cell’s environment sometimes.”
This is plainly not plausible. "Irreversible" doesn't play well with the length of time humans have been a thing.
But even reversible changes aren’t always “reversed”. They aren’t necessarily minor.
Sure, breaking an arm or skipping high school can be a “reversible” change. But not often not fully “reversed” and/or not done so in a negligible time frame. There are costs. Seems like biological development could be similar.
And as someone less knowledgeable about biological sciences than others, I think learned even more from your disclaimers!
p.s. If you know any good sources for adults to catch up on some biology basics, let me know.
it involves a localized progression along the DNA surrounded by histones, and regulatory enzymes, displaced from proximity, until the replication fork zooms on through, and it all snaps back together.
the process is error prone, strands may cross over, chromosomes may fail to migrate properly.
2) yes methylation and epigenetics resets, not so much at meiosis as at conception zygote formation
3) it doesn't 100% reset more like 98.3% resets, the remainder does NOT reset, thus, epigenetic inheritance. Sometimes that reset process fails, thusly, (epi)genetic disease. Also all this process called "imprinting" is why it was hard to clone various organisms including until recently humans - you can "reset" a skin cell 100% but that's not the ticket, you need to reset it 98.3% and leave the imprinting regions. Oh. And the specific imprinting regions are different for the chromosome that come from mom, vs, the chromosome come from dad
So the big takeaway is that DNA no longer is the main mechanism of inheritance as Darwin taught but actually epigenetic, and the basis is along the lines of horses stretching their necks and becoming giraffes. There's a lot of getting into the weeds as to how this all works molecularly is that's it's really complicated but it is inherited
1. the lack of historical context and opinion lock-in once expressed: before the human genome project many geneticists thought the number of "genes" (yes its an oversimplification) would be much much larger than what was eventually discovered to be the case. It was a shock to many biologists, that there were just about tens of thousands of genes in the genome, basically "a handful" in terms of control theory. The miracle of life started to look marginal and banal, just like many protested the earth not being the center of the solar system...
2. no highlighting the difference between single-cellular species and multi-cellular species: generational memory effects are obviously observable for single-cell organisms. For multi-cellular organisms, like humans, the concept of generation is ambiguous: is one talking about cellular generations (fertilized egg cell, dividing and the daughter cells dividing again, ...), or about organism-level generations (human parents of human children)? It becomes immediately apparent that the cell lineage from fertilized egg cell, to either sperm cell of the son or egg cells of the daughter, would involve lots of divisions, and the final sperm or egg cell would only have access to vague general variables: blood sugar levels, temperature, some hormonal levels, ...
3. Just like one can not truly study physics, without learning mathematics, and then formulating claims and observations mathematically, to truly study biology and the homeostasis it implements, you need systems biology: a mathematical description of biology. To understand multicellular organisms, one needs to understand the concept of cell types mathematically, and to summarize it in natural language cell types are the stable attractors forcing the cell contents to return to the closest state of the cell type. To make a rough analogy (cell/human, cell type/profession) then in contrary to humans, cell's don' t have any memory which is independent of their cellular content. So apart from the content of the cell, a cell is amnesiac. Imagine humans without memory, but upon seeing the room in which they work, they can constantly re-understand what role they perform, and any deviation from what is ingrained in your local DNA copy of the genome is responded to. If you find yourself in a room with ovens and lots of dough, and some of the ovens have bread, but for some reason there's a cop's badge on the table, then you know you are a baker, and you throw out the cop's badge. If you are in a special car with red and blue lights, and you are behind the wheel, but there is for some reason an oven sitting on the passenger seat, then you are a cop, and you take the oven out of your police car.
Once you understand how cell types implement the memory necessary so that a neuron in your brain doesn't start to behave like a skin cell on your anus or vice versa, you understand the ridiculous proposition of epigenetics, a quest for the holy grail of all the missing information that the human genome project failed to find... Euhm well sure there is some modulation of transcription by histone modifications etc... but all of that can be modeled in the same language of reactions that is currently used to model Gene Regulatory Networks, with Gillespie simulators etc. Instead of wishing to vindicate ones old (and wrong) forgotten statements from before the human genome project due to psychological lock-in effects, it would be more productive to point out that in practice a lot of known useful data is ignored, so why not first make use of information we know exists before ingraining vague ideas about epigenetics in the next generation of students? stop ignoring the promotor regions and consensus sequences etc when sequencing genomes, there is a wealth of information to be had there, and personalized DNA-driven medicine will never take off until these are by default sequenced as well, as they directly relate to transcription rates! you know, good old classical gene regulatory network data.
When I posit the following explanation-question that helped me to understand at least that epigenetics does akshually come from science, either the light bulb goes on over one's head or it's seething hate:
How come all of the cells in our bodies have the same DNA, but they can be so different? In other words, why are we not comprised of an amorphous blob of identical cells?
Every time I look into epigenetic inheritance studies I run into a lot of finicky experiments like this, where the outcomes appear to be highly dependent on several variables that aren’t fully understood.
One group of researchers claims to have pinned down the results, but as someone outside of this world trying to interpret the studies it’s hard to know how well they’ve really controlled these finicky experiments to isolate the single effect (epigenetic inheritance) that they claim explains everything.
- Do C. elegans offspring show a modified behaviour unrelated to a changed genome sequence?
That is a fairly simple question. The answer to it should be simple too.
You always have to distill complicated papers that babble about things to a minimum statement.
This hardly follows.
"Is P equal to NP" is also a simple question.
It’s easy to say that the truth is simple if you ignore everything about exploring whether or not a paper is an accurate representation of the truth.
The behavioral test they used showed different results under different circumstances. Even variables like temperature might impact the behavior exhibited in the test.
> You always have to distill complicated papers that babble about things to a minimum statement.
Disagree. You always have to read the papers and understand the details.
So one thing missing from the excitement around this line of work: how little these worm effects generalize to mammals.
C. elegans has very unusual biology — direct soma→germline communication pathways, minimal nervous systems, and short generational cycles. Epigenetic inheritance is much easier to observe there than in mice or humans, where mechanisms differ and dilution across meiosis tends to erase these “marks.”
This means that, even if the PA14 avoidance effect replicates, it’s not evidence that humans inherit learned behaviours. It’s evidence that worms are an interesting edge-case system.
2. The case against epigenetics in humans is laid out nicely by Razib Khan: https://www.razibkhan.com/p/you-cant-take-it-with-you-straig...
3. I've been to a few conferences which mixed geneticists with (human) epigenetics guys, and I have never been impressed with the quality of their work. Lots of different measures of "biological clocks". Lots of multiple hypotheses without much correcting for them. No clear theory. I ended up being very skeptical.
the knowledge base required, is extensive for a non biologist, and made difficult to attain without experience interpreting decades long synthesis.
thus the fundamentals are provided, should anyone desire breadcrumbs pursuant to independant edifiction.
there is no meiotic reset to default.
you should hang with some oncogeneticists for fresh perspective.
there is a claim that epigenetic mechanisms in bacteria provide weak support for such in humans, not true it was the basis for realizing that epigenetic mechanisms exist, and was central to understanding regulaion of expression.
there is a claim that meiosis resets the genome and that is absolutely untrue. regulation would be impossible if epigenetic state was wiped out, the result is most often cancer, or lethal dose effects at the cellular stage of development.
you say you are not a geneticist yet you are criticizing geneticists for presentation of hypotheses while lacking the background.
timing of binding and procession reative to halflife of the expression complex is a critical part of regulation of genetic activity.
i am a scientist as well, molecular geneticist; organic chemist, nuclear physicist. i am a true polymath, this is not a meme, i contract for a body of government agencies, as a science officer, thus my ID and fine details of my work are not up for discussion, nor is any of my work for the last 10 years.
i would however be fine discussing generalities of expression regulation systems if you like.
there is a phase of error correction that occurs after chromosomal replication, and segregation, to mitigate the damage that is part of meiosis.
if you reset; reprogram, epigenetic regulatory features during meiosis the most frequent outcome is lethal allelic dose or oncogenesis [cancer] why?
embryogenic genes, responsible for early development, are deactivated. expression of these genes are the processes of cancer, unregulated growth, and multiplication, aberrant cell signalling, loss of adhesion to surroundfing tissue structure, aberrant migration [metastasis].
the "reprogramming" [regulation of expression] is facultative, and partial, not total, and obligate.
this is why epigenetic phenomenon exist, else it would be wiped out prior to embryogenesis, and there would be no context specific expression.
https://en.wikipedia.org/wiki/Behavioural_genetics
https://assets.cambridge.org/97811084/87979/frontmatter/9781... [PDF]
Horizontal gene transfer is another way organisms can acquire new traits.
I see the paper says "central tenet of neo-Darwinism that mutations are random...". I'm not that up on neo-Darwinism whatever it is.
(I looked at Wikipedia and it seems neo-Darwinism is the term for the Darwin like thinking of the time so maybe the paper contradicts last years neo-Darwinism but not next years?)
mendel later demonstrated that this variation was passed fractionally, to decendants. this was a conserved probability of fixed combinations [consult "mendels peas" ]
the two taken together resulted in neo-darwinist mechanisms. darwin was not wrong, mendel was less wrong, contemporarily we are still scratching the surface of getting it right, primarily what rules apply to what groups, what mechanisms are conserved, what combinations of functions are served by a particular structure, departing from the one gene one function hypothesis.
current genetic theory is a synthesis, loosely referred to as neo-darwinism
The way this can work is that stressors to the mother's organism can affect the development of children, especially stressors to a pregnant mother - so transmission to the next generation is clear (e.g. a starving pregnant mother may have more sickly children). Then, for daughters, their eggs may be directly impacted by this stressor, so that their own children, which come from those egged, may be impacted. However, these children won't carry any trace of that stressor, unless it is genetic in nature.
The nurture part of it is already well established, this is the nature part of it.
However, this is not a net-positive for the folks who already discriminate.
The "faults in our genes" thinking assumes that this is not redeemable by policy changes, so it goes back to eugenics and usually suggests cutting such people out of the gene pool.
The "better nurture" proponents for the next generation (free school lunches, early intervention and magnet schools) will now have to swim up this waterfall before arguing more investment into the uplifting traumatized populations.
We need to believe that Change (with a capital C) is possible right away if start right now.
Incidentally, nobody yet I see has suggested that epigenetics could lead to better outcomes. I wonder why?
What social democracy does to a dude('s growth spurts). If people ever internalized that socioeconomic circumstances have material and profound effects on not only their own health and development, but also that of their children and children's children, both in the positive and negative direction... Man.
In order for this supposed oddly specific effect to have policy implications, it would have to be simple to identify which individuals are impacted and by how much. And it would have to be impossible to identify such individuals except by looking at their family history.
And there would have to be some policy action that is uniquely beneficial to those people.
this would also be accompanied by interviews, that would reveal high risk factors, as well as very intimate details of family history.
the payoff would have to be large, something more than the wellbeing of a single person from start to end, until we collectively grow up a bit more as a species.
related: sperm from male rats who drink heavily produces children and grandchildren with reduced brain size and abnormal behavior -- there's an epigenetic male 'fetal alcohol syndrome'
But fortunately “We provide proof-of-concept that DNA resetting can be modulated in embryos where it is deficient, using currently available drugs, to influence telomere length at birth" https://www.adelaide.edu.au/robinson-research-institute/news...
We’re still trying to figure out how much, if any, epigenetic inheritance applies to humans. If we did find some evidence, it wouldn’t be as simple as declaring that the trauma of previous generations harmed offspring. For example, it could be equally likely that offspring of prior generations that endured a lot of stress were actually more stress resilient and therefore received some advantages.
> If that is the case, it has profound public policy implications.
I disagree. As I said above, anyone jumping to conclusions that epigenetic inheritance could only confer negative traits is trying to force another concept (inter-generational trauma) into a convenient scientific carrier to make it appear to be a more valid policy position.
https://theconversation.com/moms-prenatal-hardship-turns-bab...
The trans-generational epigenetic inheritance proponents claim that trauma can induce lasting generational effects spanning multiple levels of descendants, even if it doesn’t occur during to the mother during pregnancy.
The paper this HN submission is talking about claims to have found an effect like this that persists for 4 generations.
A key problem with the inter generational trauma proponents is that they presume the effects will only be negative. However, studies like this one showed a positive adaptation. Evolutionarily, it would make more sense if epigenetic mechanisms generally conferred benefits and learned adaptations, which goes against the narratives that anything negative would produce lasting negative effects. It’s not entirely that simple, but it reveals why the intergenerational trauma equals epigenetic inheritance people are starting with a conclusion and trying to get the science to fit their narrative, which is backward from how it should be.
Another example is famine, it may be advantegous to store visceral fat in a low food environment, but if the famine ends, the next generation is more likely to carry this "advantage" which is now negative: https://www.sciencedirect.com/science/article/pii/S216183132...
"The LORD passed by before him, and proclaimed, “The LORD! The LORD, a merciful and gracious God, slow to anger, and abundant in loving kindness and truth, keeping loving kindness for thousands, forgiving iniquity and disobedience and sin; and who will by no means clear the guilty, visiting the iniquity of the fathers on the children, and on the children’s children, on the third and on the fourth generation." (Exodus 34:6-7)
His wrath often works by simply letting us have the consequences of sinful choices. Examples I've encountered include wreckless driving putting a person's head into a tree, sexual immorality leading to STD's, and greed leading managers to break people's bodies in.the workplace. What jumped out at me here was three or four generations. Would there be a natural explanation for that?
From there, one would look for two things: whether behavior can be passed down at all; whether behavior can change things, like DNA, that are passed down.
On the first, there are sins that seem to move across families. Anecdotally, I've found this is often true even when the child hated that behavior in their parents which should reduce its recurrence. (I'd like empirical data on that.) Tue best evidence was that identical twins seperated at birth also had a startling amount of similar behaviors, down to names they liked. So, we do pass behavior down which has implications for individuals, future parents, and using or evaluating sperm/egg donors.
The other issue is whether one's choices can change DNA. An underlying premise would be whether or not environmental effects can chnage DNA. Stressors like famine or toxic chemicals were confirmed to do this. Both are often caused by sins, like not taking care of one's body or others' greed (eg ruthless capitalism). There's some evidence lifestyle choices can do this, too. I saw one study showing a mechanism for how behavior is transmitted in men which the Bible night imply by putting it on Adam and his bloodline. Those studies need more replication and validation, though.
The last thing was that many countries got worse and worse over time. The specific sins increased until everyone, from adults to children, only did evil. God ordered Israel to wipe out entire people groups, even the children, while listing the sins they committed (including burning their children alive). As I try to understand the morality of it, it would make more sense if our behavior is passed down genetically because some groups could be corrupted beyond all repair. In fact, sparing just one kid later led to Haman in Xerxes' Persia nearly killing all Jews because that bloodline passed its hate and habits down.
So, the data in the long-term has heavily supported the Biblical positions that (a) behavior is passed down, (b) godless, selfish worldviews wreck countries down to the genetic level, (c) it can get to a point of no return, (d) individual choices can reduce or reverse this in large enough numbers, and (e) we therefore should repent and follow Jesus Christ and His Word as a country to receive the blessings, supernatural and natural, that come with it.
Wonderful, trying to justify the evil, bloody, genocidal, murderous god of the Old Testament with modern pseudo-science - and coming from a Christian, apparently. The religion of love and peace, of course, not like all of those other barbarians.
epi- = outside
But there might be other ways that some traits get inherited, eg by changing the cellular environment in the sperm/egg itself which could affect the offspring while keeping the genes the same.
Even the definition of a gene is not very accurate. Many important sequences yield a miRNA or another RNA. Only few sequences yield a mRNA. Some "genes" are just integrated viruses/phages/transposons etc... that were modified. One of the most fascinating one was the retrovirus in regards to the mammalian placenta: https://pmc.ncbi.nlm.nih.gov/articles/PMC4332834/ but there are many more examples. We are all DNA hybrids at the end of the day. The whole species concepts makes very little sense these days, IMO. I can see the use case for eukaryotes, but it makes no sense to me for bacteria yet alone viruses.
It’s a very young field with a lot of open questions. The concept has been adopted and abused in the mainstream so you have to be careful to separate the science from the pseudoscience.
https://en.wikipedia.org/wiki/Epigenetics#Definitions
That depends on the definition. But, if we use the modern definition, it emerged (or re-emerged) in the 1990s. It's not old, indeed, but I also would no longer call it "very young". It's soon 40 years in the modern definition, and much older if we include prior discussions.
E.g., I would regard computer science as a very young field.
If you inherit a virus from your mother, for instance, I think most would call that non-genetic inheritance, even though viruses have genes too. Same goes for methyl and acetyl markers, transcription factors, nutrients, toxins, and whatever else comes along for the ride in the meiotic cell.