I agree that the pop-psychology stuff is mostly pseudoscience, but have all of the possible mechanisms of epigenetic inheritance really been disproven? Even if the DNA structure is wiped clean of markers during meiosis and fertilization, that doesn't seem to rule out other possible non-DNA mechanisms of inheritance, like small noncoding RNAs.
I'm just wondering because I found this review paper making the case for some forms of epigenetic inheritance:
It didn't strike me as pseudoscientific, so I tried following the citations and couldn't really find any obvious problems with them.
For example, this paper has a clever mouse experiment showing that daughter mice that had identical DNA sequences differed from each other based on their father's Y chromosome (which they did NOT inherit):
and the authors speculate that this could be due to inheritance of methylation patterns, histone modifications, or noncoding RNA.
Anyway I agree that epigenetic inheritance is largely unproven, but I'm not sure if it has been disproven.
EDIT -- This preprint appears to be a negative replication of the mouse experiment I was talking about. I haven't read through the whole thing yet, but it looks like they did a similar experiment and didn't find any transgenerational epigenetic effects:
This is a review paper with notably thin empirical examples of epigenetic transmission. The mouse study, as I read it, does not require epigenetic processes because a gene is spliced out and replaced. The paper has a kind of void core, rich in speculation and short on evidence.
“For a single biochemical and developmental pathway, DNA supplies the orchestra musicians in the form of genes, while epigenetics plays conductor, bringing them together to summon a complex symphony of mechanisms and structures from the sequence of interacting chemicals.” The DNA (the musicians) is inherited from the parents; where do the epigenetics (the conductor) come from? Are the epigenetics partly inherited, partly affected by the environment—with, on your account, the latter effect being minuscule?
Your description of the germline reprogramming is apt here. While the maternal and paternal genomes are inherited in the germlines, the germline epigenetic marks are largely erased in the zygote (although not absolutely, which is how there's thought to be a capacity for epigenetic inheritance to a weak and labile degree), and a new process of diffusible morphogen gradient-mediated differential gene expression starts occurring in the developing multicellular embryo until certain lineage identities are formed. The cell lineage-specific epigenetic marks are a consequence of this transcription factor-dependent process, but then also serve to maintain cell identity during tissue expansion and maintenance due to the semi-conservative nature of modified histone segregation during mitosis.
Is the molecular biological machinery for high (or low) fidelity transmission of epigenetic markers down generations of cell lines well know? I've read (well the first 1/4 anyways) of many papers in DNA replication about the complex molecular mechanisms that drive this. However, I don't think I've ever seen anything on how epigenetic markers are passed along. It seems like this would require complex machinery, the mastery of which would have great, great biomedical utility...
Thanks for writing this! Finally a primer we can send to all of our friends
right, this is why i wrote this. i doubt i'll write about epigenetics again unless there is an evolutionary angle
Someone give this man a University Chair and a megaphone. Thank you very much for this essay, Razib; and Happy Holidays to you and your family.
Great work Razib. I shared this in all those groups where this should he shared. (You know the ones I am talking about)
I agree that the pop-psychology stuff is mostly pseudoscience, but have all of the possible mechanisms of epigenetic inheritance really been disproven? Even if the DNA structure is wiped clean of markers during meiosis and fertilization, that doesn't seem to rule out other possible non-DNA mechanisms of inheritance, like small noncoding RNAs.
I'm just wondering because I found this review paper making the case for some forms of epigenetic inheritance:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3521963
It didn't strike me as pseudoscientific, so I tried following the citations and couldn't really find any obvious problems with them.
For example, this paper has a clever mouse experiment showing that daughter mice that had identical DNA sequences differed from each other based on their father's Y chromosome (which they did NOT inherit):
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4045629/
and the authors speculate that this could be due to inheritance of methylation patterns, histone modifications, or noncoding RNA.
Anyway I agree that epigenetic inheritance is largely unproven, but I'm not sure if it has been disproven.
EDIT -- This preprint appears to be a negative replication of the mouse experiment I was talking about. I haven't read through the whole thing yet, but it looks like they did a similar experiment and didn't find any transgenerational epigenetic effects:
https://www.biorxiv.org/content/10.1101/2022.12.23.521797v1?rss=1
This is a review paper with notably thin empirical examples of epigenetic transmission. The mouse study, as I read it, does not require epigenetic processes because a gene is spliced out and replaced. The paper has a kind of void core, rich in speculation and short on evidence.
This is an excellent post; the popular conception of epigenetic inheritance is deeply flawed and I hope this helps to correct it.
In case anyone wants to dive deeper into the biology behind this, I've written a three-part epigenetics series here:
1. https://denovo.substack.com/p/what-is-epigenetics
2. https://denovo.substack.com/p/epigenetics-of-the-mammalian-germline
3. https://denovo.substack.com/p/epigenetic-inheritance-in-mammals
(I am a researcher specializing in human reproductive development.)
Razib: Thank you very much for a clear explanation of a very murky subject.
“For a single biochemical and developmental pathway, DNA supplies the orchestra musicians in the form of genes, while epigenetics plays conductor, bringing them together to summon a complex symphony of mechanisms and structures from the sequence of interacting chemicals.” The DNA (the musicians) is inherited from the parents; where do the epigenetics (the conductor) come from? Are the epigenetics partly inherited, partly affected by the environment—with, on your account, the latter effect being minuscule?
if a developmental geneticist is reading this please answer.
yes, i learned the setting of marks once but i kind of forgot. development is not interesting to me :)
Your description of the germline reprogramming is apt here. While the maternal and paternal genomes are inherited in the germlines, the germline epigenetic marks are largely erased in the zygote (although not absolutely, which is how there's thought to be a capacity for epigenetic inheritance to a weak and labile degree), and a new process of diffusible morphogen gradient-mediated differential gene expression starts occurring in the developing multicellular embryo until certain lineage identities are formed. The cell lineage-specific epigenetic marks are a consequence of this transcription factor-dependent process, but then also serve to maintain cell identity during tissue expansion and maintenance due to the semi-conservative nature of modified histone segregation during mitosis.
Absolutely loved this.
Is the molecular biological machinery for high (or low) fidelity transmission of epigenetic markers down generations of cell lines well know? I've read (well the first 1/4 anyways) of many papers in DNA replication about the complex molecular mechanisms that drive this. However, I don't think I've ever seen anything on how epigenetic markers are passed along. It seems like this would require complex machinery, the mastery of which would have great, great biomedical utility...
a lot of epigenetic research is funded and aimed to cancer.