10 ms·

Paternal stress in mice given to offspring via RNA packed into sperm

192 points by shawndumas 11y ago

SunSparc 11y ago
More proof that genetics is not read-only.
- nitrogen 11y ago
  No, this doesn't permanently alter the DNA sequence.
  - shiven 11y ago
    But, it is like commenting out regions in code. You are factually right, in that there is no editing of the DNA sequence i.e. no mutations. But this phenomenon exerts a similar end effect.
    - AnimalMuppet 11y ago
      Not "end", exactly - at least, not if you look past N generations. The question is, how many generations does it take for this to wear off? Or is it "good until cancelled"?
  - TeMPOraL 11y ago
    Doesn't matter. It's the "reflections on trusting trust" kind of thing - we, our parents, grandparents, etc. form a chain; some runtime modifications to replication mechanism could propagate forward indefinitely, without changing the DNA in the process.
    - iamcurious 11y ago
      Nice insight. To save a few clicks to those remembering this classic (or reading for the first time!): https://www.ece.cmu.edu/~ganger/712.fall02/papers/p761-thompson.pdf https://www.ece.cmu.edu/~ganger/712.fall02/papers/p761-thomp...
randlet 11y ago
Great. Another thing to worry about when trying to start a family...
- arxpoetica 11y ago
  I wanted to make the same pun.
- pen2l 11y ago
  Take a two month long vacation[1], and then do it somewhere toward the end. [1]: Yes yes, not everyone has the luxury to be able to do that. But frankly, I've found that with a healthy amount of planning it is possible. E.g. I'm planning to take a 2 month long vacation next summer... I know already my boss probably won't let me, but I don't care! I'll quit if I have to! Already have an eye out for new gigs! This is like what people say about exercising -- you don't have time? Make time for it. The POTUS can find time to exercise, probably you can too.
  - dazmax 11y ago
    Pre-paternity leave
  - s_kilk 11y ago
    I doubt this will work, given that it usually takes multiple attempts to concieve. The two month vacation would be nice, but there's nothing to guarantee that the child will be concieved at the 'correct' time.
  - nommm-nommm 11y ago
    Most people can't afford to take a 2 month vacation unless they already have a high paying job. Sure, most people can reduce their living expenses a lot but only so much. That's not even considering the fact that planning a pregnancy like that isn't feasible, especially for older couples - who are the ones who had enough time to save up for a two month vacation. Pregnancy doesn't work like that, it can take months to years and that's not even considering 10-20% of known pregnancies end in miscarriage. The idea pregnancy should be instant is harmful and leads to anxiety in itself.
annacollins 11y ago
miRNA here refers to microRNA, and that mRNA refers to messengerRNA ?
- aroch 11y ago
  Yes, mRNA <always> refers to messenger RNA. miRNA nearly always refers to microRNA. https://en.wikipedia.org/wiki/List_of_RNAs https://en.wikipedia.org/wiki/List_of_RNAs
  - stuxnet79 11y ago
    I usually just call them 'miRs' to prevent confusion and misuse of both terms.
bruu_ 11y ago
That's interesting that the mice with stressed parents dealt better with stress. I've typically interpreted this strain of study as a sort of depressing, "rich get richer" of biology concept where every generation gets more stressed out until they somehow get removed from the gene pool. But it seems like the exact opposite is the case, that there is an adaptive numbing effect
- gvb 11y ago
  "Dealt better with stress" is not the conclusion (inference) that concerns them in the paper: "This is relevant, and problematic, because blunted stress responses in humans are associated with neuropsychiatric disorders like depression, schizophrenia, and autism." (emphasis mine).
  - bruu_ 11y ago
    I interpreted it to mean that they have a blunted stress response, nothing more. Maybe a lot of people that undergo stress have a twofold reaction: 1. downregulate the response to similar stressors 2. still have some bad feelings about what happened I would rather have 1 & 2 than just 2 alone. So yeah, when they say "associated with" they aren't saying "caused"
- cpncrunch 11y ago
  >That's interesting that the mice with stressed parents dealt better with stress It doesn't say they dealt with stress better. They had a blunted stress response, and in humans that might lead to depression, etc. Presumably there must be an evolutionary reason. If the environment is very stressful, it's perhaps better to have a lower HPA axis response to stress, otherwise you would be at risk of various diseases.
ep103 11y ago
So i guess the next question is: did the mice have different sperm characteristics because they were stressed? Or was it a long term change? By which I mean, if the stressed mice were allowed to recover and have happy lives for a few months after the stress period, before mating, would these results still occur? Because if not, then it opens the possibility that just being incredibly stressed out altered the production of sperm in some temporal manner.
noname123 11y ago
Hello, I don't have access nor the time to grok the full paper. http://www.pnas.org/content/early/2015/10/14/1508347112.full.pdf http://www.pnas.org/content/early/2015/10/14/1508347112.full... Can someone give a quick ELI5 into the exact method and rough biological explanation in the study? From what I understand roughly from the artstechnica layman explanation, the microRNA expression can be influenced by an individual's environment (in the case of the mouse, 36 hours of constant light, a 15-minute exposure to fox odor etc.) These microRNA levels act somehow as regulators/promoters to chromosome molecular structure (basically whether a particular region is wound up tightly or loosely, making that region either harder or more accessible for the DNA transcription machinery), thereby effectively regulating the accessibility and expression of the genes (in this case, genes responsible for "down regulating stress [pathways] of mice") stored in that region. Although the innate DNA structure (source code) didn't change from parent to offspring, the environment influences (Larmakian inheritance or metaphorically the user-defined environment path) was passed down to the offspring via the microRNA (that was optimized for/influenced by the father's environment) in the father's sperm cells - such that the genes are regulated epigenetically in the child same as the father's from the get-go (e.g., inheriting the environment paths, importing the older browser's bookmarks). I have several questions, 1) please correct my layman understanding if any of it is off (don't have access to PNAS unfortunately), 2) if someone in the field can explain how microRNA actually regulate the chromosomes and histones, 3) Even if the microRNA is passed down to the offspring, is microRNA expression level in that offspring going to remain persistent? Meaning suppose the offspring is exposed to a totally different environment in contrast to the parent, will the offspring's microRNA eventually change to match its changing environment, i.e., how does microRNA get expressed and regulated in the first place? Thanks for posting this very interesting paper on Larmakianism making a comeback!
- fjarlq 11y ago
  https://en.wikipedia.org/wiki/Transgenerational_epigenetic_inheritance https://en.wikipedia.org/wiki/Transgenerational_epigenetic_i...
- milkcircle 11y ago
  A quick answer to your question #1/2: microRNA (miRNA) is the substrate of a very complex piece of cell machinery that uses the miRNA sequence to find complementary messenger RNA (mRNA). When miRNA binds to its respective mRNA, the machinery (whose details I will not go into) degrades the mRNA, preventing its translation into protein. So while the DNA remains unaltered by the miRNA, protein expression is regulated on the level of mRNA degradation. MiRNA and short-hairpin RNA are tremendously useful in the laboratory setting to knock down the expression of genes without having to do gene modifications. This paper shows that miRNA can be passed from father to child through the sperm, and this miRNA can affect the way certain genes are expressed. As for your question #3, I couldn't find any information in the paper regarding how long the miRNA persisted in the offspring. The miRNAs seem to have a long-term effect on genes in the paraventricular nucleus of the hypothalamus, but whether this is due to effects of miRNA solely in the development of the zygote, or whether the miRNA in the adult is also important, is unclear. It seems likely that changes due to the miRNA in fetal development alone could be sufficient in dramatically changing stress responsitivity, but this remains to be proven. In another famous study, maternal nurture plays a very important role in the epigenetic development of baby mice [1]. So it could very well be that a favorable and nurturing environment may cause epigenetic changes in the offspring that might counteract the actions of the miRNA described here. Again, this is something that the paper does not show and therefore we can only speculate at this point. Hope this helps! [1] http://www.nature.com/neuro/journal/v7/n8/full/nn1276.html http://www.nature.com/neuro/journal/v7/n8/full/nn1276.html
mikeyanderson 11y ago
This makes complete sense with me and my dad.
acd 11y ago
Also Starvation is genetically encoded "Aftermath of hunger affects three generations in study of epigenetic changes." http://www.nature.com/news/starvation-in-pregnant-mice-marks-offspring-dna-1.15534 http://www.nature.com/news/starvation-in-pregnant-mice-marks...
deleted 11y ago
[deleted]
- haberman 11y ago
  This generic critique doesn't seem to apply here. According to the article, the researchers were able to reliably reproduce the inherited stress response by artificially injecting a zygote with the extra RNA they suspected was responsible for the observed effect. That is a pretty compelling causality result.
univalent 11y ago
Awesome. I guess my daughters will need SSRIs and assorted drugs to get them through life. Just bleeping great.
- stuxnet79 11y ago
  Same problem here. What can I say. It's tough man, but you just have to pull through it. At least we are lucky, that we were born at a time where there's medication that makes you feel at least semi-normal. By the time I decide to have children, I hope humanity will be better equipped to handle the various mental illnesses.
dominotw 11y ago
https://en.wikipedia.org/wiki/Lamarckism https://en.wikipedia.org/wiki/Lamarckism
ChuckMcM 11y ago
I wonder if there is some sort of evolutionary force at work here. Sort of some kind of heads up that you're coming into the world at a stressful time, better bring your best game kind of thing. Do we also father more aggressive children when we perceive we are threatened?
theworstshill 11y ago
The equivalent of those mice experiments in human would be a tiger chasing you around for two weeks, and you finally managing to escape and reproduce. Modern men have nothing to worry about here.
Karmakosmik 11y ago
I suggest this review, published in Cell from 2014: "Transgenerational Epigenetic Inheritance: Myths and Mechanisms" http://www.sciencedirect.com/science/article/pii/S0092867414002864 http://www.sciencedirect.com/science/article/pii/S0092867414... (Open access) and this series Kevin Mitchell: http://www.wiringthebrain.com/2013/01/the-trouble-with-epigenetics-part-1.html http://www.wiringthebrain.com/2013/01/the-trouble-with-epige... (The Trouble with Epigenetics)
nonbel 11y ago
They chose to show the cortisol data from the last paper[1] as a schematic...strange choice. Compare Fig 1F in this new one to Fig 1 from the previous work. The unexplained difference between control groups from the two papers is bigger than the effect they see due to injecting micro RNAs. [1] http://www.jneurosci.org/content/33/21/9003.abstract http://www.jneurosci.org/content/33/21/9003.abstract
- nonbel 11y ago
  I extracted the data from the two figures and made a plot: http://s21.postimg.org/8it9wt9ut/Cort.png http://s21.postimg.org/8it9wt9ut/Cort.png At least the 2013 Control and 2015 PBS (the control for the current study) should be similar. They need to explain why the results are so different and figure out what is required to get reproducible results before they conclude the treatment is responsible here. Also, in the supplemental methods they write: "Data greater than 2 SDs above each group mean were removed from analyses". That is not a legitimate reason to drop animals from the study. It appears they dropped four mice only to create the impression of less variable outcomes (and to help get "significance"). I am not confident this effect would replicate in an independent lab, they seem to be playing games with the analysis.

192 points by shawndumas 11y ago

SunSparc 11y ago

More proof that genetics is not read-only.

nitrogen 11y ago
No, this doesn't permanently alter the DNA sequence.
- shiven 11y ago
  But, it is like commenting out regions in code. You are factually right, in that there is no editing of the DNA sequence i.e. no mutations. But this phenomenon exerts a similar end effect.
  - AnimalMuppet 11y ago
    Not "end", exactly - at least, not if you look past N generations. The question is, how many generations does it take for this to wear off? Or is it "good until cancelled"?
- TeMPOraL 11y ago
  Doesn't matter. It's the "reflections on trusting trust" kind of thing - we, our parents, grandparents, etc. form a chain; some runtime modifications to replication mechanism could propagate forward indefinitely, without changing the DNA in the process.
  - iamcurious 11y ago
    Nice insight. To save a few clicks to those remembering this classic (or reading for the first time!): https://www.ece.cmu.edu/~ganger/712.fall02/papers/p761-thompson.pdf https://www.ece.cmu.edu/~ganger/712.fall02/papers/p761-thomp...

randlet 11y ago

Great. Another thing to worry about when trying to start a family...

arxpoetica 11y ago
I wanted to make the same pun.
pen2l 11y ago
Take a two month long vacation[1], and then do it somewhere toward the end. [1]: Yes yes, not everyone has the luxury to be able to do that. But frankly, I've found that with a healthy amount of planning it is possible. E.g. I'm planning to take a 2 month long vacation next summer... I know already my boss probably won't let me, but I don't care! I'll quit if I have to! Already have an eye out for new gigs! This is like what people say about exercising -- you don't have time? Make time for it. The POTUS can find time to exercise, probably you can too.
- dazmax 11y ago
  Pre-paternity leave
- s_kilk 11y ago
  I doubt this will work, given that it usually takes multiple attempts to concieve. The two month vacation would be nice, but there's nothing to guarantee that the child will be concieved at the 'correct' time.
- nommm-nommm 11y ago
  Most people can't afford to take a 2 month vacation unless they already have a high paying job. Sure, most people can reduce their living expenses a lot but only so much. That's not even considering the fact that planning a pregnancy like that isn't feasible, especially for older couples - who are the ones who had enough time to save up for a two month vacation. Pregnancy doesn't work like that, it can take months to years and that's not even considering 10-20% of known pregnancies end in miscarriage. The idea pregnancy should be instant is harmful and leads to anxiety in itself.

annacollins 11y ago

miRNA here refers to microRNA, and that mRNA refers to messengerRNA ?

aroch 11y ago
Yes, mRNA <always> refers to messenger RNA. miRNA nearly always refers to microRNA. https://en.wikipedia.org/wiki/List_of_RNAs https://en.wikipedia.org/wiki/List_of_RNAs
- stuxnet79 11y ago
  I usually just call them 'miRs' to prevent confusion and misuse of both terms.

bruu_ 11y ago

That's interesting that the mice with stressed parents dealt better with stress. I've typically interpreted this strain of study as a sort of depressing, "rich get richer" of biology concept where every generation gets more stressed out until they somehow get removed from the gene pool. But it seems like the exact opposite is the case, that there is an adaptive numbing effect

gvb 11y ago
"Dealt better with stress" is not the conclusion (inference) that concerns them in the paper: "This is relevant, and problematic, because blunted stress responses in humans are associated with neuropsychiatric disorders like depression, schizophrenia, and autism." (emphasis mine).
- bruu_ 11y ago
  I interpreted it to mean that they have a blunted stress response, nothing more. Maybe a lot of people that undergo stress have a twofold reaction: 1. downregulate the response to similar stressors 2. still have some bad feelings about what happened I would rather have 1 & 2 than just 2 alone. So yeah, when they say "associated with" they aren't saying "caused"
cpncrunch 11y ago
>That's interesting that the mice with stressed parents dealt better with stress It doesn't say they dealt with stress better. They had a blunted stress response, and in humans that might lead to depression, etc. Presumably there must be an evolutionary reason. If the environment is very stressful, it's perhaps better to have a lower HPA axis response to stress, otherwise you would be at risk of various diseases.

ep103 11y ago

So i guess the next question is: did the mice have different sperm characteristics because they were stressed? Or was it a long term change? By which I mean, if the stressed mice were allowed to recover and have happy lives for a few months after the stress period, before mating, would these results still occur? Because if not, then it opens the possibility that just being incredibly stressed out altered the production of sperm in some temporal manner.

noname123 11y ago

Hello, I don't have access nor the time to grok the full paper. http://www.pnas.org/content/early/2015/10/14/1508347112.full.pdf http://www.pnas.org/content/early/2015/10/14/1508347112.full... Can someone give a quick ELI5 into the exact method and rough biological explanation in the study? From what I understand roughly from the artstechnica layman explanation, the microRNA expression can be influenced by an individual's environment (in the case of the mouse, 36 hours of constant light, a 15-minute exposure to fox odor etc.) These microRNA levels act somehow as regulators/promoters to chromosome molecular structure (basically whether a particular region is wound up tightly or loosely, making that region either harder or more accessible for the DNA transcription machinery), thereby effectively regulating the accessibility and expression of the genes (in this case, genes responsible for "down regulating stress [pathways] of mice") stored in that region. Although the innate DNA structure (source code) didn't change from parent to offspring, the environment influences (Larmakian inheritance or metaphorically the user-defined environment path) was passed down to the offspring via the microRNA (that was optimized for/influenced by the father's environment) in the father's sperm cells - such that the genes are regulated epigenetically in the child same as the father's from the get-go (e.g., inheriting the environment paths, importing the older browser's bookmarks). I have several questions, 1) please correct my layman understanding if any of it is off (don't have access to PNAS unfortunately), 2) if someone in the field can explain how microRNA actually regulate the chromosomes and histones, 3) Even if the microRNA is passed down to the offspring, is microRNA expression level in that offspring going to remain persistent? Meaning suppose the offspring is exposed to a totally different environment in contrast to the parent, will the offspring's microRNA eventually change to match its changing environment, i.e., how does microRNA get expressed and regulated in the first place? Thanks for posting this very interesting paper on Larmakianism making a comeback!

fjarlq 11y ago
https://en.wikipedia.org/wiki/Transgenerational_epigenetic_inheritance https://en.wikipedia.org/wiki/Transgenerational_epigenetic_i...
milkcircle 11y ago
A quick answer to your question #1/2: microRNA (miRNA) is the substrate of a very complex piece of cell machinery that uses the miRNA sequence to find complementary messenger RNA (mRNA). When miRNA binds to its respective mRNA, the machinery (whose details I will not go into) degrades the mRNA, preventing its translation into protein. So while the DNA remains unaltered by the miRNA, protein expression is regulated on the level of mRNA degradation. MiRNA and short-hairpin RNA are tremendously useful in the laboratory setting to knock down the expression of genes without having to do gene modifications. This paper shows that miRNA can be passed from father to child through the sperm, and this miRNA can affect the way certain genes are expressed. As for your question #3, I couldn't find any information in the paper regarding how long the miRNA persisted in the offspring. The miRNAs seem to have a long-term effect on genes in the paraventricular nucleus of the hypothalamus, but whether this is due to effects of miRNA solely in the development of the zygote, or whether the miRNA in the adult is also important, is unclear. It seems likely that changes due to the miRNA in fetal development alone could be sufficient in dramatically changing stress responsitivity, but this remains to be proven. In another famous study, maternal nurture plays a very important role in the epigenetic development of baby mice [1]. So it could very well be that a favorable and nurturing environment may cause epigenetic changes in the offspring that might counteract the actions of the miRNA described here. Again, this is something that the paper does not show and therefore we can only speculate at this point. Hope this helps! [1] http://www.nature.com/neuro/journal/v7/n8/full/nn1276.html http://www.nature.com/neuro/journal/v7/n8/full/nn1276.html

mikeyanderson 11y ago

This makes complete sense with me and my dad.

acd 11y ago

Also Starvation is genetically encoded "Aftermath of hunger affects three generations in study of epigenetic changes." http://www.nature.com/news/starvation-in-pregnant-mice-marks-offspring-dna-1.15534 http://www.nature.com/news/starvation-in-pregnant-mice-marks...

deleted 11y ago

[deleted]

haberman 11y ago
This generic critique doesn't seem to apply here. According to the article, the researchers were able to reliably reproduce the inherited stress response by artificially injecting a zygote with the extra RNA they suspected was responsible for the observed effect. That is a pretty compelling causality result.

univalent 11y ago

Awesome. I guess my daughters will need SSRIs and assorted drugs to get them through life. Just bleeping great.

stuxnet79 11y ago
Same problem here. What can I say. It's tough man, but you just have to pull through it. At least we are lucky, that we were born at a time where there's medication that makes you feel at least semi-normal. By the time I decide to have children, I hope humanity will be better equipped to handle the various mental illnesses.

dominotw 11y ago

https://en.wikipedia.org/wiki/Lamarckism https://en.wikipedia.org/wiki/Lamarckism

ChuckMcM 11y ago

I wonder if there is some sort of evolutionary force at work here. Sort of some kind of heads up that you're coming into the world at a stressful time, better bring your best game kind of thing. Do we also father more aggressive children when we perceive we are threatened?

theworstshill 11y ago

The equivalent of those mice experiments in human would be a tiger chasing you around for two weeks, and you finally managing to escape and reproduce. Modern men have nothing to worry about here.

Karmakosmik 11y ago

I suggest this review, published in Cell from 2014: "Transgenerational Epigenetic Inheritance: Myths and Mechanisms" http://www.sciencedirect.com/science/article/pii/S0092867414002864 http://www.sciencedirect.com/science/article/pii/S0092867414... (Open access) and this series Kevin Mitchell: http://www.wiringthebrain.com/2013/01/the-trouble-with-epigenetics-part-1.html http://www.wiringthebrain.com/2013/01/the-trouble-with-epige... (The Trouble with Epigenetics)

nonbel 11y ago

They chose to show the cortisol data from the last paper[1] as a schematic...strange choice. Compare Fig 1F in this new one to Fig 1 from the previous work. The unexplained difference between control groups from the two papers is bigger than the effect they see due to injecting micro RNAs. [1] http://www.jneurosci.org/content/33/21/9003.abstract http://www.jneurosci.org/content/33/21/9003.abstract

nonbel 11y ago
I extracted the data from the two figures and made a plot: http://s21.postimg.org/8it9wt9ut/Cort.png http://s21.postimg.org/8it9wt9ut/Cort.png At least the 2013 Control and 2015 PBS (the control for the current study) should be similar. They need to explain why the results are so different and figure out what is required to get reproducible results before they conclude the treatment is responsible here. Also, in the supplemental methods they write: "Data greater than 2 SDs above each group mean were removed from analyses". That is not a legitimate reason to drop animals from the study. It appears they dropped four mice only to create the impression of less variable outcomes (and to help get "significance"). I am not confident this effect would replicate in an independent lab, they seem to be playing games with the analysis.