
Paternal stress in mice given to offspring via RNA packed into sperm - shawndumas
http://arstechnica.com/science/2015/10/paternal-stress-given-to-offspring-via-rna-packed-into-sperm/
======
noname123
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...](http://www.pnas.org/content/early/2015/10/14/1508347112.full.pdf)

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!

~~~
milkcircle
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)

~~~
noname123
Thank you milkcircle for your detailed and precise answers for my specific
questions! And also going beyond to bring up another paper following up on
nurture in terms influences epigenetic development of offsprings. Thanks for
clearing up my confusion on how miRNA works ("regulate[s] on the level of mRNA
degradation"). I learn something new today thanks to you!

------
ep103
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.

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

~~~
rayiner
Starting a family isn't rocket science. Look at the world around you. It's
amazing. And it was built by people whose parents didn't wear them around in a
pouch until they were five, who fed them formula, who didn't eat a bunch of
fish oil while pregnant, and who (gasp!) smoked or drank during pregnancy.

Parenting science is like nutrition science. Lots of studies, little
consensus. Just ignore it.

~~~
shabda
They also had horrific infant mortality rate and ridiculous risk of death
during childbirth, for both mother and child.

There isn't as much clear cut answers about parenting as we would like, but
there is much evidence backed science which tells us what to do.

Your "Just ignore it." comment is pretty close to what the anti-vaxxers argue.

~~~
rayiner
I'm pretty sure all of that drop in infant and maternal mortality rate was due
to "real science" (antibiotics, surgical techniques, heroic efforts to save
pre-term babies), and not the "pop science" that bombards parents-to-be. There
is little scientific evidence that stuff leads to materially (not just
measurably) better outcomes.

~~~
djtriptych
That means the advice reduces to "Pay attention to the real science, and
ignore the pop science". Unfortunately that asks too much of a general
audience (presupposes the ability to differentiate, which we know even PhDs
occasionally have trouble with).

~~~
rayiner
The real science is the stuff the powers that be will take care of for you.
Just say "yes" when the doctor asks to vaccinate your kid or rush her to the
NICU.

~~~
TeMPOraL
That's IMO the core of the anti-vaxx issue. The real reason is not rejection
of the real science (even if it manifests this way) - it's the lack of trust
in the way "powers that be will take care of (...) you" will be good for you.
Politicians, pharma companies and all those scientists publishing bullshit for
career/grant money fucked that up.

~~~
rayiner
It's really hard to argue with the track-record of those politicians, pharma
companies, and bought scientists. Infant mortality rate is one-third of what
it was even in 1970. And that didn't happen from "empowered parents" making
decisions based on advice they read on the internet. It was the medical
industrial complex--including those companies selling NICU equipment for a few
hundred grand per bed--saved all those lives.

~~~
planfaster
> It's really hard to argue with the track-record of those politicians, pharma
> companies, and bought scientists.

As a lawyer, you should know it's pretty easy:

"Past performance is not necessarily indicative of future results."

Quod erat demonstrandum.

~~~
TeMPOraL
It's simpler than that. Past performance is something you get used to, and if
you grow up around something working, you sort of assume it's always been like
that. Part of the reason why every new generation wants to dismantle the
systems set up by their grandparents.

------
SunSparc
More proof that genetics is not read-only.

~~~
nitrogen
No, this doesn't permanently alter the DNA sequence.

~~~
TeMPOraL
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
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-thomp...](https://www.ece.cmu.edu/~ganger/712.fall02/papers/p761-thompson.pdf)

------
bruu_
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
"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_
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"

------
Karmakosmik
I suggest this review, published in Cell from 2014: "Transgenerational
Epigenetic Inheritance: Myths and Mechanisms"
[http://www.sciencedirect.com/science/article/pii/S0092867414...](http://www.sciencedirect.com/science/article/pii/S0092867414002864)
(Open access)

and this series Kevin Mitchell: [http://www.wiringthebrain.com/2013/01/the-
trouble-with-epige...](http://www.wiringthebrain.com/2013/01/the-trouble-with-
epigenetics-part-1.html) (The Trouble with Epigenetics)

------
nonbel
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
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.

------
acd
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...](http://www.nature.com/news/starvation-in-pregnant-mice-marks-
offspring-dna-1.15534)

------
ChuckMcM
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?

------
dominotw
[https://en.wikipedia.org/wiki/Lamarckism](https://en.wikipedia.org/wiki/Lamarckism)

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

~~~
stuxnet79
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.

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

~~~
aroch
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
I usually just call them 'miRs' to prevent confusion and misuse of both terms.

------
theworstshill
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.

------
mikeyanderson
This makes complete sense with me and my dad.

