High risk genes: Do they have benefits?

August 16, 2011 7:43 AM

Did you inherit your parents stress? Your grandparents stress? What about their environmental enrichment? Current research in rats is exploring possible mechanisms through which stressful and positive environments could affect our future children and grandchildren. Also something to consider in tandem: many of the genes associated with addiction and mental illness are also associated with resiliency.

"The study found that stress experienced by young female rats can impair their future offspring, but can also improve resilience."



Research on what are believed to be high risk dopaminergenic genes has similarly found that the high risk genes both impair humans raised in adverse conditions but also may offer improved resiliency. The presence of the dopamine receptor (DRD4) 7 repeat allele tends to correlate with addiction, mental illness, poor health outcomes and cognitive defecits in humans raised in adverse childhood environments. However it appears it may also offer resiliency:

"The 7-repeat allele appears to protect against the adverse effect of CA (child abuse) since the decline in resilience associated with increased adversity was evident only in individuals without the 7-repeat allele... Hence it is possible that approach-related personality traits could be mediating the effect of the DRD4 gene and childhood environment interaction on resilience such that when stressors are present, the 7-repeat allele influences the development of personality in a way that provides protection against adverse outcomes."
Also, it's possible the same genes are responsible for superior outcomes in humans raised in healthy environment:
"Children with the less efficient dopamine-related genes did worse in negative environments than the comparisons without the "genetic risk," but they also profited most from positive environments. Findings are discussed in light of evolutionary theory, and illustrated with some practical implications of differential susceptibility."

Epigenetics on metafilter: one two

posted by xarnop (38 comments total)

So environment becomes encoded in the genetics of one's offspring?

Head spinning stuff. Now I'm going through my whole history wondering what might've altered my genetic code.

Am I doing that right? Does this change the idea that offspring shouldn't be held accountable for the sins of the parents?
posted by Skygazer at 7:57 AM on August 16, 2011

Especially not if the parents went in their room while they were at camp...
posted by The Ultimate Olympian at 8:02 AM on August 16, 2011

I sure inherited my mom's anxiety!
posted by smirkette at 8:03 AM on August 16, 2011

Interesting. So let's say you have a mom and a dad who start out young and stupid and raise their first two kids in a badly chaotic environment with lots of hitting and anger and confusion, but later figure their shit out and do much better with their later set of kids. All of the kids will have the basically the same set of genes (obvs. not exactly the same but all from the same origin). The first kids will have issues with mental illness and addiction but the younger kids will be basically fine. This happened in my family.
posted by bleep at 8:13 AM on August 16, 2011 [6 favorites]

The environment makes the same set of genes do different things. Is that right?
posted by bleep at 8:15 AM on August 16, 2011 [1 favorite]

I work with researchers who, among other things, investigate the heritability of anxious temperament in primates.

I do computer stuff, not brain stuff. As I understand it, there are a few driving factors, chief among them plasticity and anxiety. You inherit these things, but exposure works with brain plasticity to influence further anxious behaviors.

So, if an individual has high plasticity and something bad happens but ends well, they become less anxious. An individual with low plasticity may actually become more anxious from the same stimulus and outcome. However, Plasticity is not a fixed variable and is itself dependent on a number of environmental and genetic variables.

There is a lot more to it, and much of it above my head.

Do you know how awesome it is to do work in SCIENCE! ???
posted by Pogo_Fuzzybutt at 8:24 AM on August 16, 2011 [5 favorites]

So is this a revision of Lamarckism? Weird.
posted by Gwynarra at 8:27 AM on August 16, 2011

The environment makes the same set of genes do different things. Is that right?

Yes, epigenetics basically looks at how the inherited cellular environment affects gene expression. There's all sorts of non-gene stuff snuggled up next to the DNA that affects it.
posted by zennie at 8:28 AM on August 16, 2011

Without an actual geneticist unpacking the actual significance of this paper for Metafilter, it doesn't sound like there's much substantial discussion that can happen.

Derpy jokes and witticisms excepted, of course.
posted by Nomyte at 9:02 AM on August 16, 2011

Epigenetics is a deep well that we've only recently discovered isn't a trash can.
posted by chimaera at 9:06 AM on August 16, 2011 [3 favorites]

The long term effects (to the second generation) of outside stress have been studied for a while. This study on the grandchildren of Dutch women who were pregnant during WWII is a landmark one.
posted by francesca too at 9:09 AM on August 16, 2011

I inherited a bad back as well as some "bad" behaviors from my family tree.

Oh well, play the hand that is dealt to you.
posted by handbanana at 9:23 AM on August 16, 2011 [1 favorite]

I think was Nomyte said is right. There isn't much we can really talk about unless we preference everything with "I'M NOT A SCIENTIST".

And I'm definitely not. But I want to talk about this. I cannot comment on the study's findings or intents. But as a person who suffers from mental illness and was abused and who thinks about the origins of my problems way too much, I prefer to subscribe to the loose-fitted (but increasingly studied) idea that 'child abuse alters the brain'.

I've always been an incredibly anxious person. While I may have some genetic predisposition to it, I am certain that it is a result of two factors. a) experiencing rejection and physical abuse most intensely in my earliest childhood years, and b) a learned behavior from witnessing the turmoil my mother was under as a child/infant. I witnessed her experiencing trauma, all from a variety of factors, she was physically sick unable to work, her ill relationship with my father, and her intense emotional instability.

Read/watch this and this.
posted by GEB's fun world at 9:26 AM on August 16, 2011 [1 favorite]

*preface, not preference
posted by GEB's fun world at 9:27 AM on August 16, 2011

That would likely be from my biological father who was a special education student and never made it beyond ninth grade. I am also non-neurotypical as well. And yes spelling is incredibly difficult for me despite that I proofread the original post numerous times. Apologese for the inconvenience to your person.
posted by xarnop at 9:29 AM on August 16, 2011 [3 favorites]

Zennie: Yes, epigenetics basically looks at how the inherited cellular environment affects gene expression. There's all sorts of non-gene stuff snuggled up next to the DNA that affects it.

I don't know about this. Honestly, as someone who's always been pretty happy with the idea of their being a true separation between genetics and environment, this turns things on it's head in a profound way.

As an immigrant, whether true or not, I've had to, for better or worse, see my new environment as the key to who I was becoming and as such being to function within it without too much difference than my peers. As I came to the country when I was 6 yrs old and neither one of my parents got beyond the 4th grade. (And lived through a the poverty and hunger of Southern Europe in the 30s and WW2 in the 40s.)

That, might be TMI, but whatevs. We're all friends here more or less is the way I view it.
posted by Skygazer at 10:09 AM on August 16, 2011

Oh, and to finish the thought, I've always done more or less well in school, and have a grad degree (first in my family).
posted by Skygazer at 10:11 AM on August 16, 2011 [1 favorite]

Le me derping on derpafilter. *Le wild genetics paper appears*. Le me derps derpy joke. Le me gusta. True Story
posted by Ad hominem at 10:35 AM on August 16, 2011 [2 favorites]

"Without an actual geneticist unpacking the actual significance of this paper for Metafilter, it doesn't sound like there's much substantial discussion that can happen."

Are you saying there are no geneticists on metafilter?! What!? This is a tragedy... what have I been doing here!?

That's it I'm heading to Genetafilter.

Stomp stomp.

(So... where is Genetafilter? there's ..not one... is there. Or rather it must behind all those acedemic paywalls. Dammit. Somewhere over the acedemic pay walls.... song birds fly... birds fly over the paywalls why.... oooooh.... why....)

The craziness is from both of my genetic parents in case you're wondering.
posted by xarnop at 11:05 AM on August 16, 2011 [1 favorite]

Mom, why did you eat all that Cheez Whiz?
posted by benzenedream at 11:07 AM on August 16, 2011 [2 favorites]

Well, that explains my step-sister, step-mother *and* her mother. They're the most anxious women I know. They answer phone calls as if the person on the other end is going to tell them about the impending apocalypse, after coming over to rob them and burn down the house. It's never "Hey" or "Hello?", it's always "HELLO?!?!" I don't know how they survive to pass on their genes.
posted by mitzyjalapeno at 11:22 AM on August 16, 2011 [1 favorite]

Some things one learns in scientist school:

1. One study proves nothing.
2. Findings from groups cannot be applied to individuals.
3. Statistical significance is not what it sounds like.
4. It takes a metric buttload of evidence to build the bridge from findings in rats to conclusions about humans.
5. It's easy and tempting to make sweeping generalizations based on a single paper.
6. It's also easy to forget that most of these studies use surrogate measures that have only tenuous connections to abstract qualities you see in your character.
7. Without reading the related literature, it's impossible to know whether this is the one study that managed to find an effect, preceded and then followed by twenty others that fail to replicate the finding.

 
posted by Nomyte at 11:26 AM on August 16, 2011 [11 favorites]

My eyes are my father's, my temper is my mother's but my stress, goddammit, is all my own. I'm not letting anyone else take the credit.
posted by Decani at 11:27 AM on August 16, 2011 [3 favorites]

IANAGeneticist, but I'm a molecular biologist so I'll shoot for a crash introduction to epigenetics, as people seem to be interested. It's fascinating stuff.

DNA is often described as something like a recipe book or set of instructions for the cell. This is a useful metaphor, but stresses too much its aspect of being a string of pure, abstract information, forgetting that it's a vast physical structure inside a very complex environment. If it's a book, it's a choose-your-own-adventure book, with conditional instructions on how to jump around between fragments of information, with some sets of pages glued together, others blotched with white-out, still others written backwards or in a hard-to-read font. And as people read through it, new combinations of pages get stuck, unstuck, revealed or hidden. The text in the book never changes, but by hiding or revealing different sections and changing the order in which its read, radically different stories get told.

Have you ever wondered why DNA -- the enormously long, thin, stringy molecule -- looks like big X's and Y's under the microscope? In the cell, it's carefully packaged into a complex 3D structure. It's not usually so densely packed that it's visible under a microscope, but it's always tightly bound to a range of scaffolding proteins, which keep it neatly organised up in such a way that you can get about 2 metres of DNA into a cell that's about 0.00002 meters across. The packing is mostly super-coiling: twist a piece of string until it starts coiling on itself; then take hold of that coil and twist it until it starts coiling on itself again, a coiled coil; then take that coil and twist...*

Anyway, the scaffolding proteins (mainly a family of proteins called histones) are not just structural. Most proteins inside the cell are constantly having new tiny decorations attached to them or chopped off to change their chemical properties and therefore function in response to the cell's current needs, and it turns out that histones are no exception. A wide variety of signals can kick machinery into action that cause specific types of histones to be modified in specific ways. This can change things like how densely a region of DNA is packed, the relative positions of sequences (not changing where they are along the genome, but changing where that section of DNA is in 3D space), and how easily the strands of DNA can be opened up. All of these -- and presumably more stuff that I don't know about -- change how easily the assemblage of DNA-reading enzymes can access a given gene. These modifications are fairly slow, and are used to make (semi-) permanent modifications to the pattern of genes that are available to be expressed in a given cell.

Getting back to the choose-your-own-adventure book, reading through the whole text of DNA would give you loads of conflicting or outright incoherent instructions and signals. Along with feedback loops consisting of proteins in the cell which control the expression of various families of genes in response to specific signals, these "epigenetic" modifications are a way of modifying the book, controlling which parts are read and in which order in order to give a useful output. Insofar as I understand it, these feedback loops are actually turing-complete (plenty of AND, OR, and NOT gates controlling cascades of gene expression in response to various sets of conditions; I wouldn't be surprised if there were some XOR), arguably making these modifications part of an analogue computer, for which the DNA is just a heavily fragmented, read-only hard drive.

The really interesting thing is that, when our DNA is copied for making new cells (including sperm and egg cells), the modifications to the scaffold proteins seem to be copied as well. There are definitely modifications made in specific cases -- the "daughter" cell has a few key genes switched on or off, leading to a cascade of changes in gene expression that leads it to become a very different type of cell -- but most of the epigenetic information that isn't deliberately changed seems to survive from one generation of cells to the next.

Which, yes, brings us to something like Lamarckism. Our experiences in life don't change the sequence of the DNA that we pass onto our children**, but that can influence the way that our DNA is packaged, and therefore how certain genes tend to be expressed. And since the patterns of gene expression are at least as important as the exact sequences of the genes that you carry, this is bound to have important consequences for a person's child.

Of course, bringing this all into a nice pop-sciency "my mum was stressed so I will be too" is hellishly difficult to do, as links between any given gene and a set of behaviors always are. It certainly seems to be true that histone modification patterns are passed down from parent to child, and it seems inevitable that this will therefore influence the child's development. But just like every other link between genetics and personality traits, it seems overwhelmingly likely that the effects, while real, are going to be subtle enough that they're extremely difficult to pick out from the consequences of your conditions in utero (are your quirks due to epigenetics or your stressed mum's weird hormone levels while you were developing?), upbringing, health (physiological and mental), and just general life experiences to date. Add to that the fact that it's one of those subjects about which everyone agrees that there's an obvious and intuitively correct answer -- we just can't agree on what that obviously correct answer is -- and this seems very dangerous to attach much weight to.

So after an enormously long speil, I come back to my standard response to biomedical studies that make it into the news: This is an interesting and possibly important result, but it's being oversold by the media and we're way too early to start talking about this little pattern in rats changing what it means to be human.


*and if I've done that right, the word "coil" is now just a shape and sound that no longer holds any meaning for you. coil coil coil.
**Barring rare events like retroviral integration into the genome of a sperm progenitor cell, or radiation damage, or whatever.
posted by metaBugs at 11:52 AM on August 16, 2011 [178 favorites]

A certain percentage of your happiness is determined by genes. I heard it was 25% or something.
posted by Hi Dan at 3:17 PM on August 16, 2011 [2 favorites]

Metabugs, that was splendid, excellent, fantastic and great. I used to work in this lab -- they should use your explanation of epigenetics on the page instead. Here I was thinking it was *hard* to explain.

And no one has done this yet?

They fuck you up, your mum and dad.
They may not mean to, but they do.
They fill you with the faults they had
And add some extra, just for you.

But they were fucked up in their turn
By fools in old-style hats and coats,
Who half the time were soppy-stern
And half at one another's throats.

Man hands on misery to man.
It deepens like a coastal shelf.
Get out as early as you can,
And don't have any kids yourself.^
posted by pH Indicating Socks at 5:49 PM on August 16, 2011 [11 favorites]

many of the genes associated with addiction and mental illness are also associated with resiliency

Not surprising. We're definitely all looney for continuing in the face of this absurd world.
posted by 3FLryan at 6:08 PM on August 16, 2011

I work with researchers who, among other things, investigate the heritability of anxious temperament in primates.

I am now picturing a bunch of tiny monkeys being forced to watch Fox News and listen to Sarah Palin soundbites while sitting in rush hour traffic and wearing uncomfortable polyester tracksuits that chafe their little monkey butts. Please do not dissuade me of these notions.
posted by elizardbits at 12:34 PM on August 17, 2011 [2 favorites]

A certain percentage of your happiness is determined by genes. I heard it was 25% or something.

I also saw that Levi's commercial.
posted by srboisvert at 12:42 PM on August 17, 2011 [2 favorites]

Here are a trio of decent epigen intro sites.

The BBC show Ghost in Your Genes is available online. (Not sure but may be identical to the PBS show.)
posted by Twang at 5:58 PM on August 17, 2011 [1 favorite]

Counting from inside to out, how many times is a dna string usually coiled? How many layers?
posted by wobh at 10:43 PM on August 17, 2011

Wobh: Counting from inside to out, how many times is a dna string usually coiled? How many layers?

MetaBug: > [....] In the cell, it's carefully packaged into a complex 3D structure. It's not usually so densely packed that it's visible under a microscope, but it's always tightly bound to a range of scaffolding proteins, which keep it neatly organised up in such a way that you can get about 2 metres of DNA into a cell that's about 0.00002 meters across. The packing is mostly super-coiling: twist a piece of string until it starts coiling on itself; then take hold of that coil and twist it until it starts coiling on itself again, a coiled coil; then take that coil and twist...*

.


2 divided by 0.00002 equaling 100,000 layers.

The coiling and elasticity of the protein DNA string reduces the number of layers, I guess and adds it's own properties, something like that perhaps. Above my maths.

So, I'll guess: < or > 100,000 layers


That narrows it down?

What a great summary by MetaBugs btw



posted by Skygazer at 10:57 AM on August 18, 2011

for which the DNA is just a heavily fragmented, read-only hard drive.

Having spent some time playing with the shattered, heavily averaged output of your everyday gene assembler, I think it's pretty clear if there were rewrites, particularly to the germline, we wouldn't actually know.
posted by effugas at 11:21 AM on August 18, 2011

It is profoundly mysterious to me and awe-inspiring how much the two meter long DNA molecule as described in metaBug's wonderful comment resembles the tape of a Turing machine.

You could with startlingly small oversimplification regard every living cell as a kind of Turing machine tapehead which accumulates within itself the multiple tapes it is almost constantly in the process of reading and rewriting, and which both allow and require it to produce new tapeheads with their own internal tapes in the twin processes of evolution and development.

Crick and Watson illuminated the structure and also thereby this function of DNA in 1953, only 17 years after Turing's incredibly seminal, in all but one sense of the word, and incredibly prophetic original publication.

Crick was sufficiently broad and deep to have been aware of Turing's work and sense it's importance. I wonder whether it influenced his work on DNA.
posted by jamjam at 11:21 AM on August 18, 2011

Which, yes, brings us to something like Lamarckism.

Remember, though in 'true' Lamarckism you have things like the geraff wanted a longer neck, got one, and then passed that on to it's children. Epigenetics is nothing like that at all. If certian things in your life change your histone "patterns" (or whatever) that doesn't nessisarally mean that the effect in your life will be the same as the effect in your children. If you don't eat any chocolate it's not going to make your children less likely to like it.

There seem to be some specific effects (like stress) that do have predictable effects in mice. But those might be things that are evolutionary switches that happen to be passed down, as opposed to 'new' evolutionary innovation that could lead anywhere.

When you look closely at how evolution works there is a ton of feedback and interplay. In some animals, you have sections of DNA that evolved to be more prone to mutation because they deal with something that is more likely to change in the environment, so that section of DNA needs to be more adapatalbe.

So some of these signals could be evolved-in responses to stimulus that are passed down to their children.

It is profoundly mysterious to me and awe-inspiring how much the two meter long DNA molecule as described in metaBug's wonderful comment resembles the tape of a Turing machine.

The tape in a Turing machine is read-write though.
posted by delmoi at 2:27 PM on August 21, 2011 [1 favorite]

delmoi,

I'm aware there's significant historical pressure making Lamarckism undesirable. But, nature really doesn't care all that much about how we'd like to model it. From Wikipedia on Lamarckianism:

>Forms of 'soft' or epigenetic inheritance within organisms have been suggested as neo-Lamarckian in nature by such scientists as Eva Jablonka and Marion J. Lamb. In addition to 'hard' or genetic inheritance, involving the duplication of genetic material and its segregation during meiosis, there are other hereditary elements that pass into the germ cells also. These include things like methylation patterns in DNA and chromatin marks, both of which regulate the activity of genes. These are considered "Lamarckian" in the sense that they are responsive to environmental stimuli and can differentially affect gene expression adaptively, with phenotypic results that can persist for many generations in certain organisms. Although the reality of epigenetic inheritance is not doubted (as many experiments have validated it), its significance to the evolutionary process is uncertain. Most neo-Darwinians consider[citation needed] epigenetic inheritance mechanisms to be little more than a specialized form of phenotypic plasticity, with no potential to introduce evolutionary novelty into a species lineage.[25]

My perspective is that, at the point we're seeing environmental influences directly modulating the genome across multiple generations, the presumption has to shift to us simply not knowing if there's an environment-to-genome path. In other words, most of the classic arguments against Lamarckianism have fallen ("How would the *genome* know about the *environment*?") and we're literally one mechanism away from environmentally guided mutation -- at some non-zero scale, anyway.

And don't say we'd see this easily. I've got these huge collections of gene fragments on my hard drive right now; they're not collected from the germline, they're not collected from a single cell, and they're averaged mercilessly. The entire field of genomic analysis is based on the assumption that the genome is fixed across the body. If it isn't -- and it actually is not, it's just a question of how much so -- these aligning mechanisms are absolutely going to average those changes away. Our tools are getting better, but they still suck. We only just found SNPs that differ between twins.
posted by effugas at 2:50 AM on August 24, 2011

(And, as another side note, there's no reason to be sure the genome isn't read-write as well. Not like we're running longitudinal studies on people's genes or germlines over decades.)
posted by effugas at 2:52 AM on August 24, 2011

One of the primary modes of epigenetic modification is direct methylation of the DNA.

That IS writing to the tape.
posted by jamjam at 12:47 PM on August 24, 2011