Skinner – epigenetic transgenerational inheritance

So the question is how was it we actually came across this idea of transgenerational epigenetics, in other words an epigenetic mark that occurs in the sperm or the egg that gets transferred for all subsequent generations to come. So it’s a form of non-genetic inheritance. Normally we think about inheritance being a replication of your DNA sequence and it goes to your offspring through your sperm or egg and then that’s what you inherited basically. Now we realize that an equally important if not larger sort of field is epigenetic inheritance, so the question is where we-how we came across that idea.  

So you have to understand most big discoveries in science don’t necessarily happen because someone thought about it upfront before they even got into it. It’s usually more a serendipitous observations. 

We were studying the sex determination period when a testes or ovary start to develop in the fetus to determine whether it’s going to be a male or a female. So I wanted to see what happens if this was interfered with. So we took an environmental chemical in a rat model. We used an outbred rat model, which is just a laboratory rat and essentially did the exposure during that sex determination period for the rat. And then essentially took this forward and then the offspring were born and we looked for any kind of deficiencies or abnormalities in the testes or ovary in normal sex determination. It turns out we found nothing. So this is a really good example of a failed experiment. We did the experiment, we did the whole sort of thing, we got all the results and there was no effect on sex determination. 

So essentially the experiment failed, so the lesson is pay attention to your failed experiments because what we then did is we aged that animal out to a year of age and what we found is when they got to be a year of age we saw a whole bunch of the cells that are going to turn into the sperm, they started dying in the testes. Not all of them but there were a large number of them, so there was basically a reduction in sperm number and motility and basically-so when they became adults. So we published that study. So that was all fine and dandy and then what happened was several months later I had a postdoc in the lab. She came into my office and she was very upset because she accidentally bred those pups when they got older into the next generation. You have the F0 mother we exposed, the F1 generation is the pups; so she took the F1 pups when they were old enough and bred them to get the F2, so the grand-offspring from the mother-the original mother. She was upset because we didn’t plan that experiment and just accidentally did a breeding.  So I said, “Don’t worry about it, just go look at the traits, look at the testes in these F2 generation animals”. She did and she came back and said, “It’s exactly like the first generation, 90% of the males had this testes deficiency”.  

So of course I didn’t believe her and I made her go out and repeat it and we took it out four generations. And so essentially what we did is we found that at each generation for four generations 90% of the males had this testes phenotype. So, that’s when we realized there’s something going on here that was outside the norm of what we were thinking.  

Normally what happens in a genetic inheritance situation was you get a trait like this testes phenotype that may be 90% in the first generation but then the next generation as you bred it out would go down to 50% approximately and then the next generation 50% of that; and so eventually within four or five generations you sort of have lost the phenotype or the trait. So essentially we didn’t see that- it was 90% for four generations.  

So this told me that there had to be some other inheritance phenomena going on that wasn’t genetics. That’s when it made me start thinking about epigenetics. At the time the technology to study DNA methylation and epigenetics-this was sort of the late/mid 90’s-wasn’t really good but we did what we could and we found that there was indeed a DNA methylation change. There was a methyl group on the DNA that was different across the genome and it was present in the sperm for the four generations. And so that was our first observation of this ability for the environment, if it causes an epigenetic change in the sperm or the egg, that this has the capacity to go forward for generations to come. Only the F0 generation female was exposed. None of the subsequent four generations had any exposure and so this exposure was sort of causing an effect that was then transferred. The biggest activity, be it for us and many of the labs that have come into the area, is to try to figure out the mechanism for how this epigenetic inheritance works. And we’re gaining a lot of speed on that but we don’t know all the details, but that’s basically what’s going on. It’s the epigenetics in the sperm or the egg is being programmed and then it gets passed through development processes for each generation. 

And so this is this non-genetic form of inheritance called epigenetic transgenerational inheritance which is now a very different thing from genetic inheritance in the environment has the ability to dramatically modify this epigenetic inheritance and then go forward. And so the individual that lives in a certain environment or organism that lives in a certain environment versus another has a way to change its physiology and phenotypes or traits so that it can better adapt to this phenotype or this environment versus this environment. We’ve known that that process goes on for a long time, we just didn’t know the mechanism and it turns to be epigenetics. And it explains huge amounts of things like how rapid evolutionary events occur which we couldn’t explain with genetics, where potentially disease comes from, a change in the phenotype, where disease comes from. So lots of things we started to – we couldn’t explain before could be explained through this epigenetic inheritance. 

So for epigenetic transgenerational inheritance when the germ lines carrying what we call epimutations, these mutations in the epigenome which is – whether it’s DNA methylation or other forms like non-coding RNA or other things-when those get programmed they’re carried forward and that’s the epigenetic transformation inheritance. So we identified it initially in rats. Subsequently it wasn’t more than a year or so then some people showed it in mice. And so they thought ‘well this is just a lab rodent sort of thing’, but then pretty much everybody that’s looked in any species they’ve sort of studied thoroughly has found this phenomenon. And that covers plants, flies, worms, fish, birds, rodents, pigs, and humans today.