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Ancestral Ghosts in Your Genome | Michael Skinner

This fascinating and consequential talk shares research that is changing and expanding what we know about genomics to include the factors that are collectively known as epigenetics.

Full talk transcript

Today I'm going to talk about the ancestral ghost in your genome. Essentially, what your grandmother was exposed to when she was pregnant in terms of environmental factors may actually influence the disease you get later in life and you're going to pass this on to your grandkids. This is what you would call a non-genetic form of inheritance, directly impacted by the environment, and it's called epigenetic transgenerational inheritance, so I'll describe that.

This turns out to be a very significant role in where disease comes from and in general just regulating most of biology. So, for the past 100 years in science in general, particularly the biological sciences, there's been a concept, theory, paradigm, dogma that's pretty much the predominate way we think about how things work and this is called genetic determinism. The concept is that the DNA sequence of the genome is the building block for biology, it basically regulates directly what genes are on and off, and that then turns around and influences the functions of different organ systems. This, then, gives you the biology of the organism.

What your grandmother was exposed to when she was pregnant, in terms of environmental factors, may actually influence the disease you get later in life.

When the DNA sequence has an abnormality in it, a mutation, then the genes are not turning on/off correctly; the physiology of the organ systems is abnormal and you have a susceptibility to develop disease. But this affects all of biology and evolutionary biology. The current concept is random DNA sequence mutations drive evolution. Pretty much, if you want to think about anything in science we think that the DNA sequence is the driver.

So, turns out the environment has a major impact on biology, and for the past 50 or 60 years, a large number of observations have been made that suggest that genetics really can't explain many of the things we're seeing. The first is there's regional disease frequencies. Go anywhere in the world, and the frequencies of different diseases is different. If you take someone early in life before the age of about 5, move them to a new region, allow them to grow up, they will develop the disease frequency where they grew up. So this can't really be a genetic phenomena — it has to be more of an environmental phenomena. We looked at a large number of the major diseases we have and we've looked for genetic mutations that correlate to those diseases. In many cases, we have found genetic mutations, but pretty much across the board, it's in less than one percent of the population with the disease. Less than one percent.

So, it's good that we found some genetic mutations, but what about the other 99 percent? If you look at pretty much any of the major diseases, the increase over the past 20 or 30 years is so dramatic — in many of them it's a tenfold increase. For autism it was 15 years, ten-fold increase. I'm sorry, there's no genetic mechanism known that could explain that phenomena. It has to be induced by the environment. If you have identical twins who have essentially the same genetics, allow them to grow up in different regions, guess what? They develop different diseases. If it was all genetics, they should have the same disease. There are hundreds and hundreds of environmental factors that are known to promote, or be associated with, disease.

The vast majority of environmental factors cannot change DNA sequence, they're not muted genes. So how is it that an early-life exposure promotes a later life event? In terms of evolution, there are these rapid evolutionary events, and basically we can't really explain them easily with classic genetics. So, there appears to be an additional factor that regulates how the DNA functions. It's not that the DNA sequence and the genetics isn't absolutely critical — it is — but it appears that there is something else that's regulating how it works.

Epigenetics provides solutions for a number of the failures for genetic determinism.

What I'm going to talk about is epigenetics. Epigenetics provides solutions for a number of the failures for genetic determinism. Again, I'm not suggesting that genetics isn't absolutely critical. It's just a small piece of a much bigger story. Epigenetics are these small molecular factors, around the DNA, that regulate how the DNA functions. What genes are on and off. But it does this completely independent of DNA sequence. And when a cell divides into two daughter cells, not only does it replicate its DNA, but it also replicates its epigenetics, so that it maintains that cell identity.

So, this is what epigenetics is. There are four main epigenetic factors that we know about. The first, when identified was DNA methylation, a small chemical group called a metho-group gets chemically attached to the DNA. When that happens, it has the ability to turn genes on and off. The next thing identified was these groups of proteins called histones. Turns out DNA is wrapped around these histones, like beads on a string, and when the histones are chemically modified, they can influence what genes are on and off independent of DNA sequence. Another one is chromatin structure, basically whether there's a loop, or coil, or twist in the DNA, can also turn genes on and off, independent of DNA sequence. The last one of these is non-coding RNAs, the small RNAs that get expressed, come back and react on the DNA to regulate how it functions, independent of DNA sequence. These are the four known epigenetic processes.

I'm going to focus on DNA methylation, because it probably has the most important role in programming events, in terms of developmental biology. In terms of DNA methylation, there are two times during the life span of an organism where there's a major reprogramming of the epigenetics. The first one is during fetal development, at the time of sex determination. When the fetus determines whether it's going be a male or female, the precursor cell for your germline, whether you're going to get a sperm or an egg, that cell is de-methylated, methyl-groups are removed. At sex determination, they are re-methylated in the male- or female-specific manner, so you end up with a sperm lineage or an egg lineage.

This is the first time; the second time is at fertilization. As you become an adult, reproduce, at fertilization the sperm and the egg come together, and immediately, within a cell division, the DNA starts to be de-methylated. This is what creates, eventually, the embryonic stem cell that can turn into any cell in the body. As the embryo develops a little bit further, it will remethylate in a cell-specific manner. So this is reprogramming of the epigenetics. There's a set of genes, though, that are protected from that de-methylation; they don't get de-methylated. They're called imprinted sites, and they basically maintain their DNA methylation and they're protected from it, thus they can get passed from generation to generation.

Thus, a non-genetic form of inheritance. So we did an experiment: We exposed a gestating female, what we call an F0 generation, to the gestating female — basically what we expose is the first generation, and we expose it during that time of sex determination, just transiently, and remove the exposure then to a number of different environment toxins. With inbreeding, those offspring were born and when they grew up, it turns out they started developing large amounts of disease. Tumors, prostate disease, kidney disease, testis disease in very high frequencies.

We induce this, and it gets passed from generation to generation even though the exposure is way back here. And the level of disease is extremely high.

So, then we bred the animals again, so we had their grand-offspring, and we had equally level high levels of disease in all the same diseases. Bred again to the great-grand offspring, this is the F3 generation, three generations removed from any exposure; the only exposure was in that F0 generation where the female also had high levels. [This generation] also had high levels of disease. Took it even further to the fourth generation — same high levels of disease. So, we induce this, and it gets passed from generation to generation even though the exposure's way back here. And the level of disease is extremely high. What we see in the males is predominately testis disease, infertility; we have prostate disease — those are specific to the male. In the female, we see ovarian disease, pubertal deffects and also pregnacy defects.

In terms of both male and female, now we see kidney disease, increase in mammary tumors, behavioral effects in terms of anxiety and stress, and a large amount of obesity, as well. Ninety percent of the animals have multiple diseases. This is one of the highest frequencies of induced diseases ever found in the animal model. We've now repeated this with eight different environmental factors: Agricultural fungicide, agricultural pesticides, industrial contaminants like dioxin, plastics like Bisfenol A, the insect repellent Deet that all of us use in terms of keeping insects away, the historic pesticide DDT, and also hydrocarbons like jet fuel or oil.

Each one of them independently promoted these transgenerational inheritance of disease. Other laboratories have also shown that nutritional deffects, both high-fat diets or caloric restriction, will do the same thing. Plants, temperature and drought did the same thing; smoking and alcohol is another factor that's been shown, and, more recently, just in the past year, a number of different forms of stress, particularly maternal stress, will actually promote this as well.

So, this is a large number of different types of environmental action. This has now been shown in plants, flies, worms, fish, rodents, pigs and humans. Therefore, it is very highly conserved, this is not a unique one-off just for a study of rats. It really has been shown in most species investigated. So this is a complicated graph, I'll explain it here. It turns out that the only cell that's going to pass any information to the next generation is a sperm or an egg. It has to be a germ cell, no other the cell in your body passes anything to the next generation on a molecular level. So, to show that this phenomena was induced by epigenetics, which we talked about earlier, we took the F3 generation's sperm, essentially, and look for epigenetic changes. This graph basically shows all the chromosomes, one through 20, and the size of those chromosomes.

This is a snapshot of the whole genome, all your DNA. Every single red arrow essentially is a differential methylation site. It's what we call an epi-mutation, and it's been induced as an abnormal differential methylation. So that's an epi-mutation, this particular signature here was induced by agricultural fungicide, in terms of epi-mutations. There were over 200 of them. This turned out to be an exposure-specific signature, in terms of where all these things are. Or you can also consider it a fingerprint of your ancestor's exposure that's being passed through the germline, for generations to come. So we did the same analysis and all those other factors we actually analyzed — plastics, DDT, jet fuel, pesticides.

You don't need to worry about this complicated graph. The only thing to pay attention to: Zero overlap. What this means is each exposure had a specific signature or fingerprint that was not overlapping with all the other ones. So, theoretically we have a diagnostic now to say what your great-grandmother was exposed to during pregnancy. Or what you're exposed to, and your're going to pass down to your grandkids. This could be a major advance for us in the field of environmental sciences. We also know, then, which diseases these are directly associated with.

Essentially, what I just described is an environmental factor, affecting the developing fetus during that time of development of the germline, the sperm or the egg, and the epigenetics got reprogrammed. As that individual became an adult and reproduced, in its germline it's passing altered epigenetics. Such that the next generation, the embryo, now has an altered epigenome. Every cell that's generated from the embryonic stem cell now has an altered epigenetics and an altered set of genes going up and down. Those tissues sensitive to that will develop disease, those that aren't, won't.  Basically, as this one reproduces amd goes to the next generation, it's the same phenomena, and this keeps going generationally. It is a non-genetic form of inheritance.

Just to show you one example. So, we did the exposure with DDT, and when the exposure was just this transient period of pregnancy for the F0 generation mother, then we bred for three generations both male and female lineage. What we found was there is a whole series of diseases in the F3 generation, but the most predominant disease turned out to be obesity. In the first generation, we did not see any obesity, but by the third generation, half the population, both males and females, had a susceptibility to develop a obesity.

This is called a susceptibility. This phenomena does not promote the disease, it promotes your susceptibility to develop disease. For example, if we had two individuals, one susceptible and one not, on exactly the same diet, exactly the same exercise, exactly the same living conditions, the one that's not susceptible wouldn't develop obesity but the one that is will. So this is truly a disease that there's a susceptibility for. Diet and exercise is absolutely critical for the onset of the disease, but your susceptibility to develop obesity potentially came from your ancestors.

This is a completely different way to think about where disease comes from. It also means what we're exposed to today is going to affect our progeny for generations to come. This is a very different way to think about, and a different mechanism, for how disease develops. What I just told you is that the environment has the ability to dramatically affect the epigenetics. This then influences how the DNA functions, in terms of what genes are on and off. These epimutations, these epigenetic epimutations, get put in place and become a permanent constituent of the DNA. This then causes this change in what genes are on off, and with organ systems, if it's a normal biology, then you're going to have normal biology going forward. If there's an abnormal expression and there's abnormal biology, you'll have a susceptibility to develop disease. Another consideration is this doesn't only affect disease etiology — you also have an increase in phenotypic variation.

Environmental epigenetics plays a significant role in evolution, which we hadn't considered before. It doesn't just affect disease, it affects all of biology.

The characteristics that the individuals have within a population are different. This has a direct impact on natural selection and evolution. Therefore, environmental epigenetics plays a significant role in evolution which we hadn't considered before. It doesn't just affect disease, it affects all of biology. Essentially, as I started out, these are those ancestral ghosts in your genome. These epimutations were put there by an environmental stressor.

Now, what I just talked about is a pretty doom-and-gloom situation. What your ancestors were exposed to is going to affect your disease, and what we're exposed to, likely a different set of contaminates, we're going to pass onto our grandkids as well. However, I'm going to give you the upside. Essentially knowing this phenomena exists, knowing that there's epimutations in your genome that may be exposure-specific, and directly correlated with disease, we can now use these as diagnostics for those past exposures, and potentially what disease you're going to get later in life.

Early in life, in your twenties, we could potentially analyze your epigenome, determine what your ancestors or you were exposed to early in life, and because of that, know what diseases you have a high susceptibility to get later in life. This allows us then to put into the whole thing called preventative medicine. We can do preventive therapeutics, preventative lifestyle changes and so forth to actually prevent the disease from ever developing. The reason we haven't done that yet is we've never had early-stage diagnostics. Genetics has not provided that to us today. Epigenetics gives us that capability.

We may not be able to fix it, but we definitely can treat it, and this would have a significant impact on future medicine and health of the population. That doesn't mean, at all, that we shouldn't clean up our environment. Get rid of these toxicants, get rid of these environmental factors. But, during the interim, we have actually a way to maybe treat the condition and help the health industry and our health care. Thank you.

Michael Skinner


Speaker Bio

Mark Skinner’s research is focused on the area of reproductive biology and environmental epigenetics. His current research has demonstrated the ability of environmental toxicants such as endocrine disruptors to promote epigenetic transgenerational inheritance of adult-onset disease phenotypes, due to abnormal germline epigenetic programming during gonadal development. This non-genetic form of inheritance has a role in disease etiology and areas such as evolution. Dr. Skinner established and was the founding director of the Washington State University and University of Idaho Center for Reproductive Biology (CRB) since its inception in 1996. Read more