Welcome back. This is module I, it's a supplementary module, again where we explore in greater depth some maybe more advanced topics. This would be the last module for Unit 4, then. In this case, what I want to talk about is Epigenetic Inheritance, and I'm going to make clear, hopefully, in a couple of minutes what I mean by Epigenetic Inheritance. But recall from our discussion about Epigenetics, first of all, what we mean by Epigenetics, or what geneticists mean by Epigenetics. Stable changes in gene expression that are not due to the sequence of DNA an individual has. We had multiple examples of Epigenetic phenomena. Some of these so called "Programmed" epigenetic processes. These are things like program they, they naturally occur in organism development. Things like X chromosome inactivation, imprinting, cellular differentiation. These are things that occur early in development and their stable over the lifetime of an organism. But we also talked about exogenous factors, environmental factors can, that can in some ways change those epigenetic marks that are set down early in development. We had the example of the agouti mice, where the mothers were fed a diet rich in methyl groups that actually affected whether or not the offspring expressed a gene associated with obesity and diabetes. The example from the Dutch hunger winter study where maternal malnutrition was associated with increased obesity in adulthood. And probably because of changes in epigenetic markings or methylation of key genes in metabolic pathways. And finally, we have the example of with the rats of how maternal licking and maternal care of a pup when reintroduced in to the nest, actually activated a gene the glucocoticory receptor gene that, ultimately allowed the rat pup to develop in to a less stress reactive adult. In talking about epigenetic inheritance, I wana focus in on this notion of stable. Up to this point our discussion of epigenetics has emphasized stability across the lifespan of a particular organism or another way of stating that, stability across mitosis. The same X chromosomes is inactivated in every daughter cell. From the original cell in which the X was inactivated. That's stable across mitosis, an interesting question to ask is, okay, these epigenetic phenomena can be stable. They can be disrupted, of course, and that's what we've talked about here as well, but they're relatively stable in the lifetime of an individual. But can they actually also be stable across generations? Can we transmit epigenetic marks from one generation to the next? Is there epigenetic inheritance? Many of you have probably heard of the botanist, the French botanist early 19th century named Jean Lamarck. Jean Lamarck developed a theory of inheritance called the Inheritance of Acquired Characteristics. For many, many, many years, certainly throughout much of the 29th century Jean Lamarck's work was a source of, or target really of derision. Biologists made fun of Lamarckian inheritance. It seemed rather silly. How did Lamarck talk about the, Inheritance of Acquired Characteristics? I'll give you one example, the Lamarckian giraffe. And, these examples of course, have a little bit of a Rudyard Kipling type of flavor to them, the just so stories. How did the giraffe gets its long neck? Well, from Lamarck's perspective a rat, a giraffe didn't originally have a long neck, it had a short neck. But though constant though, through its own conscious will, in wanting to get access to those yummy leaves, on the, on the tree, what it did is it stretched out its neck. And it stretched out its neck and then it was able to transmit that stretched out neck to the next generation. That giraffe also stretched out its neck, transmitting it to the next generation and so on and so forth. So we're multiple generation. We get a giraffe with a long neck because successive generations of giraffes have stretched their necks in order to get the leaves. This long neck, an acquired characteristic was transmitted from one generation to the next. Lamarckian, in, inheritance was totally discarded with the discovery of Mendel's laws. But has actually had a rebirth over the last 10 to 15 years. As people have begun to think about epigenetic, the possibility of epigenetic inheritance. Lamarck didn't know about epigenetics, but had he hit on something that we would understand 200 years after Lamarck? Again, I'm going to talk with you about a couple of classic studies that tend to support that there may be some forms of Lamarckian inheritance. And the first is a study of, of humans and I'm going to mispronounce this. Maybe our, if there are any Swedish students participating in this course they can help and correct me. But I'm assuming it's something like Overkalix, I guess, Sweden. Overkalix is a small town in Northern Sweden. It's way up here and Stockholm is down here somewhere. It's actually a small rural parish in Northern Sweden, but one of the things about this region of Sweden is they kept very good excellent records of the harvest. And they did that over many, many years in fact they had very records during the 19th century. And during the 19th century when, when researchers went back and looked at those records. What they found is that sometimes the harvest was bountiful and the individuals living then would have plenty of food to eat, but other times they experience essentially a famine, there was no harvest they, they went the winter hungry. So they went through periods of famine and bounty through out the 19th century, and the researchers could carefully chronicle this. Now there have been multiple studies on the descendants of individuals from the 19th century of this region of Sweden, but I'm going to focus on one. Because it's often cited as, an example that began to pique people's interests about the possibility of epigenetic inheritance. They're not actually going to show anything epigenetic here, but what they're going to show is, what you're relatives experienced back in the 19th century might actually effect something happening in the 20th century. I'm going to look at just one phenotype, it's a little bit of a complicated graph, but hopefully I'll be able to explain it to you. What these researchers here did back in 2006 is they looked at the grandchildren of individuals from the 19th century in Sweden. Again, Sweden has not only excellent records of the harvest, but excellent records of their population so they can track them over time. And they could find periods where the grandparents had access to a very ample food supply and that's actually graphed here in red, as well as periods where the grandparents had a very poor food supply. What's plotted here is essentially the relative rate of mortality in their grandchildren, actually these are the grandsons. In the grandsons. Of the paternal grandparents as a function of whether or not they had a lot of food or little food. And the point that I want to emphasize here and it really just to illustrate why this study is considered a classic is that if the grandparents had a lot of food in this particular time of their life, it's actually a period just prior to puberty. If there was access to a lot of food, actually, their grandsons experienced an elevated rate of mortality. They lived a shorter period of time in the early 20th century. That happened with the grandsons. It also happened with the granddaughters. Here's the granddaughters here, and here, you see again, if, if the, if the line is above one here, that means excess mortality. So, if the grandparents had a lot of food, actually their granddaughters and their grandsons experience excess mortality. But really only if they had a lot of food in this particular period of life, just prior to puberty. It turns out, and I'm not going to get into this, it turns out that this is only true of the paternal line. It's not true of the maternal line, as well. It's true of both grandsons and granddaughters, but it actually is only transmitted paternally. It, it, I don't want to go, it gets a little bit complicated to talk about why paternal versus maternal. But just leave it. To conclude here, what the researchers concluded is, how do you explain these grandparent effects. And, what they offered back in 2006, without really a lot of evidence, is that, m, maybe what was happening is that there maybe was some biological tag that was being passed down. Across generations, such that if you're over ate at this particular period of life, it maybe changed some epigenetic phenomena. And that epigenetic phenomena was transmitted to your children, to their children, and maybe to even your grandchildren, and that's why they experience an excess rate of mortality. It set off the research field to begin to look at these potential grandparent effects. And they speculated that it might be epigenetic. But can we really show their differences in epigenetic tags? In order to do that I'm going to talk about one additional study that actually is an experiment that experimentally looks at inheritance across multiple generations to see whether or not it could be accounted for epigenetically. Before doing that, I think it's important to recognize that there has to be some epigenetic reprogramming going on in the development of an organism. Right? An organism is created when a sperm cell and an egg cell come together and produces an embryo. But clearly, a sperm cell has an epigenetic profile that's different from an egg cell and when they come together right the cells are going to derive from that embryo are going to have all different types of gene expression patterns. They're not just germ cells. So there has to be something that translates these initial germ cells into all these other cell type that comprise an organism's body. There has to be some embry epigenetic reprogramming in early embryonic development. And if there is epigenetic inheritance, somehow it has to survive this epigenetic reprogramming. So when does the reprogramming occur? It's illustrated here. These are the days past conception in embryo age. It turns out that after the embryo is created, early in embryo development, within days the genes become demethylated. So this is just the level of methylation, so by about four days. There's global demetholation. So all those epigenetic marks that make a sperm cell, an egg cell different from every other cell, they're stripped off within the first four days of embryonic development. And then the cells are reprogrammed given different epigenetic marks. So eventually they could differentiate into different things like neurons and muscle cells and whatnot. In order for there to be epigenetic inheritance, those epigenetic marks that are being transmitted, or thought to be transmitted in this Swedish study, from the grandparents to their children, to their children's children. Have to survive this particular reprogramming event. We do know that some epigenetic marks do survive this. We know that because of imprinting. Imprinting has to survive this in some way. But could it happen more generally. So the second experiment I'm going to talk about is actually done with mice. And it's a study done by, Carrie Ressler and his colleagues at Emory University. It was actually published very recently. And what they did is actually a very intriguing study, very provocative study. They took male mice and they conditioned them to a certain odor. They conditioned them by pairing that odor, the presentation of that odor with a shock, a mild shock. It wasn't harmful but it was just uncomfortable. So what ends up happening, right? You pair the odor with the shock, the mouse learns to fear the odor, right? It's a classical conditioning. They then took those male mouse, mice. And they breed them with a female mouse that, that wasn't conditioned in this way and then they looked at their offspring. Their, in this case, their male offspring. They presented the odor without actually conditioning that odor, the same odor that their father was conditioned to, they actually presented the mice with that odor. And when they presented the mouse with the odor, they actually showed a fear response, what's called a startle response to the odor. Showing that they were already understood that there was something about that odor that they should fear. But they were never conditioned to the odor, their father was conditioned. And again, when they took these mice and bred them and produced a third generation here, the grandchildren, again, when they presented these grandchildren with this odor, they again showed a, an increased fear response, an increased startled response. They knew it was this odor because they could present them with different odors and they didn't show the heightened fear response. So somehow what the grandfather learned, the pairing of the odor with the fearful response, was actually being transmitted to its offspring. And what these researchers speculate is the only way that could be transmitted is somehow what this individual passed on in his germ cells to his offspring somehow in that germ cell there was an epigenetic tag that effected how their children would react to the odor. There was pre-conditioning of this learned response. And I recommend if, if you're really interested, there's a, a fascinating article published in a, a top journal, Nature Neuroscience in 2014. Go read the article. It's a, it's a very, very interesting phenomena. And they speculate about the evolutionary adaptive value of, of learning, of the transmission of learning in this way; that maybe if your grandfather learned to pair certain odors with fear that that would provide a mechanism to protect you later on because the same odor might be a signal of something that you should fear. But apparently, there was not just epigenetic effects within the lifespan of the organism, but apparently epigenetic effects that are transmitted from one generation to the next. Right now, on the field, it's hotly debated how broad. Are these epigenetic inherited effects. Is it just a rare phenomenon that can be explained in this way or is it much more general? Is it really a rival pattern of inheritance that rivals medallion inheritance? Today, we don't know. But we are beginning to learn that in some cases, it does appear to depend. Your functioning appears to depend on some ways on what your grandparents experienced. Their diet maybe, whether or not they experienced poverty or abuse is perhaps going to affect how you function psychologically, because of epigenetics. [SOUND] So, one last thing I wanted to, before leaving this module, one last thing I wanted briefly talk about. It's actually not epigenetic effects or epigenetic inheritance, but it does deal with epigenetics and something we'll come back to later. And I'd just like to introduce it for the first time here. There's a lot of research on epigenetic and twins. In particular, epigenetic and monozygotic, m z twins. And the reason for this is that and we've talked about this a little bit already and we'll continue to talk about it in the course, when you look at psychological traits or psychiatric phenotypes. All right. They're all heritable to some degree, but never are monozygotic twins, even though they're genetic identical, they're never psychiatrically the same. They're never psychologically the same. They're frequently discordant for disorders like schizophrenia or autism or ADHD or bipolar disorder. They differ on quantitative traits like general cognitive ability. They also monozygotic twins, as they get older, actually begin to show different patterns of aging. And, and try to understand why it is monozygotic twins, despite their identical genome. Come to differ in later life, be it for a psychiatric disorder or in their personalities or their abilities or in how the age. Geneticists have begun to speculate, well, maybe it's because of epigenetic phenomenon. They have the same genome, but they don't have the same epigenome. Maybe their epigenetics actually changes. And that, the last study I'll talk about in this regard is the classic study that was published, I guess 2005 by a Spanish group headed by. And this is just a particular picture from their study. What they did, they did is they studied global epigenetic methylation in monozygotic twins. Here happens to be what they found on chromosome 17. They studied all the chromosomes. These are a pair of, right we each have two, two chromosome 17s. So these are the two pairs of chromosome 17s from monozygotic twins. And that they're lighting up yellow means that the methylation pattern was virtually the same for both members of the monozygotic twin pair at age three. So that the yellow just means there's an equal balance across the two members of the twin pair. Here's a second pair of monozygotic twins in this case their 50 years old. In this case, the two chromosomes 17s aren't all yellow. One of the twins, if it's green it means one twin was more methylated in that region of chromosome 17 than the other. And if it's red, then that same twin was less methylated in that region of 17. But the important thing to note here is that as they got older, all the sudden, differences in methylation patterns emerged. At age three, the two twins are not only genetically identical, but they have basically the same epigenome. By the time they're 50, they accumulated a whole set of experiences that differentiated one monozygotic twin from the other. And apparently, those different experiences actually effect different parents of methylation. So perhaps, some of these anomalous observations that genetically identical individuals can be discordant for genetically inherited disorders, like schizophrenia and autism may actually be due to not differences in the sequence. Obviously, it can't be, because they're genetically identical. But perhaps, differences in the epigenome. That really brings us to the end of our discussion of epigenetics. Epigenetics is an area that's really taking off in human genetics and in behavioral genetics today. What I tried to do in these two lectures on epigenetics is just to give you a flavor for why people are very excited about this area of research. There's not a lot of findings. We've looked at some classic studies here, but there are not an overwhelming number of findings at this time. What studies that are out there though, I hope you agree with me. They're very provocative. They're very suggestive that indeed over the next ten years, we have a lot to learn from epigenetics. Thank you. [SOUND]
