Welcome back. This is the last module, module h of unit four. And in this module what I want to talk about is genetic regulation. And I think it's important for us in this course, even though this is not a course on molecular biology of course, it's a course on behavioral genetics. But it's important for us to recognize that our genomes are highly regulated. And I'm going to try to illustrate this, primarily at a conceptual level, by talking about Epigenetics. And it turns out actually in previous modules in this unit I've already given you two examples of genetic regulation. The first is X chromosome inactivation. In a female who has two X chromosomes sometime early in development, randomly in each cell, at that particular point in development, one of her chromosomes becomes inactive. And the chromosome X that becomes inactive in that cell is actually stably inactive. That is, every cell that derives from that initial cell will have the same X chromosome inactive. That's an example of genetic regulation of epigenetics, a term that I'll define here in a couple min, minutes. Now there's two things about that example that I want to emphasize. First it's, it occurs early. In the case of female X chromosome inactivation, that actually occurs within the first couple weeks of embryonic development. At that stage there are multiple cells of course and each cell randomly one of the two Xs, different in different cells obviously because its random, one of the X is inactive, becomes inactive. So it happens early, and secondly, it's stable. Once an X becomes inactive in a particular cell. All the cells that derive from that cell will have the same x inactive. The second example of genetic regulation we've had is imprinting. Recall that imprinting the gene expression depends upon the parent, the sex of the parent who transmitted the gene to you. Some genes are only expressed if you inherited them from your father. Other genes in the human genome are only expressed if you inherited them from your mother. Approximately 1% of our genes are differentially expressed or imprinted in this way. Again, this happens early in the case of imprinting, actually very early, in the production of the gamete cells. And secondly, it's stable. Throughout the lifespan of the organism, some genes are only expressed from the father's chromosome, others only expressed in the mother's. There's a third way of genetic reg, or a third example of genetic regulation that's actually much more fundamental than this, than these two. In every cell in our body, in every nucleus of every cell in our body, we have the same DNA. The same three billion base pairs of DNA. Yet our body is made up of many different types of cells. We have muscle cells, we have neurons, we have liver cells, we have kidney cells. So what makes a muscle cell different from a neuron or a neuron different from a muscle cell? Or a liver cell? What makes them different is their gene expression profile. An embryonic stem cell is a stem cell that has the potential to express any one of the 20,000 plus genes in the human genome. But again early in embryonic development those stem cells begin to what biologists call differentiate into different cell types. Some will become liver cells. Others become neurons. Others will become muscle cells. What differentiates a liver cell from a neuron are the genes that are expressed in the liver versus the neuron. Some of our 20,000 genes are actually expressed in every one of our cells. Other genes are only expressed in liver cells. Other genes only express in certain types of neurons, and that's what gives each one of these cells a different functionality. This happens early. It begins to happen within the first weak of embryonic development. And again it's stable. Cells that differentiate as muscle cells, don't all, all of a sudden start becoming neuron cells. They are stably muscle cells throughout our life span. So how does this differential genetic expression occur? What are the underlying mechanisms? What epigenetics is is the study of genetic regulation. Epigenetics means, literally, it's Greek for on top of the genes. And formally it, it refers to stable changes in gene expression that are due to differences, that are not due to differences in the DNA sequence itself. So it's something that is sitting on top of the sequence. Thus the term epigenetics. Now there are many processes or many epigenetic processes ongoing. And, and this is not, of course, on epigenetics. And I'd really, what I'd like to do in this particular topic is introduce conceptually the, the concept here of epigenetics. [SOUND] So how does epigenetic control come about at a conceptual level? Genes are packaged into chromosomes. Our DNA is packaged into our chromosomes. And again those chromosomes exist within the nucleus of every cell in our body. We have three billion base pairs of DNA and if you think about that that's a lot of DNA to be in every nucleus in our body. Wouldn't that take up a lot of space? If you stretched it out, in fact, if you stretched those 3 billion bases out, it would actually stretch out to be three meters long. And clearly, we don't have three meters in every nucleus in our cell. So the DNA's actually exist within a very compacted form in the nucleolus of the cell. It's compacted into these protein complexes. And it begins to unwind when the genes are transcribed. Many of the mechanisms of epigenetic control actually involve gaining access to that compacted DNA. If it's compacted it can't be transcribed. If it's unwound it can be transcribed and a gene product produced. There are multiple mechanisms of epigenetic regulation but the one we know most about is called DNA methylation. And for our purposes I think it does a good job of illustrating what people think about in terms of epigenetics. In DNA methylation, here's a, a little schematic of a gene. Here's the gene, here's the five prime end of the gene that we've talked about before. In many genes in our genome, upstream on five prime end of the gene, is what is called the promoter sequence, which we talked about as well. And in the promoter sequence of many of our genes, not all of them but many of them, there's a sequence of DNA called a CPG island. And what that means is it's the base cytogene, cytosine followed by guanine, and p just refors, refers to the bond between the C and the G. So in the promoter regions. Of many of our genes, we have CG repeated multiple times. Now it turns out, that these CG islands, these CpG islands, there's a possibility of adding a methyl group to the CG basis. When a methyl group is added to the CG basis, it actually blocks the transcription of the gene. In that case, the gene is said to be methylated. The gene is not transcribed, the gene product is not produced. If the gene is not methylated, those methyl groups are not attached to the promoter region, blocking the transcription. If it's unmethylated, the gene can be described and the gene product produced. So methylation is one way by which genes can become regulated. With the discovery of DNA methylation as an epigenetic mechanism came the question, well, we know from imprinting, from X chromosome inactivation, from cellular differentiation that these epigenetic phenomena occur early and they're stable over the life span of an organism. Could our experience, says or could, aspects of our environment actually change these basic epigenetic processes. What I'm going to do is actually go through three classic studies that illustrate that this indeed takes place. The first is the study that was published in 2000 by a researcher named Randy Jirtle at Duke University. And what Randy Jirtle was studying are what are called agouti mice. And an agouti mouse is a mouse that's has a ravenous appetite, so they overeat, they become obese. They become diabetic. And they have this orange yellow coat, coat color. It turns out that all these mice here are examples of agouti mice. They're actually genetic clones of one another. They're essentially monozygotic twins. This is the tepic, typical phenotypic presentation of an agouti mice. Obese, diabetic, orange-yellow coat color. But this mouse actually has exactly the same genotype as that mouse. How do they come to differ? Well, what Jirtle did is, he took the pregnant mouse dams, and he fed them diets that were rich with methyl groups. Methyl groups are conveyed by things like broccoli, or lentils. So he fed some of the mothers a high, a diet high in broccoli let's say. And others didn't give them a lot of methyl groups. The mothers that were fed a diet high in methyl groups. Ended up with mice offspring that looked like this. They didn't have the agouti coat color. They weren't, didn't have a ravenous appetite, so they weren't obese, and they weren't diabetic. The mothers here weren't given this methyl group rich diet. And they got the typical mouse offspring, agouti mouse offspring. What explains this? It turns out that in this case, giving the mother a diet rich in methyl, methyl groups ended up methylating the agouti gene in this mouse. Because it's methylated, the transcription machinery didn't have access to the, that gene, it wasn't transcribed. The gene product wasn't produced, the mouse didn't have the coat color, didn't have the appetite, and did not have obesity and diabetes. So maternal diet actually could lead to a change in methylation of this particular gene. That involves something that is not behavior, could there be similar examples of greater interest to us in this course? Behavioral phenotypes. Well in 2004, a research group from McGill University in Canada actually provided the first convincing demonstration of, of similar epigenetic phenomena in, in this case, rats and involving behavior. And this group is led a researcher, a neurobiologist, named Michael Meaney from McGill. And this is actually, it's a very interesting example, I think. It's based on an old observation in, psychology. When rat pups were removed from a mother, and maybe they were removed because they were put through an experiment, and then replaced with the mother,. When those rat pups grew up, they were found to be less anxious or less fearful rat pups. Somehow removing them from the mother early in life and it had to occur within the first two weeks of life, for some reason removing the rat pup at that time made the rat pup less anxious as an adult. What Michael Meany was able to show through a series of elegant physiological experiments, was that somehow removing the rat pup from the mother early in life, led to an increased density of a particular receptor in the hippocampus of the brains of these mice. The particular receptor is called the glucocorticoid receptor, which I've actually highlighted here and the glucocorticoid receptor in the hippocampus is actually involved in the stress response. So what Meany was able to show first, was removing the rat pup from the mother, actually somehow physiologically resulted in a greater density of glucocorticoid receptors, in the hippocampus, and that greater density of glucocorticoid receptors, ultimately led to them being less stress reactive as adults. But how did removing them lead to a greater density of this particular key receptor? That's what they were able to solve in 2004. What they showed in 2004, was that when the rat pups were removed, and then replaced. The gene that codes for the glucocorticoid receptor became demethylated. In normal rat development, the glucocorticoid receptor gene is methylated right at the time of birth. Methylated again, means that in the promoter region, these methyl groups are attached. Because they're attached, the transcription machinery can't gain access to the gene. The product, in this case, the glucorticoid receptor is not produced. So, in typical rat development, that gene is turned off, as it were, right at the time of birth, but when the rat pup was removed and placed back into the, the nest with the mother, the gene got turned back on, it became demethylated. And what Meany and his colleagues were able to show, is that, what actually led to the demethylation, was what the, wasn't so much the removal of the rat pup. But rather, what the mother did when the rat pup was reintroduced into the nest. The mother would lick and groom the rat pup and that licking and grooming by the mother actually turned on this gene, that ultimately led to them being less fearful as adults. A very interesting and convincing epigenetic illustration. So we've had an illustration of medical phenotypes in the Agouti mouse, and then behavioral phenotypes in a rat, but can we show similar phenomena in humans? The last classic study I'm going to talk about is indeed a study with humans. But unlike mice and rats, we can't do an experiment, right? We're not going to. Experimentally, start trying to add methyl groups to pregnant women. We have to take advantage of so called experiments of nature. And one classic experiment of nature is what's called the Dutch Hunger Winter study. So, a little bit of brief history here. Towards the end of World War II in the winter of 1944 to 1945, in retaliation for the resistance movement in Holland, the Germans embargoed food into the Western regions of Holland and, and that would be these regions here including Amsterdam and this was in retaliation to efforts by the resistance movement in Holland. What's more is that winter in 1944-1945 was particularly harsh. It was a very cold winter, the canals froze, there was very little food stuff. And people lived on very, very low diets. The typical person at the beginning of winter maybe was getting 1000 calories a day in terms of the ration. By the end of winter, only 500 calories a day. That's maybe one-fourth or one-fifth, what a typical person should get on a daily basis. So there's a very strong famine that was going on. And of course, as a, as a consequence of that, there was increased mortality. Individuals who were in utero during this Hunger Winter have been followed up for 70 plus years to try to understand what the impact of internal malnourishment is on their development. And so, I'm going to be talking here about those individuals who were in utero during this Hunger Winter and what were the consequences of having your mother starve during the time that you were in utero. Well, the first thing is that actually in many regards, these individuals did quite well. There are no effects on IQ, no effects on blood pressure. No effect's on women's fertility. There are no effects on many variables that this research group studied as they followed these people over the 70 years. But there is somethings that they did showed differences on. They had higher body mass index or they had higher rates of obesity. They had disrupted glucose metabolism, they even had higher risks of schizophrenia. It turned out that what they observed in adulthood here, increased rates of obesity, disruption of the glucose metabolism. Really applied to only a subset of the individuals in utero during that Hunger Winter. It was the subset that experienced malnourishment in the very early stages of embryonic development. If you only experience malnourishment at the late stages of fetal development just before you were born, what ended up happening is you, you'd, you were born with a low birth rate, but you didn't really have many long-term consequences. It was only those individuals that were experienced the malnourishment at the very early stages of embryonic development that experienced these long-term consequences that I've highlighted here. It turns out that those individuals in follow up studies and I'm not going to go into detail about these studies, but suffice it to say that what's been shown is that in fact and consistent with this notion that there are these effects on early gestational period is that they had disrupted methylation of some key genes in the metabolic pathways. Some genes were methylated that weren't normally methylated. Other genes were demethylated. Probably accounting for at least the increased risk of obesity. The increased disruption of glucose metabolism. And maybe even schizophrenia, although that's much more speculative. This brings us to the end of Unit number Four and what we've done in Unit Four are three things. One is I'm trying to be, build for us a vocabulary of genetic terms. Genetic principles, genetic mechanisms that we're now going to begin to start applying to behavioral phenotypes. In the next unit, we'll be taking up schizophrenia. Later, general cognitive ability. Secondly, it, I think is a fundamental importance for us in this course that we have an understanding at least at the conceptual level not as molecular biologists of what genes are. What they do and importantly, how they are regulated by our environments. And then finally, something that we definitely will build on later in the course, understanding how we come to differ from one another genetically. In what ways do we genetically differ? Sometimes, it just in a single basis. Other times, it's in much larger sequences of DNA that might be deleted or duplicated in our genome. I do have a supplementary lecture in this particular module, well, I'll take up Epigenetic inheritance. Thank you. [SOUND]
