[MUSIC] This module will discuss various patterns of inheritance of what we call Mendelian diseases. The diseases that we use the name Mendelian to honor Gregor Mendel, the monk who did his pea experiments and described the rules of inheritance for these kinds of diseases. The diseases that are rare and that run in families. One fabulous example of an inherited disease is shown by the British Royal Family. This is a family tree of Queen Victoria, the elderly woman in the picture. And she's shown with her favorite daughter, Princess Beatrice, who is way over on this side of the family tree, married to the Prince of Battenberg. Now, Queen Victoria, herself, was healthy, and Princess Beatrix was healthy. But you'll notice that many members of her family, and they're all males, indicated by the male symbol, have a disease. And we'll come back what that disease was in a moment, and how it is that this particular disease effected multiple members of the royal family. Most famously the, Prince Nicoli who died at the age of 14. He didn't die of hemophilia, he died because he was shot in 1917. Interestingly Queen Victoria has another disease in her family. On this family tree she's shown at the bottom. At Queen Victoria, you can see on the bottom, and several generations up is King George III. Mad King George III. Who is thought to have a disease called porphyria, another genetic disease. And Porphyria, one of the characteristics is that people don't think straight. They get mad, they get crazy. And it's thought that during one of his episodes of madness, he managed to give away the United States and allow the United States to become independent of Great Britain. It's a geneticist's view of history. So, one of the key features of creating an understanding of these diseases that run in families that run across generations that are relatively rare is to construct the family tree. And so a family tree might be constructed this way, the squares are male, the circles are females. And their very symbols that can be inserted into those a male and female symbols to indicate for example who is affected and who's not affected. Who is alive, who is dead. Who has a mild disease, who has a severe disease. So you can see that each one of these family trees start with the a set of parents, four children, two of them marry, each one of them has two children. Those children then in turn have between three and four children each. So that's a family tree. And here's a pattern of inheritance, which is pretty typical of one of these relatively rare diseases. An affected parent, several affected children. Each child that's affected has the chance of having an affected child themselves. So the rules in this particular family tree are that males can transmit the disease to females across generations. Females can transmit the disease to males across generations. Both sexes are affected in approximately equal numbers. Approximately half of the offspring of an affected person has the disease. So this is a disease, this is a pattern that we call autosomal dominant. Autosomal means that it's transmitted in one of the 22 autosomes, not the sex chromosomes. And dominant means that a single copy of an abnormal gene will transmit the disease. So this is the way it looks in a reduced family tree. The affected parent has a chromosome that carries an affected gene. I've colored the chromosome in red. But remember, the chromosome has thousands of genes and only one of those genes is abnormal. It might be abnormal at a single nucleotide, but I've colored it in red just to indicate the one that carries the abnormality. The grey ones are normal. So when the egg and the sperm from this set of parents come together to generate a new fertilized egg that will generate a child, they can do it in one of two ways. They can generate an abnormal chromosome from the mother and a normal chromosome from the father, resulting in a child that has the genetic abnormality. Or they can do it in a way that the normal chromosome from the mother and the normal chromosome from the father come together to generate a child who does carry the genetic abnormality. So in this way you can see that there are four possibilities, and they're shown here. So about 50% of the offspring, on average, because this is a chance event each time a fertilized egg is generated. On average, half of the children will develop will carry the abnormality and may develop the disease. So we often abbreviate this as B would be the the normal gene, and little b in red would be the abnormal gene. So we can go back to the large family tree now and assign what we call a genotype to each one of the family members. So there are a couple of important features here. First again, females transmit to males, males transmit to females. About 50% of the offspring of a carrier individual are also carriers. There are no individuals who are offspring of normal individuals who carry the disease. So everybody on that side of the family tree, the descendant of the mother who is not a carrier, none of those individuals have the disease. Occasionally, and actually it turns out far more than occasionally, you'll get a situation like this, in which the family tree looks just about the same as before, but now there's one person who doesn't seem to have the disease. I've colored everybody in red who has the disease. That person does not have the disease. That can arise from a number of different mechanisms that we'll talk about those in subsequent modules but that's called variable penetrance. That means that not every single person who has the genetic abnormality will necessarily get the disease. And of course it complicates interpretation of a family tree like this, because you have to scratch your head an say, well what would happen if. Now that we have genetic testing, we can actually establish that this person is actually a gene carrier, a mutation carrier, and transmitted the disease. This person, in this family, if we know what the disease is we would say this mother is an obligate mutation carrier. She has to carry the mutation in order for her children to have developed the disease that her father had. Here are two examples of diseases that are transmitted in autosomal dominant fashion. I've mentioned both of these before. The familial example, the familial hypercholesterolemia, where a single genetic abnormality, often in the LDL receptor is sufficient to result in very, very high concentrations of LDL cholesterol. In the extreme form a person will actually have more than one abnormality that results in the extreme extreme form of familial hypercholesterolemia. Those are children who will get heart attacks when they're 10 years old. That's extremely unusual, but it's quite common to see people with LDL cholesterol levels that are very, very high and make them susceptible to early heart attacks. Marfan syndrome is the other example, again, a single base pair change in the DNA is sufficient to alter the structure and function of the fibrillin protein to result in this particular disease, which again can be lethal because of the aortic root problem. But here's another inheritance pattern and it doesn't look like autosomal dominant does it? Because the only infected individuals on this family tree are males. So the problem here is that this is what's called a sex link disease and it's transmitted on the sex chromosomes. The abnormality is actually on the X chromosome. And the X chromosome carries an abnormality that results in disruption of the function of a particular gene that's carried on the X chromosome. Now, the mother does not have the disease because she has a normal copy of the X chromosome. The father in this particular family tree doesn't have the disease because he has a normal X chromosome. But when they generate fertilized eggs, sometimes the mother will donate her abnormal X chromosome, the father will donate his normal Y chromosome. That generates a male child who does not have any normal X chromosome, and therefore will get the disease. The other possibility is that you generate a carrier child by transmitting the abnormal X chromosome, and the normal X from the mother, and the normal X chromosome from the father. So again, there are four different ways in which these combinations can arise on average. And on average, one of those, the male children will be 50/50 affected. The female children, half of them will not be carriers, and half of them will be carriers. And this, of course, is the problem in this particular family tree. Queen Victoria and her daughter were carriers of the hemophilia mutation. So they don't have the disease, but they transmit the disease hemophilia across generations to their male offspring. And that's a well recognized X linked disease. Here's another example, and in this example, this is sort of an extreme example, the pattern looks like it might be autosomal dominant. But look at the first generation, everybody is affected, and then all of the mothers transmit to their sons and daughters. All the daughters transmit to all of their children, but the sons never transmit. So this is not a problem of the X chromosome. This is not a problem of an autosome. This is a problem of the mitochondrial DNA. The piece of DNA that is exclusive to the mothers. So the mother transmits her mitochondrial DNA to each of her children. The males of course don't transmit their mitochondrial DNA because the mitochondrial DNA that their children get come from their wives, come from the female parent. So, this is a pattern that looks like it's mitochondrial inheritance. And here's the final pattern that I want to talk about, and this is an isolated individual who comes from two separate family trees. You can see that there are two separate family trees. The parents are unrelated in this particular case. So, the problem here is that each parent carries an abnormal gene, but the presence of a single abnormal gene is insufficient to produce a disease. So they don't know, they look normal, they feel normal, and they, in fact, generally look pretty close to normal. Although with sophisticated testing, sometimes we can detect subtle abnormalities in the parents. But one time in four, the parents will manage to transmit an abnormal gene from both mom and dad to the child. So the child now has two abnormal genes and disrupted function of that whatever protein it is that, that gene encodes and that in turn results in a disease. 50% of the offspring are carriers and so they can transmit the subsequent generations if they mate with someone who's also a carrier. And then one child in four does not inherit the mutation. The problem here is interesting because the chances of this happening depend on two individuals coming together to generate a child which has two abnormalities. The chances of that happening are increased when the parents are related to each other. So if families share genetic material, then the chances of cousins or second cousins generating this kind of inheritance pattern is greater than two random individuals. So for this to happen, either the parents are related or the carrier state is extremely common across the population. So the two diseases that are the hallmarks of this particular inheritance pattern, which is called autosomal recessive. Meaning, you have to have two copies of the abnormal gene to generated a cystic fibrosis and sickle cell disease. 1 in 30 white people of Northern European extraction carry the cystic fibrosis a cystic fibrosis mutation. When we do the math, that means 1 in 30 fathers and 1 in 30 mothers. The chances of those finding each other and mating by chance, or 1 in 900, and 1 in 4 of those matings will result in a child with cystic fibrosis. That's 1 in 3600. So 1 in 3600 is pretty common, but it belies the fact that this carrier state is extremely common, 1 in 30. And the same holds true or African populations where the sickle cell trait is 1 in 25 or 1 in 30. Again, resulting in a high burden of sickle cell disease, but that reflects a very high burden of carrying the sickle cell trait. And of course, remember we talked about Mendel. And Mendel's original observation in the peas was that smooth peas and wrinkled peas appear at a ratio of 3:1. And the mechanism is exactly the same. The wrinkled pea characteristic is recessive. That pea plant has to inherit an abnormal gene from mom and an abnormal gene from Dad. And among those three normal pea plants, two of them are what we call heterozygous. They carry one admirable gene and they carry one normal gene, and one of them is homozygous for the normal gene function. So, the problem that we run into in contemporary genetics, is two fold. One of them is these Mendelian diseases. Sickle cell disease. Cystic fibrosis. Many heart diseases. Many forms of abnormalities that are transmitted from parents to children. But increasingly we're recognizing that there are families in which certain kinds of diseases run, and we're confused sometimes about the way in which these are inherited. Part of the confusion arises because of this problem of variable penetrates that I discussed before. That not every single person who carries an abnormality of the gene, a mutation, will not necessarily develop the disease. So, here's a problem for the physician in the office. The woman in red comes to you and says, my father just died of stomach cancer. Should I be concerned that I am going to have stomach cancer? The usual answer might have been, well, why would you even think that? You're paranoid. But in the 21st century, we have to start to think about conditions that run across families which may be harder to recognize. So a clever physician might take a family history. A family history here might include for example an aunt who has uterine cancer. Well, you sort of say, well uterine cancer and stomach cancer those are two kinds of cancers, maybe they're related, maybe not. And then you start to look at the other rest of the family. And the grandfather has polyps in his colon, but he doesn't have cancer. Is that a syndrome or not? Well it turns out this kind of collection of diseases is very typical for a disease called Lynch syndrome, which is known to be genetic and has many different manifestations. Colon polyps, uterine cancer, stomach cancer. So this woman is correct to be concerned, and there's actually now testing available to see whether she has Lynch syndrome and therefore needs to extra supervision in her life to see whether she's developing certain forms of cancer. The same kind of thing might happen in this family. This man comes to you and says, my father died of a heart attack when he was 42, should I be concerned? You take the family history, there's a stroke, there's a leg amputation, and you start to put it together and that signifies severe disease of the arteries of the body. Not just the heart but of the brain and of the legs. And that, in turn, suggests that this person might have a disease like familial hypercholesterolemia anemia and suggests certain kinds of genetic or other testing they should have. So I think one of the areas in personalized medicine that we're going to have to start focusing on, is getting family histories right. And that in fact, requires engagement of families. A family has to be able to look back at their own relatives, to ask their own relatives, what is it that grandaddy died of? What is it that his father died of? And construct these family trees. And so that's going to be an important component of medicine going forward. Not just for Mendelian diseases, but diseases like this which turn out to be quite common and run in families. And the genetics will tell us something about risk and may tell us something about treatment. There are tools. This is one that's on the web available from the US Surgeon General that allow families to start to construct their own family trees. And I think that's going to an increasing part of a medical practice as we move into a era. The power of empowering yourself by knowing what your family history is. [SOUND] >> [APPLAUSE]
