Biology: Pleiotropy: Multiple Phenotypic Effects

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You know, if you think about the fact that in a polygenic situation, multiple genes can affect one trait; you're probably using your intuition to say, well, then there must be situations where one gene can affect many traits. Or maybe that's counterintuitive. Because, if you think about it, you know, I've been kind of on this bandwagon; genes get expressed. Well then, how can the expression of one gene, therefore one protein, cause a multitude of effects. Boy, can it! And I want to talk to you today, now, about pleiotropy. What is pleiotropy? Pleiotropy is what I just described. When the expression of one gene has multiple phenotypic effects. And sadly, our best examples of this are in human genetic disorders, multiple phenotypic effects. And the one I want to use is a human genetic disorder called sickle cell anemia. Sickle cell anemia is a very powerful one to use because it has an unbelievable number of sad effects to those that are completely effected by it.
A quick review of sickle cell anemia. Sickle cell anemia runs in--the disease is in 1 in 400 people of African American descent and what it is caused by is a defective hemoglobin gene. Now the hemoglobin gene, let's say is H. That would be a normal hemoglobin. So if you have a normal hemoglobin gene, you're going to express normal hemoglobin and even if you are recessive, but hybrid or heterozygote, you're going to be phenotypically normal. However, someone who is hh does not make any normal hemoglobin and in making no normal hemoglobin, ends up with a changed hemoglobin molecule and that hemoglobin molecule causes the entire red blood cell--because remember hemoglobin is a protein in red blood cells. It causes that entire hemoglobin to twist or sickle. And that is the primary effect of the genotype. A defective hemoglobin protein, but it's pleiotropic. Because, you see, there are what you and I call in terms of human medicine, symptoms of this disease, but as geneticists, they are pleiotropic effects.
What are some of those pleiotropic effects? Well, let's take a look. All right, so if we have an individual who is homozygous for the sickle cell allele and they make, therefore, sickle cell abnormal hemoglobin, here's what their blood cells look like. And you can see there's one that's maybe a little bit closer to normal shaped, but they have these twisted convoluted shapes, which create a host of pleiotropic effects.
All right. Let's take a look at one of them. First of all, one of the things that happens is that as these blood cells pass through the spleen, they accumulate. They literally get clogged up in the spleen and, as you know, the spleen is an organ that is unbelievably important in the immune system. So it literally--one effect of the sickle cell is just an overall physical weakness, but that's not all. Another thing that happens is it causes the red blood cells to be much more fragile. And so we get this breakdown of red blood cells, thus it's an anemia. There's not enough oxygen carrying capacity of the red blood cells. And so, because there's an anemia, it can cause in some situations, not all, impaired mental functions, literally starvation of neurons. Because of the breakdown of red blood cells, it can cause heart failure. Because of the breakdown of red blood cells, it can cause physical weakness also. So again, a multi-symptomic pleiotropic effect for one, and there's still more.
Because, and this one has the most far ranging effects, because of the clumping of the cells, it causes blood vessels to clog. And look at all of this that this can cause. Because then in those capillaries, the red blood cells literally clog up and hook onto each other. The sickle shapes causing heart failure, causing pains in their joints, causing again the possible neuronal disturbances, neurons from brain damage and even paralysis. It can cause damage to other organs. It can cause kidney damage. It can cause pneumonia and other infections. This is joint pain. This is a horrible disease and many of you probably know, or yourselves, have sickle cell anemia. The good news is we've made enormous medical progress on this. However, it will not go away. It is a genetic disorder carried by that h.
A lot of human genetic disorders are multi-symptomatic, if you will. And I want to talk to you a little bit about human genetic disorders and twist them a little bit to get them to fit into this pleiotropic model, but even more importantly, let's just take a look at some of these disorders because you guys are really well versed by now on this whole idea of DNA makes RNA, RNA makes protein, therefore, we have an expressivity thing.
All right. Well, one of the things that is very common is this idea of lethal recessives. Now I'm talking about disorders now. Lethal recessives are a group of diseases, disorders, diseases that can cause death without medical care. Now we spend billions of dollars fighting these diseases and trying to keep people alive with these, but in a condition without medical care, these diseases are lethal. For example, one that's very common in people of white European descent is cystic fibrosis; CF. Cystic fibrosis is a genetic disease. It runs in about 1 in 2500 people of white European descent. What it is is a protein problem. See, proteins? O.K.? And what happens is this. It's a problem in transporting. This is a cell. It's a problem with chloride ion transport. And it's a problem with osmosis. And what happens is because of this buildup of chloride ions, you get a mucous build up. And you get a mucous buildup in your lungs. You get a mucous buildup in many of your organs, your pancreas. It's pleiotropic in that sense because the mucous buildup is throughout all of your organs and, indeed, eventually can cause death. Cystic fibrosis is a lethal recessive disease.
Another one is one that is particularly prevalent in people of Eastern European Jewish descent or Askenazic Jews. Jewish people from Central Europe have this disease, this disorder that runs in their gene pool called Tay-sachs syndrome. You probably know a little bit about Tay-sachs. Tay-sachs is another one of those genetic disorders that are caused by a protein malfunction. It's a recessive gene. It's a protein that breaks down lipids in the lysosomes or its protein that's a lipid breakdown protein found in the lysosomes of brain cells. This particular protein, if it doesn't break down lipids, what happens is you get a lipid buildup eventually and it takes place in your nervous system, eventually leading to complete organ breakdown. You lose your breathing capacity, you become paralyzed, again, kind of pleiotropic. Now, you know, one of the things I want to stop and say is why do things tend to run in ethnic groups?
Well, this comes from the whole idea of the fact that ethnic groups until very, very genetically recent times, the past several hundred years, were isolated. Think about it. There's this whole idea of the fact that people in Eastern Europe generally stayed home because there were no airplanes and boats and therefore, their gene pool was limited. And that's why you get genetic disorders that run in races, that run in families, that run in areas because people tended, before the days of rapid transport, tended to marry people within their region. And so if there was a defective gene in a country, in a region, in a race, it stayed propagated. I am just so curious to see what's going to happen in thousands of years to the frequency of these genes in our populations as we get more inter-racial and more inter-area and cross religious marriages. You predict. You can figure that one out.
One last thing. If we're going to talk about human disorders, let's just make some generalizations, because I've been talking about the expression of genes. There's two things I want to tell you. Actually, there's three things I want to tell you. The first thing is this. Generally speaking, if the disorder or if the mutation of a gene, the idea of a gene not working, is in a functional enzyme, if it's enzymatic, that tends to be recessive. Can you see why? Or a protein. If it's a functional protein, and it doesn't necessarily have to be an enzyme. For example, hemoglobin is not an enzyme. If it's a functional protein, then it's generally going to be recessive. Here's why. Look at hemoglobin. Hh, you get a dose of normal and in more cases than not, that's sufficient to make you phenotypically not have the disorder, not have the disease. O.K. On the other hand, if the mutation is in a structural protein, think about that. If it's a structural protein, like achondroplastic dwarfism, that's a cartilage problem. What happens in that situation is this. In that case, D is a defective gene. And what happens to someone who is Dd, is they lack some structural protein. So they don't have normal growth. And if they don't have normal growth, we call that having the syndrome of achondroplasia. And, in fact, what I've told you that that was a lethal dominant, which is pretty rare, but nevertheless it's there; this particular one in its DD stage is lethal. Now some genes are lethal even in the Dd stage. Any of you know the singer, Woody Guthrie? He had a lethal dominant gene and this one comes up later in life. You see, most lethal dominant genes, you don't even know you have them because you die from them. But Huntington's disease, we'll use another one for that, Hh. Huntington's disease is a lethal dominant and it kills you at about 40 years of age, a nervous system breakdown. And so that's a lethal dominant gene. So, you know, I don't want to ruin your day here talking about all these horrible diseases, but the bottom line is, they're disorders, more than they're diseases. They're something not ordered in the enzyme, in the protein. And if you go back to that whole idea, you can understand Mendelian genetics, if you just understand molecular genetics.
Mendelian Genetics and Mutation
Inheritance Patterns
Pleiotropy: Multiple Phenotypic Effects Page [2 of 2]