Genetic Influences in Disease Overview

Hello everybody and welcome to Patho, Genetic Influence in Disease. And here are your objectives and outline, as well as the outline for the weekly prep. So the reason why I put the outline for the weekly prep in there is because genetics, to understand this lecture and what happens with abnormal, you have to have a little bit of review of what happens from the A and P point. of genetics. And we know that the definition of a gene is a segment of the DNA molecule that's composed of an ordered sequence of nucleotide bases. So if we look here, we see that this is the DNA. The DNA lives in the nucleus of just about every cell, 10,000 trillion cells, and there's six feet of DNA, which tells you if there's a lot of DNA in a itty bitty little cell that's microscopic, that that DNA has got to be coiled pretty dang tight to fit in there. And again, we talk about the gene is the nucleotide bases on the DNA. And I think of the DNA as, or the gene that's on the DNA is kind of the rungs of a ladder. So you can see that it's located on the strand of DNA. When we talk about the... function of the gene, we refer to it as coding for the synthesis of proteins. Now, what does that mean? Well, it means that pretty much every process in our body is protein-based. And so, if you think about the permanent features that we have or permanent inherited features that we have, such as hair color, eye color, blood type, these are coded by our genes. These are all kind of organized and directed. at the function of the gene. But then there's also some other proteins that are made daily, such as hormones and certain enzymes and antibodies, and those are also kind of ruled by our genes too. Now, when there's a mutation of a gene, the protein that that particular gene is responsible to manufacture will also then be made incorrectly. So if we look at this is our chromosome or our strand of DNA, and on that DNA is a gene, we say that if there's a mutation of a very specific gene, and in an example, this particular gene is the one that codes for the proteins that make up a lactase, which by its last definition, ASE, we know that this is some kind of enzymes. And if you remember lactase. Lactose is a type of sugar that's found in milk. So if this is the gene that codes for the proteins that makes up the enzyme that breaks down milk and some kind of mutation alters that gene, then that means that lactase is not going to be made properly and therefore lactose will not get broken down. Now, this is a very common mutation. Just about most adults as they... advance in years can have a problem with milk intolerance. Now what about our genes? What is the difference with genes and chromosomes? So when we go back to what our basis of knowledge is, we know that the DNA helix contains genes, that DNA is long strands that can be coiled within the nucleus of our cells, but at some point our DNA can be either scattered about the cell or it can be formed into a specific shape and that rod-shaped body of shape of our DNA is known as the chromosome. And we think of sometimes our chromosome simplistically as a string of pearls with the beads being genes. I don't know, what ladder, rungs of the ladder, pearls, beads, whatever you want to do it. We have our strand of DNA that has our genes on it, and those DNA can be in various shapes throughout their lifespan. Most common for us are the chromosome shape. Now, a person will receive 23 chromosomes from each parent, so 23 from mom and 23 from dad, so that you make up a total of 46 chromosomes. 22 of the... chromosomes are autosomal, which means that they're not sex chromosomes, and each pair is closely alike. Or so they say. I don't see how chromosome 3 looks alike, but if you're a geneticist, an expert, then you find that they are. Then we have one pair of chromosomes that is known as the sex chromosomes. Now, for the purpose of study, the geneticist can put the chromosome pairs together, and they're arranged in what's known or thought of as a map or a karyotype. And again, The pairs are going to consist one chromosome body from mom and one from dad. Now, the autosomal chromosomes, that is one chromosome 1 through 22, if we look at them here, that's what we're going to focus on in this course. For each of these chromosome pairs, we know that the genes are on the chromosome pairs. And the partner genes are known as a pair of alleles. And they're arranged. close together or across from each other. So I think of our pair of alleles like shoes. If you're someone that's very organized, when you walk into a closet, you might have 22 pairs of shoes, but you've got them arranged in their pairs closely together so that when you get ready in the morning, you can just grab the pair. So that's pretty much how our chromosomes are arranged. Also the pair of alleles that do the same function are pretty much partnered together on this pair. Now, a pair of alleles are almost exactly alike. In other words, the pair will code for the same thing, but one part of that pair or one allele can either be dominant or it can be recessive, which means when these alleles are paired together. we're going to notate, number one, the dominant gene with an uppercase letter and the recessive gene with a lowercase letter. And when we put the pair together, we're going to call them genotypes. Just like when you put your Jimmy Choo's together, you're going to call them a pair of Jimmy Choo's. Well, this pair of alleles is going to be known as a genotype. Now, you can inherit. These genotypes randomly or in three different ways. If you inherited two dominant genes, we're going to call this an autosoma, excuse me, a homozygous dominant. If you inherited two recessive genes, then your genotype is going to be homozygous, meaning the same recessive. And then if you inherited one recessive and one dominant gene. then that is going to be heterozygous. Again, these genes are inherited and they will code for the same thing. So if you inherited from your parent this pair of alleles here that we have identified with the letter H, we can see that one of the pair is a dominant gene as annotated by a dominant gene. capital or uppercase H, and one is a recessive gene. And if you were looking at this genotype, how would you describe it? And of course, the term would be heterozygous. Now, when we think about the phenotype, that is either an anatomic, physiologic, biochemical, or behavioral characteristic, we identify that the uppercase or dominant gene is going to code for thick hair and the recessive gene is going to code for thin hair. So in an individual who has heterozygous, what is the feature or what phenotype is going to be displayed? And we know that this individual will have thick hair because that's what the dominant gene coded for. Now let's do another example to make sure that you have this concept. If we look at this individual who inherited the recessive trait of blue eyes from the mother and the dominant gene of brown eyes from the father, then this pair of alleles is going to be known genotype-wise as heterozygous. And what phenotype would this child display? And of course... this is going to be a brown-eyed baby because the brown gene is dominant. When we look at the letter J, the letter J of the dominant gene will code for extra strong bone joint or joint structure. Excuse me. And then the recessive gene will code for weak joint structure. And when we look at this child who is inherited the recessive trait from mom and dad, and when they pair together, their genotype is going to be homozygous recessive, and the phenotype is going to be weak joint structure. So that's how we figure out how our offspring are going to have which trait. Now again, I said there is a sex, a pair of sex chromosomes, that's chromosome 23, and we're not going to talk about that in the course, even though there is some information that are in your lecture notes, that's just for your information. Now when we have individuals to pair together, parents that pair together and produce offspring, There are individuals who know they have a history of certain disorders and they want to know what are the odds of having offspring with that disorder. So that means a geneticist is going to have to take DNA or a blood sample from both mom and dad so that they can determine what genes the individual has. And then they can do what's known as a Punnett square to be able to predict what are the chances of. offspring having certain traits. So when we look at this example, we can see that mom has for this disorder or physical trait, let's say that T is for crooked teeth, the dominant gene of the capital T is for crooked teeth, and the lowercase is going to be for straight teeth. So when we look at mom, we see that she is number one, homozygous dominant. and she is homozygous dominant for the crooked teeth trait. And then we see that dad is heterozygous, meaning he has one dominant gene for crooked teeth, and then he has the lowercase or recessive gene for straight teeth. And so geneticists is going to do a Punnett square to determine what is the likelihood of their child having either crooked teeth. or straight teeth. Now you know genes and genetic disorders are very complex. I have really simplified it because that's all you need to know is just the simple version. So when we look at a punnett square and the ability to do the punnett square we know that we're going to have mom on one axis and then we're going to have dad on another axis and it doesn't matter whether you put mom on this axis or up here you just have to include both sets. of genotypes. And so when we put this all together, we see that we put mom here, dad up here, and then we've gotten one gene pairing from each parent because that's how they're inherited. And so we can see that these are the combinations in these four kind of spaces that the child can come up with. Now, what do you do from here? How do you figure out the percent? chance? Well, this is the tricky part because you have to identify what are you being asked. So if I said to you, what are the percent chance of this child from this couple of having crooked teeth, you're going to have to number one circle where that gene is. And we can see that if mom is the carrier and dad is the carrier of crooked teeth, and it is a dominant trait, then we can see that the kids will all have this dominant trait. So every single child is going to have the 100% chance of having crooked teeth. Now, if I said to you, which one is at risk for carrying the gene or the recessive gene, you would say... 50%. So you have to be very careful with what type of question you're being asked when it comes down to the percent chance. So that's the piece, that's the tricky part. I think a Punnett square is very easy to configure. It's just make sure you pay attention to what the question is asking you. Now we're going to talk about probably A. the new information that we're presenting in this course, and that is the genetic disorders. And here's your outline for the lecture. When we talk about genetic disorders, this is defined as a disease that's caused by abnormalities in an individual's genetic material. And if you have lots of extra time and you read different patho textbooks, it is categorized or genetic disorders are categorized in different ways. One is inherited versus spontaneous, whereas inherited disorders, these examples are six-cell cell or some other different inherited disorders. And then spontaneous genetic disorders can occur in a variety of different ways. And I've just given you one example of a spontaneous genetic disorder here. And the reason why I'm kind of glossing over this is because we'll talk about the development of an oncogene later. What we're going to talk about or how we're going to categorize genetic disorders in our course is based on four groupings. And we're going to talk about mitochondrial, multifactorial, chromosomal, and single gene disorders. So let's talk first very briefly about mitochondrial DNA disorders. And we know, hopefully, from A&P that the majority of the DNA is found in the nucleus, but there isn't. is some small bits of DNA that is found in the mitochondria. These disorders, mitochondrial DNA disorders, are fairly uncommon, so we're not going to discuss any specific mitochondrial disorders because you really have plenty of information in the course. Now we're going to talk about multifactorial genetic disorders, and just as the name sounds, this is really a combination of different triggers. that can cause genetic disorders. In other words, there's likely some environmental, plus there's some inherited genetic parts to it, and then some tendencies. So what do I mean? So we're talking about various cancers, such as certain types of lung cancers, may be multifactorial. In other words, if it was strictly a one-time gene disorder that causes lung cancers, then that would mean that, say, everyone that smoked would get lung cancers. So why doesn't everyone that smoked get lung cancer? Because there has to be some other factor in there, either another environmental piece to it, or maybe there's some kind of gene that the individual that puts this person either at risk for cancers or puts this person at risk of not getting cancers. And so that's where the multi-factor. factorial piece in there because there isn't, for certain disorders, a guarantee that you're going to get it. And there are other common diseases such as hypertension, coronary artery disease, and diabetes that are also known to contain a portion of environmental contribution, contributing factors, as well as inherited components. So what about teratogenic or teratogenic disorders? So a teratogen is an influence from some outside factors such as drugs, radiation, viruses, and these outside factors can cause congenital defects. And these congenital defects or abnormalities are basically glitches or problems that occur during fetal development. So when we think about a teratogenic disorder, we're really talking about congenital defects in our courses or in our course. In other words, there's some gray area, but we're going to keep it strict fact. Teratogenic disorders are congenital defects, and these are not genetically inherited. In other words, the disorder occurs occurs because of exposure to certain things, drugs, radiation, viruses, that causes a developmental glitch, but it's not going to be inherited in future generations. Now, there are some specific answer or examples of teratogenic disorders, and one of those is fetal alcohol syndrome. Again, alcohol is considered a drug, and there are certain amounts of symptoms. alcohol that could become toxic to a developing fetus. How much alcohol is toxic? Well, it's not really known. And so that's why the thought is you really shouldn't drink alcohol or a woman shouldn't drink alcohol when pregnant because it's really not known how much will cause the glitch in the fetal development. There is also certain drugs that can cause fetal development glitches and one example that we're going to use in this course is thalidomide. Now thalidomide was a drug that was researched or barely researched and then actually utilized in the 50s in certain European countries because it prevented nausea. And vomiting, which we all know, or some of you might know, is more common in the early stages of pregnancy. And what happened was women that were prescribed thalidomide for their nausea and vomiting, there was a tendency for their babies to be born with abnormal limbs. So you can see not only are they very short, they're somewhat webbed also. And so it wasn't... too much of a United States issue because of the Food and Drug Administration that is so strict in this country, but it was found or occurred in European countries more so because they don't have lestringin. And it is for this reason, because of this unknown factor of drugs on the market and their risk for congenital defects, is why we really can't do research on drugs for during pregnancy, and so there's very limited research on that. And so that's why, if ever pregnant, there is a recommendation of not taking any drugs or very few drugs that are considered to be safe. Now, another type of chromosomal disorder or chromosomal aberration is a type of genetic disorder that results from alterations to the development or structure of a chromosome, which in turn will then alter some, many, a few of the genes that are on that chromosome. And of course, once genes are altered, then these genes will not code properly or correctly for certain proteins. And so when we think about our cells, it was previously mentioned that there are times when our DNA and therefore our genes are kind of scattered all over. the cell and then there are times whenever that cell is about to divide and then multiply where the DNA is pushed into those ordered chromosomes and so there can be problems during that movement around with chromosome and it usually falls into manners. There is either an alteration to the numbers of chromosome or there's an alteration in the structure of chromosomes let's talk first about alterations to numbers of chromosomes and probably the most common disorder or syndrome is down syndrome and it's a disorder of abnormal numbers of chromosomes and it's associated or mostly or usually associated with pregnancies of women who are older than 35 years now it's always present or there is always a risk of down syndrome you But the risk numbers, the ratio goes up markedly for women who are older than 35 years. And what happens is a glitch that occurs very early during cellular division. So this would be an early stage of pregnancy. And instead of ending up with 46 chromosome, the fetus has 47 chromosome. And that extra chromosome occurs at site number of chromosome number 21. So the other name for Down's is commonly known as trisomy 21. Now the phenotype or the characteristics that can be seen vary greatly from child to child. And with trisomy 21 or Down syndrome, there is usually some kind of mental retardation. Again, it varies greatly from mild to marked retardation. And then there's certain. physical characteristics that can be seen, such as low set ears, epicanthic fold to the eyes, which is in here, and then short limbs. That's different than webbed limbs. There are shorter limbs in relation to compared to somebody with normal growth and development, and then a larger than normal tongue. Now, the other type of chromosomal abnormality can occur to the structure of the... chromosome, and that we're going to use an example of the Philadelphia chromosome. So what can happen with the structure? Well, again, as we talk about the fact that the DNA helix, the strand of DNA is scattered all over the cell at times, and then at times it comes together to form that chromosome. And when it's coming together to form a chromosome before the cell divides, then there can be some problems with the coming together to form the cell. form that chromosome. There can be some deletions, duplications, rearrangements, such as translocation. That means one portion is moved or translocated to another. And all of these things or some of these things can occur. and the best example of a translocated gene is that of the Philadelphia chromosome, which we'll talk in detail a little bit later. Single gene disorders is another way that genetic disorders can occur, and when we talk about single gene disorders, this is probably the one that we're most familiar with. This is due to an inherited mutated gene, so it's a single gene. that is mutated and then inherited. And the single gene disorders are inherited in very recognizable patterns. And again, whatever that gene that is inherited, that is mutated, it will code for a specific protein product, and it will cause the malfunction of whatever it's supposed to be organizing or manufacturing. When we talk about the inherited patterns, it is usually an autosomal dominant or autosomal recessive disorder, or it can be a sex-linked disorder. So when we talk first about autosomal recessive disorders, we're talking about the mutated diseased gene is usually or is always the recessive gene. And this mutated diseased recessive gene must partner up with another mutated recessive and disease gene for the individual to show or have the phenotype of the disorder. And hopefully that makes sense to you because we know that if it was paired with a dominant gene, then the trait wouldn't be noticed. So again, when we talk about autosomal recessive gene, the individual must have inherited the recessive and mutated gene from mom and the recessive and mutated gene from dad. Now, our specific example is going to be sickle cell anemia. Again, we talk about a specific allele. So this is a certain allele that's on the chromosome that is responsible for creating hemoglobin. So this is very specific to sickle cell anemia. And so from mom, we have this disease mutated recessive gene, and from dad, we have this diseased and mutated recessive gene. So if during fertilization, the baby or child inherits this recessive gene from mom and dad, then the individual, the child, will be homozygous recessive. And it just so happens that these alleles, these diseased alleles, these abnormal recessive alleles code for abnormally shaped hemoglobin. They're sickle shaped. And we know that the hemoglobin is carried by the red blood cell. And there's actually about 250 million hemoglobin molecules per red blood cell. And if many of them are sickled, then that is going to cause the shape of the red blood cell to become sickled too. And because the red blood cells are now sickled and they're not their usual round and smooth and pliable shape, these red blood cells are more easily damaged as they go through the bloodstream. Not so much in the big blood vessels, but when they go down to the smaller blood vessels, these red blood cells become damaged and destroyed, and therefore the individual with sickle cell has anemia. Anemia means that they have fewer than normal red blood cells. Again, know the terms. This is your medical terminology piece. And so I think it's a little bit easier to kind of identify from this visual aid that if you look on this slide here, this individual has the normal round-shaped red blood cell that's very pliable. And this individual not only has sickle-shaped red blood cells, but you can see with the gaps in the slide that there are fewer red blood cells. So not only do they have fewer red blood cells, but the... the fewer red blood cells that they do have are poor quality because they are sickled shape. Again, what phenotype would an individual with a homozygous recessive sickle cell disease trait or sickle cell gene, what will they show? So one of their signs and symptoms or clinical manifestations, that's the phenotype, is going to be SOB weakness and fatigue. Now you can say, oh mom, dad, I learned a new term, SOB. That stands for... shortness of breath. It is always used or frequently used in the healthcare record. It stands for shortness of breath and these individuals will have weakness and fatigue and this is due to two reasons. We know that the hemoglobin that is on the red blood cell is responsible for carrying oxygen and if there are fewer red blood cells, then that means there is fewer oxygen carrying capacity. In addition, the hemoglobin is sickle-shaped, and this deformed sickle-shaped hemoglobin is not as efficient as carrying as much oxygen as a healthy hemoglobin or a normal-shaped hemoglobin is. In addition, these individuals can get what's known as ischemic pain, and it tends to be featured or occur in the joints. So, what happens with... this well all the words are there in your notes but let's look at a picture of this so normally your normal shape red blood cell is able to kind of bend and flex and slither through the small small blood vessels on its way to the different cells in the body but when the individual has sickled red blood cells these sickled red blood cells have a tendency when there's smaller vessels to kind of clump together and kind of basically form an obstruction to the flow of blood. So I've kind of thrown in a picture of a joint, because for whatever reason, that seems to be where these individuals experience this ischemic pain, meaning that oxygen is not getting down to this area of the body, and it will cause profound pain whenever oxygen doesn't get to tissues. And so that's why when you put the two words together, you're... They have ischemic pain, meaning that the pain occurs not because of damage to the joint, but because of the inability of blood and therefore oxygen to get to the joint. Now, this is kind of an artist's rendition of what this feels like, because these individuals do have profound pain. And it does occur not every day, but with certain increased activity. when the joints in the body need more oxygen with activity, and that is usually when they get this ischemic pain. Now, what else can occur? Because I said that this sickle cell disease is inherited in recognizable patterns, but what other combination of genotypes can individuals get? So, if, for instance, mom does not have the mutated recessive gene, she would be autosomal or she would be a dominant, has a dominant gene for hemoglobin coding, and dad has the recessive gene, then we know that the genotype is going to be heterozygous genotype for sickle cell anemia. And because we know that the mom's dominant gene is going to code for normally shaped. hemoglobin, then the individual will just be what's known as a carrier, meaning that the offspring that has this heterozygous genotype is not going to have the disease, but they're going to carry the disease. Now, sickle cell is one of those gray areas because there are times, so rarely is what we have listed in the lecture notes, A carrier can have a milder phenotype. In other words, the carrier can get milder signs and symptoms of sickle cell anemia, such as ischemic pain or perhaps anemia. And when your heterozygous individual is a carrier and then has signs and symptoms, that carrier... changes, the terminology is now known as the individual has sickle cell trait. So let me say that again. If an individual is heterozygous, meaning carrying the trait. They're known as a carrier of sickle cell disease, but if the individual is heterozygous and has mild signs and symptoms, then they are then changed to someone that has sickle cell trait. So the individual will not, the healthcare individual will not know if an individual has sickle cell trait until they present with mild signs and symptoms of the disease. Now someone who has mom who has a the the genotype of autosomal dominant or is homozygous dominant we call that homozygous normal and if dad is homozygous normal then these individuals with the two traits are not going to be a carrier or they will not have the disease so i said this wrong If mom and dad are heterozygous and their offspring inherit the dominant genes from mom and dad, then they will be homozygous normal. That means that they will not either carry the disease or they will not have the sickle cell trait. And so therefore, their offspring will not be at risk. Email me or your instructor if you're confused about this. Now let's move on to the other way that individuals can inherit genetic disorders, and that's the autosomal dominant disorder. Now this one is different because the strong gene or the dominant gene carries the disorder, and then the lowercase gene is going to code for whatever trait that is normal. Again, sex-linked disorders are not, so this will be the last genetic disorder, single gene disorder that we talk about. Autosomal dominant disorder, again, the dominant gene is the mutated and diseased gene, and the recessive gene is not. So when we have an individual who is at risk for getting an autosomal dominant disorder, and we're going to talk specifically about polycystic kidney disease, an autosomal dominant disorder, we know that on a certain locus, there is a pair of chromosomes Alleles, a pair of alleles that's responsible for coding the creation of normal kidney tissue. In other words, niprons. That's what normal kidney tissue is. And if during fertilization the person inherits the kidney tissue disease that wants to code for abnormal kidney cells, in other words, has this dominant gene, then the individual is going to have the disease such as PKD because they have the mutated gene that is the strong one. Now notice that even if the individual has a dominant gene that codes for normal kidney tissue, it doesn't matter. The individual will still have polycystic kidney disease because for whatever genetic reason, that mutated dominant gene even trumps a normal. dominant gene. And so that is the way that autosomal dominant disorders function, especially in PKD. So what happens to individuals who have this dominant abnormal or mutated gene? Well, what happens is, is this gene will code for these tissue cysts or an abnormal tissue that consists of cysts. And what will happen over time is as more and more cystic kidney cells or nephrons are produced, it will reduce the various kidney functions and can ultimately lead to kidney failure. Put a circle around this. Polycystic kidney disease will ultimately lead to an individual getting kidney failure because of these cystic formation of kidney cells. So if we use the letter P to designate PKD, the genotype for someone that has the disease is either going to be homozygous dominant or heterozygous, because again, that uppercase dominant disorder is going to code for abnormal cystic nephrons or kidney cells. So only a person who has... homozygous recessive would not have the disease and would also not genetically transmit the disorder to their offspring so let's Let's look at the signs and symptoms or clinical manifestations of polycystic kidney disease. You can see from the picture that if you have normal kidney and then here is a polycystic kidney where all of these cysts are formed, it causes the kidney to be much larger than a normal kidney. There will be hematuria, which means blood in the urine because of these cystic kidney cells. Proteinuria, that's leakage of protein into the urine. They get frequent kidney infections, pain at the costofortigeral angle and abdomen. Where is the costofortigeral angle? Well, if you look at someone's back, it's about in the middle of their back, kind of in the middle to lower portion of their back, because that's where the kidneys sit. And so individuals with cystic, polycystic kidneys. They can have pain whenever the healthcare provider kind of pops or punches lightly on their back on that costophysiological angle. They can have kidney stones also. Now we're going to move on to our last topic of the genetic disorder, and that's recombinant DNA. This is a type of genetic engineering. It is huge right now, and I'm going to talk about it for about one minute. So we're going to barely scratch the surface. So What is it? Recombinant DNA is a new DNA that results from scientists purposely combining two or more different sources of DNA. In other words, they're engineering or altering the DNA in bacteria so that these bacteria will make proteins that the bacteria would not ordinarily produce. So what is the current application of this process? Because If you're a scientist, this is very complex and we're not going to go into it in this course, but this recombinant DNA has been utilized, researched, and helped create human growth hormone for children who don't have or who don't make human growth hormone. For individuals who have diabetes and they don't make insulin, this is exogenous or this is insulin that is of course course made outside of the body and therefore purchased by the individual with diabetes. And then there are certain individuals who lack blood clotting factors such as factor 8 and so if they don't make it they can now buy it. And then there are other drugs, TPA and tenecteplase. These are drugs that are clot busters that are used for patients with strokes and heart attacks. I hope this recording is helpful. Please email your instructor if you have any questions on this material.

So if we look here, we see that this is the DNA. The DNA lives in the nucleus of just about every cell, 10,000 trillion cells, and there's six feet of DNA, which tells you if there's a lot of DNA in a itty bitty little cell that's microscopic, that that DNA has got to be coiled pretty dang tight to fit in there. And again, we talk about the gene is the nucleotide bases on the DNA.

And I think of the DNA as, or the gene that's on the DNA is kind of the rungs of a ladder. So you can see that it's located on the strand of DNA. When we talk about the... function of the gene, we refer to it as coding for the synthesis of proteins. Now, what does that mean?

Well, it means that pretty much every process in our body is protein-based. And so, if you think about the permanent features that we have or permanent inherited features that we have, such as hair color, eye color, blood type, these are coded by our genes. These are all kind of organized and directed. at the function of the gene. But then there's also some other proteins that are made daily, such as hormones and certain enzymes and antibodies, and those are also kind of ruled by our genes too.

Now, when there's a mutation of a gene, the protein that that particular gene is responsible to manufacture will also then be made incorrectly. So if we look at this is our chromosome or our strand of DNA, and on that DNA is a gene, we say that if there's a mutation of a very specific gene, and in an example, this particular gene is the one that codes for the proteins that make up a lactase, which by its last definition, ASE, we know that this is some kind of enzymes. And if you remember lactase. Lactose is a type of sugar that's found in milk.

So if this is the gene that codes for the proteins that makes up the enzyme that breaks down milk and some kind of mutation alters that gene, then that means that lactase is not going to be made properly and therefore lactose will not get broken down. Now, this is a very common mutation. Just about most adults as they... advance in years can have a problem with milk intolerance.

Now what about our genes? What is the difference with genes and chromosomes? So when we go back to what our basis of knowledge is, we know that the DNA helix contains genes, that DNA is long strands that can be coiled within the nucleus of our cells, but at some point our DNA can be either scattered about the cell or it can be formed into a specific shape and that rod-shaped body of shape of our DNA is known as the chromosome. And we think of sometimes our chromosome simplistically as a string of pearls with the beads being genes. I don't know, what ladder, rungs of the ladder, pearls, beads, whatever you want to do it.

We have our strand of DNA that has our genes on it, and those DNA can be in various shapes throughout their lifespan. Most common for us are the chromosome shape. Now, a person will receive 23 chromosomes from each parent, so 23 from mom and 23 from dad, so that you make up a total of 46 chromosomes. 22 of the... chromosomes are autosomal, which means that they're not sex chromosomes, and each pair is closely alike.

Or so they say. I don't see how chromosome 3 looks alike, but if you're a geneticist, an expert, then you find that they are. Then we have one pair of chromosomes that is known as the sex chromosomes.

Now, for the purpose of study, the geneticist can put the chromosome pairs together, and they're arranged in what's known or thought of as a map or a karyotype. And again, The pairs are going to consist one chromosome body from mom and one from dad. Now, the autosomal chromosomes, that is one chromosome 1 through 22, if we look at them here, that's what we're going to focus on in this course.

For each of these chromosome pairs, we know that the genes are on the chromosome pairs. And the partner genes are known as a pair of alleles. And they're arranged.

close together or across from each other. So I think of our pair of alleles like shoes. If you're someone that's very organized, when you walk into a closet, you might have 22 pairs of shoes, but you've got them arranged in their pairs closely together so that when you get ready in the morning, you can just grab the pair.

So that's pretty much how our chromosomes are arranged. Also the pair of alleles that do the same function are pretty much partnered together on this pair. Now, a pair of alleles are almost exactly alike. In other words, the pair will code for the same thing, but one part of that pair or one allele can either be dominant or it can be recessive, which means when these alleles are paired together.

we're going to notate, number one, the dominant gene with an uppercase letter and the recessive gene with a lowercase letter. And when we put the pair together, we're going to call them genotypes. Just like when you put your Jimmy Choo's together, you're going to call them a pair of Jimmy Choo's. Well, this pair of alleles is going to be known as a genotype.

Now, you can inherit. These genotypes randomly or in three different ways. If you inherited two dominant genes, we're going to call this an autosoma, excuse me, a homozygous dominant. If you inherited two recessive genes, then your genotype is going to be homozygous, meaning the same recessive.

And then if you inherited one recessive and one dominant gene. then that is going to be heterozygous. Again, these genes are inherited and they will code for the same thing. So if you inherited from your parent this pair of alleles here that we have identified with the letter H, we can see that one of the pair is a dominant gene as annotated by a dominant gene. capital or uppercase H, and one is a recessive gene.

And if you were looking at this genotype, how would you describe it? And of course, the term would be heterozygous. Now, when we think about the phenotype, that is either an anatomic, physiologic, biochemical, or behavioral characteristic, we identify that the uppercase or dominant gene is going to code for thick hair and the recessive gene is going to code for thin hair.

So in an individual who has heterozygous, what is the feature or what phenotype is going to be displayed? And we know that this individual will have thick hair because that's what the dominant gene coded for. Now let's do another example to make sure that you have this concept. If we look at this individual who inherited the recessive trait of blue eyes from the mother and the dominant gene of brown eyes from the father, then this pair of alleles is going to be known genotype-wise as heterozygous. And what phenotype would this child display?

And of course... this is going to be a brown-eyed baby because the brown gene is dominant. When we look at the letter J, the letter J of the dominant gene will code for extra strong bone joint or joint structure.

Excuse me. And then the recessive gene will code for weak joint structure. And when we look at this child who is inherited the recessive trait from mom and dad, and when they pair together, their genotype is going to be homozygous recessive, and the phenotype is going to be weak joint structure. So that's how we figure out how our offspring are going to have which trait.

Now again, I said there is a sex, a pair of sex chromosomes, that's chromosome 23, and we're not going to talk about that in the course, even though there is some information that are in your lecture notes, that's just for your information. Now when we have individuals to pair together, parents that pair together and produce offspring, There are individuals who know they have a history of certain disorders and they want to know what are the odds of having offspring with that disorder. So that means a geneticist is going to have to take DNA or a blood sample from both mom and dad so that they can determine what genes the individual has.

And then they can do what's known as a Punnett square to be able to predict what are the chances of. offspring having certain traits. So when we look at this example, we can see that mom has for this disorder or physical trait, let's say that T is for crooked teeth, the dominant gene of the capital T is for crooked teeth, and the lowercase is going to be for straight teeth. So when we look at mom, we see that she is number one, homozygous dominant.

and she is homozygous dominant for the crooked teeth trait. And then we see that dad is heterozygous, meaning he has one dominant gene for crooked teeth, and then he has the lowercase or recessive gene for straight teeth. And so geneticists is going to do a Punnett square to determine what is the likelihood of their child having either crooked teeth. or straight teeth.

Now you know genes and genetic disorders are very complex. I have really simplified it because that's all you need to know is just the simple version. So when we look at a punnett square and the ability to do the punnett square we know that we're going to have mom on one axis and then we're going to have dad on another axis and it doesn't matter whether you put mom on this axis or up here you just have to include both sets. of genotypes.

And so when we put this all together, we see that we put mom here, dad up here, and then we've gotten one gene pairing from each parent because that's how they're inherited. And so we can see that these are the combinations in these four kind of spaces that the child can come up with. Now, what do you do from here? How do you figure out the percent?

chance? Well, this is the tricky part because you have to identify what are you being asked. So if I said to you, what are the percent chance of this child from this couple of having crooked teeth, you're going to have to number one circle where that gene is.

And we can see that if mom is the carrier and dad is the carrier of crooked teeth, and it is a dominant trait, then we can see that the kids will all have this dominant trait. So every single child is going to have the 100% chance of having crooked teeth. Now, if I said to you, which one is at risk for carrying the gene or the recessive gene, you would say...

50%. So you have to be very careful with what type of question you're being asked when it comes down to the percent chance. So that's the piece, that's the tricky part. I think a Punnett square is very easy to configure.

It's just make sure you pay attention to what the question is asking you. Now we're going to talk about probably A. the new information that we're presenting in this course, and that is the genetic disorders.

And here's your outline for the lecture. When we talk about genetic disorders, this is defined as a disease that's caused by abnormalities in an individual's genetic material. And if you have lots of extra time and you read different patho textbooks, it is categorized or genetic disorders are categorized in different ways.

One is inherited versus spontaneous, whereas inherited disorders, these examples are six-cell cell or some other different inherited disorders. And then spontaneous genetic disorders can occur in a variety of different ways. And I've just given you one example of a spontaneous genetic disorder here.

And the reason why I'm kind of glossing over this is because we'll talk about the development of an oncogene later. What we're going to talk about or how we're going to categorize genetic disorders in our course is based on four groupings. And we're going to talk about mitochondrial, multifactorial, chromosomal, and single gene disorders.

So let's talk first very briefly about mitochondrial DNA disorders. And we know, hopefully, from A&P that the majority of the DNA is found in the nucleus, but there isn't. is some small bits of DNA that is found in the mitochondria. These disorders, mitochondrial DNA disorders, are fairly uncommon, so we're not going to discuss any specific mitochondrial disorders because you really have plenty of information in the course. Now we're going to talk about multifactorial genetic disorders, and just as the name sounds, this is really a combination of different triggers.

that can cause genetic disorders. In other words, there's likely some environmental, plus there's some inherited genetic parts to it, and then some tendencies. So what do I mean?

So we're talking about various cancers, such as certain types of lung cancers, may be multifactorial. In other words, if it was strictly a one-time gene disorder that causes lung cancers, then that would mean that, say, everyone that smoked would get lung cancers. So why doesn't everyone that smoked get lung cancer? Because there has to be some other factor in there, either another environmental piece to it, or maybe there's some kind of gene that the individual that puts this person either at risk for cancers or puts this person at risk of not getting cancers.

And so that's where the multi-factor. factorial piece in there because there isn't, for certain disorders, a guarantee that you're going to get it. And there are other common diseases such as hypertension, coronary artery disease, and diabetes that are also known to contain a portion of environmental contribution, contributing factors, as well as inherited components.

So what about teratogenic or teratogenic disorders? So a teratogen is an influence from some outside factors such as drugs, radiation, viruses, and these outside factors can cause congenital defects. And these congenital defects or abnormalities are basically glitches or problems that occur during fetal development.

So when we think about a teratogenic disorder, we're really talking about congenital defects in our courses or in our course. In other words, there's some gray area, but we're going to keep it strict fact. Teratogenic disorders are congenital defects, and these are not genetically inherited. In other words, the disorder occurs occurs because of exposure to certain things, drugs, radiation, viruses, that causes a developmental glitch, but it's not going to be inherited in future generations. Now, there are some specific answer or examples of teratogenic disorders, and one of those is fetal alcohol syndrome.

Again, alcohol is considered a drug, and there are certain amounts of symptoms. alcohol that could become toxic to a developing fetus. How much alcohol is toxic? Well, it's not really known.

And so that's why the thought is you really shouldn't drink alcohol or a woman shouldn't drink alcohol when pregnant because it's really not known how much will cause the glitch in the fetal development. There is also certain drugs that can cause fetal development glitches and one example that we're going to use in this course is thalidomide. Now thalidomide was a drug that was researched or barely researched and then actually utilized in the 50s in certain European countries because it prevented nausea.

And vomiting, which we all know, or some of you might know, is more common in the early stages of pregnancy. And what happened was women that were prescribed thalidomide for their nausea and vomiting, there was a tendency for their babies to be born with abnormal limbs. So you can see not only are they very short, they're somewhat webbed also.

And so it wasn't... too much of a United States issue because of the Food and Drug Administration that is so strict in this country, but it was found or occurred in European countries more so because they don't have lestringin. And it is for this reason, because of this unknown factor of drugs on the market and their risk for congenital defects, is why we really can't do research on drugs for during pregnancy, and so there's very limited research on that.

And so that's why, if ever pregnant, there is a recommendation of not taking any drugs or very few drugs that are considered to be safe. Now, another type of chromosomal disorder or chromosomal aberration is a type of genetic disorder that results from alterations to the development or structure of a chromosome, which in turn will then alter some, many, a few of the genes that are on that chromosome. And of course, once genes are altered, then these genes will not code properly or correctly for certain proteins. And so when we think about our cells, it was previously mentioned that there are times when our DNA and therefore our genes are kind of scattered all over.

the cell and then there are times whenever that cell is about to divide and then multiply where the DNA is pushed into those ordered chromosomes and so there can be problems during that movement around with chromosome and it usually falls into manners. There is either an alteration to the numbers of chromosome or there's an alteration in the structure of chromosomes let's talk first about alterations to numbers of chromosomes and probably the most common disorder or syndrome is down syndrome and it's a disorder of abnormal numbers of chromosomes and it's associated or mostly or usually associated with pregnancies of women who are older than 35 years now it's always present or there is always a risk of down syndrome you But the risk numbers, the ratio goes up markedly for women who are older than 35 years. And what happens is a glitch that occurs very early during cellular division. So this would be an early stage of pregnancy. And instead of ending up with 46 chromosome, the fetus has 47 chromosome.

And that extra chromosome occurs at site number of chromosome number 21. So the other name for Down's is commonly known as trisomy 21. Now the phenotype or the characteristics that can be seen vary greatly from child to child. And with trisomy 21 or Down syndrome, there is usually some kind of mental retardation. Again, it varies greatly from mild to marked retardation.

And then there's certain. physical characteristics that can be seen, such as low set ears, epicanthic fold to the eyes, which is in here, and then short limbs. That's different than webbed limbs. There are shorter limbs in relation to compared to somebody with normal growth and development, and then a larger than normal tongue.

Now, the other type of chromosomal abnormality can occur to the structure of the... chromosome, and that we're going to use an example of the Philadelphia chromosome. So what can happen with the structure? Well, again, as we talk about the fact that the DNA helix, the strand of DNA is scattered all over the cell at times, and then at times it comes together to form that chromosome.

And when it's coming together to form a chromosome before the cell divides, then there can be some problems with the coming together to form the cell. form that chromosome. There can be some deletions, duplications, rearrangements, such as translocation.

That means one portion is moved or translocated to another. And all of these things or some of these things can occur. and the best example of a translocated gene is that of the Philadelphia chromosome, which we'll talk in detail a little bit later.

Single gene disorders is another way that genetic disorders can occur, and when we talk about single gene disorders, this is probably the one that we're most familiar with. This is due to an inherited mutated gene, so it's a single gene. that is mutated and then inherited.

And the single gene disorders are inherited in very recognizable patterns. And again, whatever that gene that is inherited, that is mutated, it will code for a specific protein product, and it will cause the malfunction of whatever it's supposed to be organizing or manufacturing. When we talk about the inherited patterns, it is usually an autosomal dominant or autosomal recessive disorder, or it can be a sex-linked disorder.

So when we talk first about autosomal recessive disorders, we're talking about the mutated diseased gene is usually or is always the recessive gene. And this mutated diseased recessive gene must partner up with another mutated recessive and disease gene for the individual to show or have the phenotype of the disorder. And hopefully that makes sense to you because we know that if it was paired with a dominant gene, then the trait wouldn't be noticed. So again, when we talk about autosomal recessive gene, the individual must have inherited the recessive and mutated gene from mom and the recessive and mutated gene from dad.

Now, our specific example is going to be sickle cell anemia. Again, we talk about a specific allele. So this is a certain allele that's on the chromosome that is responsible for creating hemoglobin.

So this is very specific to sickle cell anemia. And so from mom, we have this disease mutated recessive gene, and from dad, we have this diseased and mutated recessive gene. So if during fertilization, the baby or child inherits this recessive gene from mom and dad, then the individual, the child, will be homozygous recessive. And it just so happens that these alleles, these diseased alleles, these abnormal recessive alleles code for abnormally shaped hemoglobin.

They're sickle shaped. And we know that the hemoglobin is carried by the red blood cell. And there's actually about 250 million hemoglobin molecules per red blood cell.

And if many of them are sickled, then that is going to cause the shape of the red blood cell to become sickled too. And because the red blood cells are now sickled and they're not their usual round and smooth and pliable shape, these red blood cells are more easily damaged as they go through the bloodstream. Not so much in the big blood vessels, but when they go down to the smaller blood vessels, these red blood cells become damaged and destroyed, and therefore the individual with sickle cell has anemia. Anemia means that they have fewer than normal red blood cells. Again, know the terms.

This is your medical terminology piece. And so I think it's a little bit easier to kind of identify from this visual aid that if you look on this slide here, this individual has the normal round-shaped red blood cell that's very pliable. And this individual not only has sickle-shaped red blood cells, but you can see with the gaps in the slide that there are fewer red blood cells. So not only do they have fewer red blood cells, but the...

the fewer red blood cells that they do have are poor quality because they are sickled shape. Again, what phenotype would an individual with a homozygous recessive sickle cell disease trait or sickle cell gene, what will they show? So one of their signs and symptoms or clinical manifestations, that's the phenotype, is going to be SOB weakness and fatigue. Now you can say, oh mom, dad, I learned a new term, SOB.

That stands for... shortness of breath. It is always used or frequently used in the healthcare record.

It stands for shortness of breath and these individuals will have weakness and fatigue and this is due to two reasons. We know that the hemoglobin that is on the red blood cell is responsible for carrying oxygen and if there are fewer red blood cells, then that means there is fewer oxygen carrying capacity. In addition, the hemoglobin is sickle-shaped, and this deformed sickle-shaped hemoglobin is not as efficient as carrying as much oxygen as a healthy hemoglobin or a normal-shaped hemoglobin is. In addition, these individuals can get what's known as ischemic pain, and it tends to be featured or occur in the joints. So, what happens with...

this well all the words are there in your notes but let's look at a picture of this so normally your normal shape red blood cell is able to kind of bend and flex and slither through the small small blood vessels on its way to the different cells in the body but when the individual has sickled red blood cells these sickled red blood cells have a tendency when there's smaller vessels to kind of clump together and kind of basically form an obstruction to the flow of blood. So I've kind of thrown in a picture of a joint, because for whatever reason, that seems to be where these individuals experience this ischemic pain, meaning that oxygen is not getting down to this area of the body, and it will cause profound pain whenever oxygen doesn't get to tissues. And so that's why when you put the two words together, you're... They have ischemic pain, meaning that the pain occurs not because of damage to the joint, but because of the inability of blood and therefore oxygen to get to the joint.

Now, this is kind of an artist's rendition of what this feels like, because these individuals do have profound pain. And it does occur not every day, but with certain increased activity. when the joints in the body need more oxygen with activity, and that is usually when they get this ischemic pain.

Now, what else can occur? Because I said that this sickle cell disease is inherited in recognizable patterns, but what other combination of genotypes can individuals get? So, if, for instance, mom does not have the mutated recessive gene, she would be autosomal or she would be a dominant, has a dominant gene for hemoglobin coding, and dad has the recessive gene, then we know that the genotype is going to be heterozygous genotype for sickle cell anemia. And because we know that the mom's dominant gene is going to code for normally shaped.

hemoglobin, then the individual will just be what's known as a carrier, meaning that the offspring that has this heterozygous genotype is not going to have the disease, but they're going to carry the disease. Now, sickle cell is one of those gray areas because there are times, so rarely is what we have listed in the lecture notes, A carrier can have a milder phenotype. In other words, the carrier can get milder signs and symptoms of sickle cell anemia, such as ischemic pain or perhaps anemia.

And when your heterozygous individual is a carrier and then has signs and symptoms, that carrier... changes, the terminology is now known as the individual has sickle cell trait. So let me say that again.

If an individual is heterozygous, meaning carrying the trait. They're known as a carrier of sickle cell disease, but if the individual is heterozygous and has mild signs and symptoms, then they are then changed to someone that has sickle cell trait. So the individual will not, the healthcare individual will not know if an individual has sickle cell trait until they present with mild signs and symptoms of the disease. Now someone who has mom who has a the the genotype of autosomal dominant or is homozygous dominant we call that homozygous normal and if dad is homozygous normal then these individuals with the two traits are not going to be a carrier or they will not have the disease so i said this wrong If mom and dad are heterozygous and their offspring inherit the dominant genes from mom and dad, then they will be homozygous normal.

That means that they will not either carry the disease or they will not have the sickle cell trait. And so therefore, their offspring will not be at risk. Email me or your instructor if you're confused about this. Now let's move on to the other way that individuals can inherit genetic disorders, and that's the autosomal dominant disorder. Now this one is different because the strong gene or the dominant gene carries the disorder, and then the lowercase gene is going to code for whatever trait that is normal.

Again, sex-linked disorders are not, so this will be the last genetic disorder, single gene disorder that we talk about. Autosomal dominant disorder, again, the dominant gene is the mutated and diseased gene, and the recessive gene is not. So when we have an individual who is at risk for getting an autosomal dominant disorder, and we're going to talk specifically about polycystic kidney disease, an autosomal dominant disorder, we know that on a certain locus, there is a pair of chromosomes Alleles, a pair of alleles that's responsible for coding the creation of normal kidney tissue.

In other words, niprons. That's what normal kidney tissue is. And if during fertilization the person inherits the kidney tissue disease that wants to code for abnormal kidney cells, in other words, has this dominant gene, then the individual is going to have the disease such as PKD because they have the mutated gene that is the strong one. Now notice that even if the individual has a dominant gene that codes for normal kidney tissue, it doesn't matter.

The individual will still have polycystic kidney disease because for whatever genetic reason, that mutated dominant gene even trumps a normal. dominant gene. And so that is the way that autosomal dominant disorders function, especially in PKD. So what happens to individuals who have this dominant abnormal or mutated gene?

Well, what happens is, is this gene will code for these tissue cysts or an abnormal tissue that consists of cysts. And what will happen over time is as more and more cystic kidney cells or nephrons are produced, it will reduce the various kidney functions and can ultimately lead to kidney failure. Put a circle around this. Polycystic kidney disease will ultimately lead to an individual getting kidney failure because of these cystic formation of kidney cells.

So if we use the letter P to designate PKD, the genotype for someone that has the disease is either going to be homozygous dominant or heterozygous, because again, that uppercase dominant disorder is going to code for abnormal cystic nephrons or kidney cells. So only a person who has... homozygous recessive would not have the disease and would also not genetically transmit the disorder to their offspring so let's Let's look at the signs and symptoms or clinical manifestations of polycystic kidney disease. You can see from the picture that if you have normal kidney and then here is a polycystic kidney where all of these cysts are formed, it causes the kidney to be much larger than a normal kidney.

There will be hematuria, which means blood in the urine because of these cystic kidney cells. Proteinuria, that's leakage of protein into the urine. They get frequent kidney infections, pain at the costofortigeral angle and abdomen.

Where is the costofortigeral angle? Well, if you look at someone's back, it's about in the middle of their back, kind of in the middle to lower portion of their back, because that's where the kidneys sit. And so individuals with cystic, polycystic kidneys. They can have pain whenever the healthcare provider kind of pops or punches lightly on their back on that costophysiological angle.

They can have kidney stones also. Now we're going to move on to our last topic of the genetic disorder, and that's recombinant DNA. This is a type of genetic engineering. It is huge right now, and I'm going to talk about it for about one minute. So we're going to barely scratch the surface.

So What is it? Recombinant DNA is a new DNA that results from scientists purposely combining two or more different sources of DNA. In other words, they're engineering or altering the DNA in bacteria so that these bacteria will make proteins that the bacteria would not ordinarily produce. So what is the current application of this process? Because If you're a scientist, this is very complex and we're not going to go into it in this course, but this recombinant DNA has been utilized, researched, and helped create human growth hormone for children who don't have or who don't make human growth hormone.

For individuals who have diabetes and they don't make insulin, this is exogenous or this is insulin that is of course course made outside of the body and therefore purchased by the individual with diabetes. And then there are certain individuals who lack blood clotting factors such as factor 8 and so if they don't make it they can now buy it. And then there are other drugs, TPA and tenecteplase.

These are drugs that are clot busters that are used for patients with strokes and heart attacks. I hope this recording is helpful. Please email your instructor if you have any questions on this material.

Transcript for:Genetic Influences in Disease Overview

Transcript for:
Genetic Influences in Disease Overview