MBG Molecular Genetics of Disease Part 1 Transcript PDF

Okay, so now we're on to essentially a, really what only amounts to a snapshot of the wide world of molecular biology implications and genetics of human disease. And so how the next three lectures will go is we'll start with, here's a bunch of places where genetics matters and molecular biology and...

Okay, so now we're on to essentially a, really what only amounts to a snapshot of the wide world of molecular biology implications and genetics of human disease. And so how the next three lectures will go is we'll start with, here's a bunch of places where genetics matters and molecular biology and signaling matter, moving into cancer. And we will talk about both hereditary cancers and hereditary conditions with cancer as a primary or main consequence or increased cancer risk. So with that in mind, we do have to once again remind us of that somatic versus germline rule. Some changes to you in your lifetime are something you can pass on, especially in terms of a developing fetus and a pregnant female. That being said, most of the changes that occur in your lifetime are not gonna be passed down to your kids. Those are the somatic changes. The only time that we are truly concerned about risk to future generations is when the changes exist in the germline. When we use the phrase molecular biology of human disease versus genetics, we are really talking about how genes are essentially interacting. The molecular biology piece of this is all of the interactions, cellular behaviors, how the liver influences the whole system, how signaling from a thymus induces different changes in other cell types, our paracrine, autocrine, and endocrine signaling concept. It is all of the interactions. It's the consequences of the genetics. We had an entire block on the molecular genetics because we were all about the processes that gave us DNA, RNA, and protein. And so from this aspect, when we use the word genetics here, it is literally the heritable conditions. What genes correlate with a disorder? The molecular biology explains how that gene matters, but the genetics is all about, where did I get it? What does it mean for me? Does that make sense? So when we're trying to tie these pieces together, we're gonna do what we did with inborn where we sort of say, okay, here's the pathway. But it's also that element of this gene is most correlated with this outcome because we are talking about complex and multifactorial disorders and diseases. Getting the gene doesn't guarantee anything in a lot of these cases. And the spectrum of consequences is so variable that sometimes the elevated risk is marginal, but still worth noting. Does that make sense? Okay, when we talk about molecular biology, it's relevant to a whole host of disorders and diseases and every system in your body. And so I cannot teach you every one of them. We'd be here for years. You know, like four next door. So my job is to again give you the ones that are the most important, that are either going to teach you something specific about the genetics of it, or that will enable you to have a nice foundation for future interest in medicine. So from our perspective, please note that when it comes to these, oftentimes if a change is impactful enough, it's gonna hit more than one system. That gene is going to find itself being important in different ways in different systems. We have a lot of cell type specific responses, but that doesn't mean that's the only cell type that's going to have a response. So there's lots of overlap with these things. Just a reminder, gain of function means that we are getting more of, we're turning something on. We are dysregulating it in a pro go kind of way. Loss of function means we are turning something off. We are losing the product. We are losing the pathway. That molecule is no longer functional or functional to a lesser degree. With cancer terminology, a gain of function is considered a proto-onco or onco gene. Differentiation there, proto-onco, potential for oncogenic activity. Onco, actively creating oncogenic potential. Actually causing a problem. A tumor suppressor gene is correlated with regulation, turning things off, controlling other things. So losing that loses us that activity. We have to talk about how structural rearrangements correlate with gene activity. Fusion genes dysregulate them. Best example is the BCR-ABL we had talked about previously where we stuck two pieces together and that dysregulated a major pro go signaling that will come back up in our cancer. These things can happen spontaneously. De novo, be inherited or somatically. All of the above. But when you get the change, has different implications for what you exhibit. So let's start with respiratory. Who's heard of asthma? Who's heard of chronic obstructive pulmonary disease? COPD. Why have you heard of both of these things? Besides the fact that you've been in classes with these things for like what, 12 weeks? They're common. Asthma is incredibly common. Why are they common? Air pollution. Effects of environment are substantial onto the mucous membranes of the respiratory system. Inflammation, highly probable in a system that is constantly exposed to antigens, right? Chronic inflammation of the respiratory system is what we expect to observe in these two conditions. There is a genetic component to your risk, especially if you develop it in childhood. COPD is particularly linked to what behavior? So these are vastly different in many, many ways. But there are some underlying themes, some things that we can look at for these. Number one being combination of genetic and environmental factors. These are multifactorial disorders. So in this case, we actually have a little bit of an interest in micro-RNAs. Where have we heard about those before? So we can target micro-RNAs to help alleviate some of the negative inflammatory signals that are promoting that difficulty to breathe. And so if you look, there's actually several that overlap between the two conditions, but also some that are uniquely linked to their own individual conditions. And so ultimately, what we're talking about is trying to draw a connection between the immune system, inflammation, environmental exposure, and genetics. Your genetics dictates what level of signaling you can or will be prone to doing. Your environmental exposures are going to dictate the responses that exist. And your level of inflammation can be mitigated or increased based on those environmental exposures. So this, I hope, looks a little bit familiar. Maybe, I mean, you know, we have our prostaglandins, we have lymphin, TH2, maybe. Obviously, I'm not asking anything about it, I just wanted to make sure we had a connection to things you'd seen. Ultimately, we're talking about allergen-induced signaling and how that's going to contribute to inflammation within the compartment. Areas that are exposed to high levels of antigen have high levels of immune activity. So for our COPD and our asthma, we're really interested in those micro-RNAs. But inflammation can also come up in other places. And COX2 is uniquely important to that concept of environmental factors like cigarette smoke. Because COX2 plays a role in both asthma and COPD to increase or worsen the symptoms of those two conditions. So this is the genetic predisposition, but also a molecular change that takes place. And so with COX2, we have a critical role in prostaglandin production. This is a cyclooxygenase. It is going to essentially ensure whether we move forward in prostaglandin production or get stuck. And we need to not get stuck to avoid the massive inflammation that can occur. And so when we can't properly have COX2, we can't get the proper regulation of the vasculature and can't deal with the inflammation and we end up in a cycle of stimulating more inflammation. And so we just worsen symptoms that are already there. Does that make sense? So I don't expect you to look at this but or to memorize this pathway. Just understand that COX2 has an important effect in ensuring that this process can be regulated. And if we lose COX2, we end up in a negative situation. We can also have gain of function mutations in COX2 that have differential effects. Ultimately, COX2 activity must be at the proper level. Too much, too little. We have symptoms that result in cyclical inflammatory responses that can worsen as well. So basically, I want you to take COX2, COPD and asthma connection. When you inherit the mutation in COX2, you can have multi-system abnormalities because of that close connection to development and the immune system. COX2 mutations are actually known to correlate with lower or poor prognosis in cancer, specifically colorectal cancer. So here is a link to a develop, a condition that can develop over time but then also links to somatic changes that worsen prognosis in cancer. We can see COX2 mutations in mitochondrial disorders. We can see them in ischemic reperfusion injury where we have that inflammation that induces further damage. And we usually see loss of function being correlated with an autosomal recessive inheritance pattern. So somatic development is vastly different than inherited. And the compartment you're in matters. So here is COX2 variation associating with increased risk of cancer. So giving us a little bit more about this, we can see COX2 is important because of a neurogenetic connection from a previous lecture. Given its role in inflammation, we have also looked at it in terms of degenerative brain disorders. And so we see this important role of this signaling and this behavior in plasticity and cellular motility. And so it's very closely linked with amyloid beta activity. And so that matters because we know that that is correlated with what? Alzheimer's. And essentially what you're doing is if COX2 is up, we are increasing NF-kappa B signaling and increasing inflammation. And when you increase inflammation, especially in the brain, there are potentials to dysregulate other signaling and specifically amyloid beta production and you can end up with worsening or creating neurodegenerative disorders. Does that make sense? COX2 is kind of important and does a bunch. It's basically a takeaway from that. So why would I bring up something that has such systemic effects, talk about it from first the perspective of something that can be environmentally induced like COPD and then move toward neurodegenerative disorders? I'm loving that. I have no idea why you do the things you do, Dr. Steading, like this is, why do you ask us these questions? The idea here is that this is the same type of mutation but when you get it matters. Having it from infancy, having it from the initial stages of in utero development is different than an environmentally induced or adult onset change. Changes that you have that happen over your lifetime matter to the development of environmentally influenced conditions. Cancers are not a guarantee but having a mutation from birth increases your likelihood of a particular cancer. And so here's this one thing that functions in so many different signaling pathways and therefore in so many different compartments that we really need to pay attention to it in slightly different ways because there's a difference between increasing its activity or decreasing its activity and both have implications for disease. So I'm just giving you one molecule to do all of that because it's doing all of that. And what's really cool about this piece is it also means that here's this one thing we can target. If it's a gain of function mutation in COX2, we can target COX2 with an NSAID. A simple nonsteroidal anti-inflammatory. That's pretty amazing. And there's actually been some promise for using an NSAID even in cancer as a supplemental therapeutic. Sometimes simple answers have profound implications. Another example that we'll get into in biochem more is that we can use a simple vitamin to treat and fully cure a form of leukemia. Sometimes simple answers really do give us a lot. So harkening back to block two because we can't just ignore that block, we talked about structural rearrangements of the Y chromosome, especially in terms of recombination with the X chromosome, right? Turns out one of the most critical reasons this is a problem is the gene DAZ. DAZ is actually essential for male fertility and spermatogenesis. The most common cause of male infertility are micro deletions in the Y chromosome, specifically in some of those pseudo-autosomal regions. Why would we expect small losses in the pseudo-autosomal regions? Because of the high rate of recombination between the X and the Y. So this region also known as the azospermia region or AZF region has many of the genes associated with literal spermatogenesis. Loss of function mutations, deletions, micro deletions, and specifically the deleted in azospermia, DAZ. Isn't that nice? No, we don't like the naming conventions when it matches perfectly, I do. Deleted in azospermia is literally the gene lost to cause azospermia or absence of sperm. So this loss is highly correlated with recombination. And its job is essentially maturation of sperm, inducing sperm development. Hence, lose this gene, you lose functional sperm. Make sense? What's interesting to tie it back to now block three is we're actually affecting RNA binding domains. Lots of tandem repeats. Ultimately, we do not produce a functional, three-dimensional protein and thus cannot produce functional sperm. Are we having fun with the condition and now the next one? Metabolic disorders or metabolic syndrome. This ties back to our inborn errors of metabolism. However, metabolic syndrome as the name syndrome implies is a much more all- encompassing concept. We're gonna have multiple factors involved. So why we talk about metabolic syndrome is because we have multiple pieces that come together to create this whole condition. And so we're gonna specifically see insulin resistance, obesity, hypertension, elevated levels of triglycerides, all of these metabolic pieces coming together to create an overall syndrome. If it's important to metabolism, you have the potential to impact every system in the body. In this particular condition, we actually have increased insulin resistance. We literally alter insulin signaling and the ability to respond to insulin properly. What is insulin supposed to do? It's supposed to play a critical role in regulating blood glucose, right? There's a connection. The fed state should increase glucose availability, which should increase insulin so that the cells can take in that glucose and have fun doing cell stuff. I don't know, I'm trying. I know it's a Friday. So in this case, we're affecting that just in specific ways that involve lowering the surface receptors of insulin. So we can't respond to insulin in the way that we should. We can't promote the ability to uptake glucose in a more enhanced way. We can't respond to the fed state in the way that we're supposed to. This signaling affects many of our growth factor signaling pathways we've seen before, including PI3 kinase. Glute IV translocation is directly induced by the availability of insulin. It's a receptor that moves when insulin is present and now we're not doing that movement. So if we're not moving that glucose receptor to the surface, glucose isn't coming in to the same degree. So I don't expect you to know all of those pieces, but I do want us to see that we have these ties in signaling to the ability to actually undergo metabolism. So without the fuel, we're gonna affect the ability to make our storage form of fuel, glycogen. We're gonna affect the ability to synthesize proteins. We are going to affect the cell's ability to do its job. Cells need fuel to function. When it comes to risks of a metabolic syndrome where we have this systemic impact on metabolism, we actually found what are called two quantitative trait loci. What did we talk about when it came to quantitative traits? It's a lot more gene involved. Sorry, go for it. Please answer for me. It's controlled by multiple genes. I did not give you guys enough space on that one. I should have stopped and stared at you for a while. Sorry about that. So multiple genes involved and the more genes we have, the more wide ranging the phenotype can be, right? Where changes in each individual gene can also increase the probability of the condition. So if I have five genes involved, changes in one is one rate versus changes in all five. Very different risk rate, right? Risk level. The candidate genes for this clearly tie to the behaviors of the condition. LDL-R, transforming growth factor beta, a stimulatory from interleukin six and select and eat. Now I know those are just words to you or they may be familiar from other classes, but ultimately this is just an increased risk of things like the hypertension, the diabetes, the insulin resistance all occurring together. And those QTLs, those quantitative trait loci, have to be altered in very specific ways to increase that risk. But you will see multiple genes being affected in metabolic syndrome. Does this make sense? I know I skipped ahead too fast there. If you want more information, many of the links to papers on these are included in the notes if you wanna spend some time looking, but the level of expectation is sort of each piece, each disorder we're talking about adds another little, oh, that's how genetic works in this situation. Are we still following that? So for that one is one of our quantitative traits. And so now cardiovascular disease. So we've done respiratory, we did a little bit of neuro, now we're cardiovascular. Now we did metabolic, now we're cardiovascular. The heart, literally building a heart takes what? So many genes, so many signals. You can look all the way back to our drosophila friends to see things like hemi-segment production of key cell types to trigger the proper structures of a heart. Cardiac anomalies can be very common under many chromosomal abnormalities, right? One of the more common, of course, being that tetralogy of fallot, which you may be familiar with from some of the other classes. If not, just that's a fun one to figure out more about. Look up tetralogy of fallot, F-A-L-L-O-T. So, in terms of what we're interested in, we wanna try to tie this back to some of the other things we've done. And so we talked a little bit about an ischemic reperfusion injury. And this is the idea of inflammation, promoting signaling that can then further do damage. And so in the case of this, we're gonna talk about linking some of these things we've already talked about specifically to the cardiovascular disease. Reactive oxygen species are bad because they're reactive and they do damage, right? I know, I'm trying to do some softball questions today. What do they damage most predominantly? What is one of the areas that gets regularly exposed to reactive oxygen species and is thus incredibly sensitive to lipid peroxidation poking holes in it? Mitochondria, right? Our mitochondrial friends. In this example, we are actually talking about how we can end up into a progressive state of damage to the cardiovascular system through a cyclical re-signaling. Reactive oxygen species increase TGF beta signaling. This is associated with apoptosis and hydroph. I can never say that word, hypertrophy. I know there's better way to say that, but I apologize. Hypertrophy works for me, I'm sorry. And it's not correct, I apologize, but apoptosis is. Anyway, this signaling is a direct cause of ischemic reperfusion injury. We end up in a promoting, reintroducing, promoting, reintroducing due to this constant conversation between reactive oxygen species and TGF beta. And so what is an ischemic injury? I've been saying that word a lot today and I think we should probably make sure we're all on the same page. Ischemic injury, go for it. Lack of blood flow because what are you specifically costing the tissue? Oxygen, reperfusion is what? Restoration of the oxygen. What does the sudden influx of oxygen have the potential to do? Produce reactive oxygen species. So now we have a situation where we were deprived of the oxygen, weren't properly dealing with oxygen. We are now flooding it with oxygen which loves its electrons. Our sudden presence of oxygen produces reactive oxygen species which promotes signaling mechanisms. And then we have a signaling mechanism that creates more ROS, so reactive oxygen species. We now have a cycle that can just bounce around and do damage. And so areas that experience ischemic attack and then get reperfused quickly with oxygen are prone to this cyclical damage caused by inflammation and signaling. When that's your heart, that's pretty critical. When it comes to how this relates to other pieces and beyond the injury piece, TGF beta signaling also triggers other cell types and can change the patterning of cells. And so you can actually promote growth of cell types you don't necessarily want in a certain area, right? You can trigger immune responses. You can trigger transformation of fiber blasts. This is less than ideal. Jumping from an ischemic TGF beta linked reactive oxygen species connection to an inherited condition associated with TGF beta signaling, we have Marfan syndrome. And Marfan syndrome is a rare, autosomal dominant disorder that affects multiple systems, but one of the most profound implications of it is this tremendous height and weakening of the heart. The heart gets a lot of activity that causes it to not maintain its ability to handle load as well as it should. To simplify as much as possible for this. When it comes to the signaling, we are actually inheriting a Fripplin-1 mutation that affects the ability to properly trigger and regulate TGF beta signaling. And so something that seems unrelated in fact has this tremendous impact because we are actually altering TGF beta and it's very mutation dependent, but in this particular instance, the connection to the cardiovascular system is significant damage. Does this make sense? So lots of cardiovascular implications for TGF beta. Gotta do immunodeficiency when you're in immuno. No? So the primary immunodeficiency disorders or the congenital immunodeficiencies are conditions in which the primary observed effect is the immune system in part or entirely. So a lot of times it's going to be absent or at least reduced function of specific cell types or the entirety of the immune system. That's its main classification. Each individual change that you observe is rare, but collectively they're very common. And in fact, it's one of the areas of genetics that's the most changing right now because even last year we identified 56 new ones of this. Isn't that interestingly? Sequencing has led to a better identification of these disorders. Many of these, there's over 400, I cannot talk to you about all of them, so I'm talking to you though as a class first. Many of these are going to have very specific cell alterations. Lymphocytes, macrophages, T cells only, NK cells, T and NK, T and NK and B, depending on what the change is. It's really important that we do these kinds of studies because not only is this an area in which early intervention can have a significant impact, but it can often be curative. So we have bone marrow transplantation which can be completely curative for these conditions, especially when done early. Some gene therapies have been extremely effective. Prevention of exposure can be critical to maintaining healthy outcomes. I could talk about any one of these that I want to of the 400, and so I picked one that tied more with signaling that you might be familiar with. But what I do wanna note is there are three main things that we see in almost all of these conditions. Severe and unusual infections. Autoimmune and autoinflammatory diseases are common, and we will often see a predisposition to other malignancies. But all of them will have some impairment of the immune system. Could be completely absent function as in an a-thymic situation where you don't even have a thymus. Our example is gonna be XLA. And XLA matters because we're going to be affecting a tyrosine kinase, Bertram's tyrosine kinase. This is an X-linked recessive disorder, meaning what? It's X-linked, it's recessive, we're gonna see it affecting more males than females, and in fact, the rate in males is substantially higher. If our rate overall is one in 379,000, but our rate in males is one in 190,000. So that's much higher. This intracellular tyrosine kinase is this yellow one right here, and you can see it's talking to all this stuff. Anything up there like screams out at you, super familiar? Ras-Raf-Meckirk? Maybe? So growth signaling. Please note, this one is a loss of function. Over 900 different variations of this have been found to be pathogenic. What does that imply? Pretty foundationally important, right? Any changes to this seem to have significant impacts on its function. Your tyrosine kinase, what are some residues that are super important? Tyrosine residues, nope. Which variant you get can influence disease severity? You will experience recurrent infections. And so we reached our last 30-second, don't click over, thought we had 30 seconds, we do not, but this is a great place to stop because this is everything cancer moving forward. So ultimately, the entire last part of this is all molecular biology of cancer, genetics of cancer, differences between somatic mutation and inherited risk. Hereditary disorders that are cancer disorders versus those that have an increased risk of cancer. Questions or concerns? Okay, so just in summary, Monday, no longer required. Highly encouraged, not required. And I will pre-record Wednesday of next week's content so that you have all of it going into break. So wherever we stop on Monday, I will record the rest of the semester in tiny little snippets so it's easier to digest. By tiny, I mean like 20 to 40 minutes because my definition of tiny is off. But we will do those pieces and you will have all of that before you come back. So we can spend a whole week just practicing. Sound good? Okay, have a great day. I went over again, only because I was saying bye.