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Okay, so I think we'll get started today. We're going to be doing a little bit of genetics and cancer, which is quite a big topic in memes and something that I I saw this like, a little bit. But it's something that is quite important in terms of medicine. And the part one a and part would be courses. Today we've got Misha Alice, and those are best teaching us a little bit of genetics cancer on. Hopefully, this will be super useful to everyone so often, you know. Thanks, Mikey. Um So if if you go to the introduction slide, please. Do you next week? Yes. In my name's nation. Um, I'm on the second day of the graduate course. We've got Allison. A list here is well, who are on the history in for I respect to be off the underground course. Um, and this will be going over a lot. Um, but like, rest assured that you don't necessarily need to know everything. And to be honest throughout this entire cost and life, you will never be able to know everything. So don't worry about that. Um, as a refresher course, it should be something like they shouldn't be too many new things. But there might be a little bit of extra stuff that we've added in. Um, but yeah, this is what we're covering and that they get so we'll start with the absolute basics. First DNA is made off a sugar for state and a night or space, um, and then charge in a space is ah, adenine guanine, um, which are Hermogenes on time. And it's, I seem to tell your urine's, um, a pairs of tea forming to hydrogen bonds and jeepers with see forming 300 involvements. Um, sharp glass rule First, her want one story cometriq ratio of purines and permit Dean's, and that is that there are equal amounts of a anti and CNG, an idea. The forms a right 100 double helix structure with 10.5 bass past pretend it's 2 90 m lied and has major mine agrees that different proteins utilize the majority of our DNA is noncoding, Um, and there are 20,000 genes within our DNA and just tonight, thesis eyes of the tea and I'm and the genome is not indicative of how many genes that will be. We have about 2 m of DNA in each of our nuclear. So that's a lot to back into such a tiny place on Deanna Stupid called. In order to achieve this, it's like leave, um so DNA. Initially, it's packed into chromatin, and this is chromosome, well, DNA that is wrapped around his stones and other proteins. Two forms of Claritin are you Cram it in, which is a more open for DNA. That's transcription we active and heterochromatin that's condensed and not transcription. The active histone modifications, including a circulation methylation phosphorylation and you become tenation. Allow these properties. Um, and this is quite a help. A little picture that helped me get my head around. How do you get something? It's slightly so in the course, you'll learn about pro carrots and you carry it. But I have just like this done. You carry it now, um so DNA replication starts at multiple origin sites that smart by chromatin markers and local credited structures pull a M. Primates make RNA primers on Deanna before the polymerase to synthesize from on. DNA has to be since Austin the five prime three point direction. So for the three prime five prime strange, that's easy. Um, and this time I'm kind of shows that quite well for the other strong, which is five crime, three prints grand. Um, DNA needs to be synthesized in short Kazakh E fragments in the five times three prime direction RNA primers for the sake. Fragments is removed by ribonuclease on replicated DNA. Pull Emma rays, um, pulled out to replace this place is the residual primer making clap structures on. This is cut off both block and then you play spend one, and then DNA ligase joins the Akasaka fragment. So that's how we go from having a fragmented strand Terfel seconds ground. Um, so when you just as a quick note when I run in RNA needs to be made at the most basic level. DNA is on zipped are in a pull Emma rays attached to the part that's to be transcribed and makes are in a and then this is processed before undergoing translation to the proteins that it codes for. I'm not gonna go into more detail than that. Um, so here the pick, the picture in the top left is a carrot tight. Um, and a karyotype is when all the chromosomes in the genome. A paired and ordered humans have 23 pairs of crime, A zones, each made up off one chromosome from biological mother and one for a biological father. On. These homologous spurs of chromosomes contain the same genes, but different variations when a chromosome *** to get cystic remitive that continue exact same genes each of replication. And these sister chromatism them pulled apart during cell replication within a pair of homologous crime signs, which is one from 11 from your dad. There are gene local right, always I, which is where a gene is located in the crime. Same. Yeah, Leo's alternative forms of different genes that to give Marcus So you have different values from Mom and Dad, which is what supports here in variation. So what's you've got your genes there know a sort of thing that will always stay the same. You can your jeans been undergoing mutation, so one type of mutation is single nuclear type variance. This is where a single base within your DNA changes so they're transitions, which is the change between from a pureeing base to another period. Baseball from a pyramid in base to another pyramid in base Transversing is, which is a change from appearing to a pyramid. Single nucleotide variance can have an indulgence origin, for example, the damn in a shin of five methyl Cytisine in a CPG island. Or they could be exogenous induced by UV radiation or another mutation. These generally happen noncoding regions, so answer important because most of the DNA doesn't coat for proteins, but they can occur in the coding region. That's where you might start running two issues on There are a few ways to, um, fix single nucleotide variance that aren't perfect. These include based excision repair on nuclear total excision repair. You'll learn more about these next throughout the year. Then there are some other types of mutations, including in Dells and structural Variants in Delaware. Sequence of the is deleted or inserted. The's can either cause of frame shift because DNA is red in groups of three bases, which would cause the whole protein that is coated for by the gene to be put out of kilter or in frame, which is west. Say there's an instructional delusion of a multiple of three basis, which causes the reading for him not to be chef but there might be an insertion or loss of them. You know, acids. There are also structural variance eso They could be copy number variance where the number of copies of genius increased. They could be rearrangements of the gene eso a gene might be flipped within same chromosome, or it might end up on another chromosome. That's got a translocation. Andre also transpose a bill elements which are mobile genetic elements that are a bit like a retro virus andare able to move through the jeep move from into different bits of the gene. Gino. So, um, you take shins can occur either in the journal, which is the set of cells that going to form the gamete or in the somatic cells themselves in the body. Um, mutations occur randomly, but the rates of mutation could be increased by mutagenic agent. So should you be like, Sorry, we have I've I've moved on a slight. Yeah. Okay. And then again, sorry. So but you're more than your genes. Uh, it's why you don't look exactly like your parents. Your genotype gives rise to the phenotype, which is your expressed characteristics based on your genotype. So you're not going to be able to express the characteristic that isn't in your genes. Your phenotype could be a affected by dominant recessive Leal's. So some genes. The summer Leal's, which is a form of a gene, could be extracts really strongly. So if you have that allele, you will always see that characteristic. So in the diagram here, you can see if a If this bird has one copy of the Big A, it will always be red. Where's you need two copies of Ah, recessive illegal? To express the trait. Some genes also have incomplete penetrance, so that means that they're. If you have that gene, you might not always express the phenotype. You might need a certain environmental trigger toe happen on also variable expressivity of jeans so they're different next life. Sorry. They're different inheritance patterns for both normal characteristics and also for disease. So, um, you can inherit things in the dominant way, which is where, if you have the trick, if you carry the gene trait will be expressed taken. Eso conditions, which are inherited in a dominant way, include Huntington's disease. Then you can have recessive conditions such a cystic fibrosis, where you require a copy of each gene from both parents, a copy of the legal from both parents in order to express the condition. And this means that too healthy parents who are carriers can have an effective child wears and dominant conditions. One of the parents has to have the disease on do A can also be co dominant, so your blood groups are expressed code only. So if your mom is saying your dad, this be you could be a B. Diseases can also be excellent, which is where the Gene X is on the X chromosome on. So if it's an excellent process of condition, it's more likely to effect boys because they've only got one copy of the X chromosome. They've gotten it back up. That condition's include dust and much muscular dystrophy. And then you can also have on excellent conditions and also be dominant, which would mean the girls are as affected. His boys on down. You've got mitochondrion depletion disorders, mitochondrion DNA, which is passed down from your mother only on. But, uh, you can have mitochondrion depleting disorders there. And if you're watching the recording cause this and then have a guess, um what family tree matches. Which inheritance pattern? Um, for those of you that here I can tell you the red and blue one shows in orders are more dominant condition because you can see the only affected individuals can have affected Children. Then you've got here and excellent recessive condition because it's it's past two boys. Generally, the square means male um on. Then here is an autosomal recessive condition because unaffected bottom because unaffected, um, parents can have effect Children so. But of course there's more to the expression of your genes, then's just what they are. So epigenetics are sort of around the genes. Epi. Genetic modification of expression is a physiological process which controls jean expression. It allows cells to be specialized on allows, allowing different genes to be expressing different cell types. That's why you don't grow, you know, hair on your eyeballs. It can be achieved in the number of different ways, either three modification of the A modification of Testones using methylation, a circulation and a few other processes, little said genomic imprinting, which is where certain genes only expressed. If the parent of origin is correct, so unexamined of a condition, there's a pair of conditions which both involved something going wrong with same better chromosome 15. And if the paternal chromosome goes a bit wrong, then you get profitability syndrome on. If the maternal chromosome goes wrong, you get in German syndrome. Um, epi Jeremy complaint is also a physiologic is a physiological process on entire chromosome could be imprinted. So in women, because you've got two copies of the X chromosome and one copy will become inactivated to prevent a double dose of certain genes little form of our body, which could be seen in the human nucleus. Um, then coming back next light, please. Coming back something you might have come across when you did Ecology A level is the harder Weinberg principal, and it's this equation here. P squared plus two p Q plus Que squared? He was one. It states that a little frequency is in. The population will remain constant across generations, is really useful for root basic calculations of a little frequency for organisms that deployed. I got two copies of each crimes own on sexually reproducing so, but it does rely on many assumptions, which makes it not a fantastic model for human use. It seems that there's no genetic drift, no mutations know genetic shifts know overlapping generations know selection, No mutation, and mating is completely random, which doesn't happen. Human populations right, next light. And then there are different types of selection, which is where certainly lose will be selected for within a population so that frequency will increase. Um, selection could be positive, which means that you want to trade to appear in the population so those individuals will are more likely to survive and pass on their genes, their offspring. This also negative selection, which is selection against to treat on does balancing selection, which is sort of selection for two traits. There are some cases in which a negative characteristic is selected for within a population. If the heterozygote haven't advantage, that's where um, individual have one copy of a normal gene and one copy of that disease gene. This includes sickle cell disease, which is prevalent in west in sub Saharan Africa because ah Hatteras, I go isn't resistant to malaria. Genetic frequencies can also be affected by the bottle that genetic bottlenecks the founder effect in genetic drift, which explains the increased prevalence of genetic disease in some populations that started from a very small group of individuals. Okay, so one of the kind of clinical applications that comes up in the middle, of course, off genetics that you might have covered at a level is cancer genes arms. Er, there are a couple of key definitions you should be aware of. So to miss suppress a gene is a gene that controls cell division on its loss of function. Of these genes that drives cancer is you get uncontrolled cell division and then on on cojean is a dream that when functioning, normally drives cell division. So if you get over expression of that gene, then you end up with cancer is well on. The expression of these jeans is often controlled by methylation, so all of the machinery that we were talking about earlier for jean expression methylation of the DNA is inhibitory to that machinery. Bindings that's a physical block toe, everything that you need to be recruited for a gene to be expressed so hyper math elation, too much methylation of a tremor suppress a gene means that it's not expressed on that cell cycle isn't controlled, and then you can develop cancer on then hypo methylation so loss of methylation off on on cojean means that it will be over expressed on that can also lead to cancer. So one specific example off cancers that could be helpful for your essays and that some of you will have covered is breast cancer s O in some breast cancers. Eastern binds to an eastern receptor intracellular. Really? Um, and then this allows that receptor to move into the nucleus or access the transcription factor promoting the expression of genes that Dr Proliferation, Um so, Uncle jeans on, then that needs to the more rapid and uncontrolled division of spells and the breast. Is she giving you breast cancer on? This is also the basics off the chemotherapy drug tamoxifen s. So it is a selective eastern receptor modulators. It tries to stop this process. Um, so the Human Genome Project is another clinical application of kind of genetics. It comes up in the course, and a lot of fuel. A study. They're available. Um, so a GI name is a complete set of genes in a cell, while a protein, um, is a full range of proteins a cell is able to produce. So as Alice was saying not every cell produces every gene that it has because you have, like, different tissues. Skin. And when the only available DNA sequencing technique was saying a sequencing coat, the details of that particular method will be covered in more detail in men's. But essentially, you take a copy of a genome. When you break into random fragments, a new sequence, those fragments. You then repeat this with another copy of the same gene. Oh, on. Then you sequence loose fragments, and you kind of line them up. Keep on C, which bit overlapping on that using a computer. On the basis of all the overlapping sequences, you can reassemble the complete sequence. Um, so the final genome the human genome, was determined in 1966 and since then the research has moved onto you looking at the protein. So in a simple organism, this is quite easy. But it's harder. The more complex organism is, as we, as always mentioned, have noncoding DNA and regulatory genes, so the genome doesn't directly translate into the old story. I mean, these are all the way into the protein. Um, some of the other things you're covering the course in next generation sequencing their fancy methods. But essentially they're just faster. You can run multiple samples at once, and you typically didn't quite a small chip on. This is a lot of kind of exciting clinical implications because we construct to do kind of genetic medicine. Genetic counseling? Um, if you go back to breast cancer, there's a lot of research that's been done about Braca one on record, too. And carries of that gene often get offered. Um, kind of anticipate three surgeries and stuff like that to treat them before cancer develops because they'd be team so high. Risk of developing cancer, breast cancer. I can't. So another thing that comes up in Mimms on you'll probably heard a lot about recently. It is PCR eso just briefly a recap. He's PCR to amplify DNA to make copies of particular fragment on the goal is to make enough copies that you can then analyze the samples. For example, sequence it. It's important to note that you can only amplify given target, and the reason for that is because the process relies on primers and this is a short sequence of DNA. There's complimentary to the three prime end of the day that you're competing, said. To carry out DNA, you need the sample. You need prima's. You need free neck via ties that you're going to use to build the new strand. Um, and then you need DNA. Plumeria is on a buffer in a tube, so the plum Aries it's often do used is tack your memories. Um, and that's because it doesn't denatured when it's heated, which is one of the steps in the process. So the process starts with denaturant see heat, the stronger here, it says 95 degrees, and that's to break the hajj. Drumlin's with strength separate than a kneeling, which is where you cool it slightly to 50 to 60 degrees. So the prime a scan, kneel or form 100 runs with the three pregnant of the stroke that you're copying, um, and then extension. So you increase the temperature to 72 degrees for a minute, and then the tack polymer easy will bind to the primaries and start extending the copying strand with the nucleotides that you've put in your sample. So the practical applications of PCR we've all heard of PCR test for covert it. You can also do things like this on the slide where you separate strands and look at whether profiles much. So this is gel electrophoresis is, and what you do basis of this is that DNA has a negative charge. And that means that if you put your sample in a well on a gel plate, any person electric current through the DNA well front will separate according to the size on the charge that it has so heavy, biggest fragments of DNA will be heavier. And if you apply a current to the gel for a given time, the heavier DNA won't travel as far as the small fragments, which I liked. Um, so this means that you'll be able to separate out a mixed sample. Um, and the reason you might want to do PCR before you do General Electric pheresis is that it gives you enough to you know, that you can directly visual visualize different bands. Um, so a clinical example of the implication of genetics is cystic fibrosis on It's one of the most kind of well known or most famous genetic diseases on it follows the mundane ian inheritance pattern that we discussed earlier is in its water so more recessive. Um, so you need to 40 copies to experience symptoms on the carriers usually have no symptoms. Um, all individuals assist if I braces now. Well, in the UK, at least we'll have genome sequencing. Um, and that is to determine the precise mutation that's causing that it effective. Um, CFTR, which is the gene that goes wrong, Insisted I braces, Um, this provides the opportunity before parents to be screened for future future family planning on we can also kind of have therapies that modulate the CFTR gene. And they're one of the kind of major success stories of 21st century medicine. Um, and this is because difference mutations in this gene cause dysfunction in different ways, and then the modulators can enhance or even restore expression off functional CFTR um, CFTR, um and then another clinical example just to end on is down syndrome trisomy 21. Um, and, uh, the way that genetics can kind of try into this is that obviously, it's a genetic disorder. You've got an extra copy of creams and 21 on you can do some preimplantation screening for this. If you have a couple that's having IVF. You take a sell out off the, um, embryo and you can have a look at the carrier type and see where there any chromosomal abnormalities. Um, and then another way that you can screen for genetic diseases in early pregnancy is prenatal testing to something called amniocentesis, where you pass a needle into get sample of the amniotic fluid and you take the cells out from there and you profile them in the same way you look at the karyotype. Um, or you can do something called chorionic villus sample thing. Um, where you take a sample of the placenta and you profile those cells. Surgeon. It's have implications in kind of, um, obstetric health is all. So that's the end of our presentation. I'm gonna leave this, um, QR code up here. If any of you watch this recording, if you could scan it and goes feedback, that would be great. We really appreciate it on. We hope that you've kind of refresh your memory of stuff that you've covered at a level or in the eye. Be that might be helpful for you with names. Awesome. You guys a zit said please, uh, scan a QR code on. So I'm a few back for me if you're watching the recording, Um, it's really easy for us to get some information on how we can improve a lectures this year. Also in future years, okay?