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Ok. Um Right. Hello guys. Sorry, sorry, this is delay, sorry for the delay. Actually, this should be working now and we should be live. Um Yeah, I've just realized that I can't actually annotate my powerpoint which defeats half its purpose. So I'm gonna try have to try and explain it. Um Yeah, I'm I'm trying to find a way to annotate it but yeah, anyway, sorry. Um Hope you guys are all fine. Hope you guys are enjoying the holidays. I know if you're Imperial. I know if it's some other uniss as well. Uh You're gonna be doing a lot of like um sort of like uh revision for your mocks and stuff. Hopefully you can hear me as well by the way. So please tell me if you can hear me. Um just put it in the chat should be fine. Um Please someone messages in the chat. No, anyone. Can you guys hear me? Yes, good. All right, great stuff. Cool. Fine. Ok, so um my name's Isha, I'm a second year medical student Imperial. Uh today I'll just take you through to some genetics, some very basic genetics. Um And the main thing about genetics itself is just that you wanna understand the logic behind it and the concept itself rather than memorizing so, conditions and then you can just apply that same logic to any questions that need to write you. Um, and I'll teach you some tips, I'll teach you how I did it, um, and all that stuff as well. Um, so, yeah, I'm also pre K officer, er, for, for, for, for the beer, so for the Medical Association. Um, so if you guys have any questions about that, you can ask me right at the end as well. Um, this should take about an hour. It shouldn't be that long. Um, II kind of defeated the whole purpose now because I can't actually annotate stuff. Uh, which is what I was trying to do, but I'm gonna try my very best to explain it. Um, I may talk a bit fast at times as well, so tell me if I'm taking too fast and stuff. Um. Uh, yeah, cool. Uh, great. Ok. Um, so here's the outline for today. We'll just go through the main laws and modes of inheritance, then go onto pedigrees. Er, which again was the main thing and I should have got something going where I can if I can't. So, um, but I'll try, maybe I can try and draw it out and show it to you guys on the camera as well. Um, which I'll actually know I'll do that. Yeah, fine. I'll do that. Uh So, yeah, so that's pedigree. Um, and then we'll go on to unemployed and chromosome disorders. This is like a key one that comes up exams. You can have a lot of SBA S on this stuff. Er, genetic testing again is just pretty much mainly know knowledge, but there's a way you can, like, walk yourself through it, which I'll sort of explain today and then finally, uh single new polymorphisms and Hardy Weinberg principle for all of our other students, I know we imperial, we don't really do that, but for kings and for UCL, er, et cetera, we, we, we, we put that in um and I'll try my best to explain it again if you have any questions, pop them in the chat. Um I'll try my best. But, yeah, cool. OK. Uh Also just before I move on that picture on the right, by the way, um It's part of like a lot of uh research that's going on at emperor itself. Uh It's like a combination or intersection of genetics and um what do you call it? Genetics and like, er, cardio, well, cardio imaging and stuff. Um So there's a whole research group going on there. Uh I forgot the professor's name, but if you wanna get involved then uh just search it up and you see that picture come up, you know, in the right place. Um But yeah, also don't ask why I'm wearing a bean today. It's really cold inside. And, um, my, my, my, my head doesn't the greatest. Um, but yeah. Ok, we'll start. Cool. Ok. So with modes of inheritance it's very much, uh, you just need to figure out what mode it is, um, how it works and, uh, just apply that really. That, that, that's literally it. You don't need to know any sort of diseases for them. You don't need to know, well, you, you know, the common ones but other than that, um there's no need to memorize stuff. Just, just, just go along really. Um So, yeah. OK. So when, when it comes to ultrasound done and this is something that you've done in a levels as well. Er, you're just basically talking about how, um it, it, it's something that has to phenotypically, er, manifest in a heterozygote. And what I mean by that again, II should have drawn it is, um for example, if you have like that, if you can see it, it's a heterozygous. Um all pretty much the capsule venous more so with an autosomal dominant uh condition, uh you have two alles at each locus. A locus is a position on actual gene itself. The one, the dominant one was one that has effect. So, in this heterozygote, uh whether you're dominant, uh well, whether your homozygous is dominant or heterozygous, this condition will have the phenotypical effect on you. Um It's a single gene added, use, meaning that it's monogenic. Um And it will be passed on in their generations. So the key thing with, what about the autosomal dominant disorders are that you've got a vertical pedigree and by a vertical pedigree, I basically just mean that we'll come onto this in the next slide. But um you're just going down the family tree rather than going across it because because of the dominant allele, it's been passed down from generation to generation. Um Interestingly enough, it can be arried Dean over by, by Deano. I basically just mean that uh it, it can arise spontaneously within you. Er but this only really happens um early on so early on. So it only happens like in uh it's eggs, egg cells or sperm cells and we call those germline mutations. So if you have a mutation at that point, it will be passed on to you. So you will experience it and it can be passed on to your future generations as well. So that's the whole point of a German mutation. But we'd still call that uh de novo because uh your your parents didn't have it and it and it only sort of mutated within you if that kind of makes sense. So yes, German mutations can be passed down. Um the opposite of that again, if you wanna put it in the chart while I'm talking uh is uh what hopefully don't put somatic somatic. Er So it's somatic mutations. Somatic mutations are basically occur in like um cells that aren't egg cells or sperm cells. So they occur in like non embryonic cells, non GS and those ones can't be passed down while germine ones can. Ok. Um So if it does happen that you get this sort of like mutation going on and all that stuff, um uh you know, then you can result in mosaicism and all mosaicism is, it's just like um two different populations of cells within the uh the, the body itself with two different genetic makeups. So one population of cells has a certain genetic makeup with mutation, for example, and some don't without mutation. OK. Um A and each child, an affected person has a one in two chance of being affected. Again, I would have drawn this out but I can't. So what I mean by that is um an affected person. All right. Look at the vocabulary here, by the way, cos this will come up with the exams as well, but affected person and if they're talking about an autism or dominant disease, they'll always mean a heterozygous person. So capital D and small D, it'll almost never unless they explicitly state that as homozygous is dominant, it will never be capital D capital D. OK. So um yeah, so if, if it's, if it's an affected person, so this affected person would have a heterozygous um the genotype and then they'll cross over with someone with a homozygous recessive genotype. Then of course, you can see um, if I do a simple cross diagram, uh there's like a one in two chance of them being affected. Yeah. Good. All right, cool. Um, so, yeah, on the right, you can see that you've got 2022 pairs of autism which are basically non sex chromosomes and the 23rd pair being chromosomes. And then a pair you can see like a visual demonstration of um, that one dominant daughter and the father being passed down to two, that one male on the far right, and that one female on the far left, hopefully that's fine. This is a pretty straight forward. Um What I mean again, as I mentioned earlier is that it's a ver ped pedigree pattern. So it means it's going downwards, it's going across generations. Again, it's because you've got this dominant, er geo, this dominant allele um which has passed down from generation to generation. Again, it's nothing saturated, it's autosomal. Um So males and females are equally as likely to pass it on. Don't let them trick you out. Cos I know James Gardner loves this stuff. He'll, he, he'll definitely play in some tricky questions. Um But yeah, and three things you need to remember about aom dominant disorders. One, they gain the function, which means that um that, that, that new gene, that sort of dominant the dem one, the one, the capital d, for example, that now makes a new protein which can have a new function often it's something that, that aggregates. So over here on the right, you can see Huntington's. Huntington's, by the way, is a classic example of an aal dominance disorder. We'll talk about that more later. Um, so gain of function. So your, your, your protein is now, uh, clear the enzyme at a much faster rate or it's just, um, aggregating a lot more. For example, uh, it could be a dominant negative effect. And what I mean by do dominant negative effect is just that um the, so the mutated form of the protein, so that capital d all that is basically just gonna be interfering with the function of the, the normal one. So the, and this kind of leads on to haploinsufficiency as well. Cos you know how in the, in a, in a heterozygous person itself, uh they'll have one mutated form which will be the dominant one and they'll have one normal one because the normal one is recessive, it can't produce enough protein for normal functioning. Does that kind of make sense? Right. So that's why haploinsufficiency II is the thing. It's not the part of autosomal dominance because you lose one copy. Er, and that, that's the mutated copy, you lose that. Er, and since you've lost it, the other one can't produce enough protein to continue functioning. Ok. So those three things getting a function, dominant negative effect happen, insufficiency know those three things like the back of your hand. All right. Um, cool. Ok. So now we want to watch the more recessive again, straight forward. Um, a and straight away you want to talk about horizontal pedigree patterns now, rather than vertical ones. So this one won't be going down trees and you can see on the right over here as well. Um, I'm not sure if there's a later point or anything. Nope. Ok. Nothing's working great. Um, yeah, so on the bottom, right, you can see that you've got this, er, family tree and, um, the one right at the bottom you can see this consanguinous relationship and by consanguinous, I mean, just marrying your cousin pretty much. Um, we, this is not really a thing nowadays. Well, yeah, but, uh, back in the days it really was, um, and that double line over there that, that, that square and that, er, circle between the square and cycle means that it's a constant wi relationship. Um, and with constant relationships, your risk of autosomal recessive disorders increases a lot. Um, you can spot autism recessive disorders really, really easily, er, in large family trees. So this one over here is a Philip, I think. Uh, sorry. No, Charles. Second of Naples back in the day, if you see loads of loops in family trees, again, there was a question in one of our papers but if you see loads of loops in family trees, that's basically saying, uh, alarm bells should be ringing saying it's a cons one relationship and autosomal retested diseases would be prevalent here um because their risk increases, right? Ok. Um So, yeah, ag again, uh in this case with autosomal recessive diseases, um people are usually sort of carriers, right? Uh If they're a carrier, they've lost one copy of the gene. But you know how in autosomal dominant disorders that other copy couldn't produce enough. In this case, it can, so that, that normal gene that's not lost, that can produce enough protein to maintain function. So you're fine. All right. Um So for a, for your autosomal recessive disorder to be sort of expressed, you need two copies of the abnormal gene. OK. So you need small d small D. All right. Um Again, so you know how a autosomal dominant was gain of function. This is loss of function. A classic example with the in cystic fibrosis, uh with a defective chloride ion channel. Um that chloride ion channel or the protein that codes for that chloro ion channel has been lost, it's lost that function. Hence why it's a more recessive? Ok. Um So yeah, uh they can often like link it to like uh some other topic as well. Things like bronchiectasis, bronchiectasis is a chronic inflammatory condition you might learn about in resp um And that can sometimes be caused by cystic fibrosis. So they can be like, oh, this person presents with this. Uh they've known to have a genetic disorder, cystic fibrosis and then defective chloride ion channel. What sort of is it? And then they'll ask you a couple more follow up questions. All right. Um Again, it is males and females being equally affected uh because it's autosomal and um the each subsequent sibling of an affected child has a one in four chance of being affected. Again, what I mean by that is basically if you've got two heterozygous uh parents, right? So these two parents aren't affected but they're carriers, then um if I do a simple cross diagram again, this affected child is this one over here and they've, they've got like a yeah, the one that I've colored in and then they've got like a one in four chance of being equally affected again because it's um not affecting your, your, your sex. So it's not affecting the sex chromosomes. Um Each child each time has the same chance of being affected. Don't change it depending on. Oh, it's a second child. No, that doesn't matter because it doesn't affect sex. It doesn't affect anything else. Alright. Um Fine. So we talked about autosomal uh do dominant recessive diseases here. Now we're on to the extinct recessive ones. Um Just a quick overview itself. If you're xy, you're male, if you're XX or female. Um the X chromosome is a lot larger. It codes for about 800 more proteins and we'll come on to why? That's so um important later on. Um but yeah, uh these excellent recessive conditions themselves, they affect mainly males. Again, you can answer in the chat while I'm talking to you. But, um, they do affect mainly males. Why do they mainly affect males? Well, if it's an excellent recessive disorder, if you think about it, females have, uh, an XX chromosome, but males have an xy Chromos, right? So, in females, for example, if they have an excellent disorder like that, um, you can see the r as well. Hopefully. Yeah. Um then they've got one recessive all over here, but the other one's dominant in that sense and it sort of counters it out and that means that it's not expressed within the phenotype itself. So it's, it's pretty much just like an autosomal recessive one, but in this case, just with sex chromosomes, hopefully that makes sense because the other X chromosome balances it out, right? Um But in males, they don't have another extra chromosome to balance it out. So you can't, it, it, it turns out to be uh a sort of dominant disorder in males. So that's why you can see in males with the X ry, it's much more prevalent cos they've only, they only need one X chromosome um or they only need that mutation on that one X chromosome for it to be affected or for it to take effect phenotypically in females. You need that same mutation on both ex Chromos for you to be pheno phenotypically er expressed. Ok. Um again, the brother of an affected son uh has a one in two chance of having disorder. Now, you've gotta be smart about this one. Cos with X link recessive disorders, each son gets his X chromosome from his mother. So if you know they've got an affected son, you know that the mother is the one who's carrying that X chromosome, that X linked recessive chromosome. Ok. Um A and the father isn't all right. So again, if you do a simple cross, you do one X Rx over here and an Ry xy. So this explains it. Well, it should explain at least. Um again, yeah. So you can see at the top over here, for example, this bit uh these two over here, these are your females. So there's one in two chance of them being a carrier and these are your males, there's one in two chance of them being affected. Hopefully, that makes sense. Um Again, I'm really sorry. II was meant to anything on it, but I can't. Um Yeah, and hemophilia is a classic example of excellent recessive diseases. Um hemophilia, of course, a being er deficiency and clotting factor um eight and B being in, in, in, in factor nine. So they can link that very easily into your hematology as well. Um And they might give you like a pedigree diagram and they can just, this is a classic poem really. Um But yeah, cool. OK. So now we've got to a dominant diseases. Um In this case, uh I don't really need to draw stuff out because I can see it on the, on the, on the bottom, you would again have very much a vertical pedigree pattern. So it would be going down generations with the recessive ones like X thing, recessive and auto recessive, it's horizontal. So it's going across generations, but with the, the dominant ones, it was going down because that dominant alle dominates, I guess and it goes down. Um So, yes. OK. So if you've got, for example, an affected father um by affected father, I mean, again, they've only had, they only have to have it on the uh on, on the X chrom for it to be, for them to be affected. Um A and this type of females as well, they only need to have 10 on the X chromosome for them to be affected too. Um But it is a lot milder and it's variable in females compared to males. And again, uh this is because of X inactivation. So, X inactivation is something that happens uh very early on in embryonic development itself. Um It's, it's, it's like it, it's a random process. It's very early on in embryo development. And all happens is that some cells uh well, sorry, all cells inactivate one of the X chromosomes in females mainly. OK. All all ii in females. Well, only in females, all cells inactivate one of the exch now if that inactivated chromosome, that extremism happens to be the one that has this sort of extinct dominant disorder on it. Then in that cell, that disorder will not be expressed. And therefore, it'll be a lot milder because a lot of the cells, let's take, statistically, half of the cells won't be activating, it won't be displaying that X chromosome with that disorder on it. And therefore, it will be a lot milder in males. You can't do that because in males, they only have one X chromosome and it will be expressed at all times. Ok. Um So again, that's an example of mosaicism. That's a classic example of mosaic cos some uh some female cells are expressing e the X chromosome with a disorder and some uh female cells are expressing the disorder with expressing their cells or expressing the chromosome without the disorder. Hopefully, that makes sense. Ok. Um So yeah, if the mutated gene is on a inactivated extra chromosome, those cells will not express a mutation and therefore the severity we be mitigated. Uh Another example of it would be excellent hypophosphatemia, which is um excellent dominant, right? And finally, it is pretty much the most straight forward one. Ying disorders, obviously, they would only affect males because males are the only ones with the Y chromosome. So all sons of an affected father are affected. So I doubt they'll give you this er question and exams. It'll be really big. But if you see that only males are being affected and it's affecting every single um son of that male of that father. Then you know that's gonna be uh a wied um condition or white disorder. Um Again, an example is retinitis, pigmentosa wi linked. Um And yeah, you can see the pet passion over here on the right. Um So yeah, uh over here at the bottom, you can also see that II II was again trying to annotate stuff. I couldn't do it. Oh, well, but yeah, I was trying to sh show how males are described as squares, uh female circles. A deceased male thing about playing across through it, but with only one line through a deceased female is the same thing. Only one line through um a, a proband. What I mean by a proband is the person in question. So they often say proband er in II in, in exams and they may even sometimes ask you to take a picture of your own pedigree di that you created. Um, but they'll be, they'll often have like an arrow pointing at the person itself. Um So yeah, an affected male is someone who's got like, um uh I just, I should call it through effective female. The same. If you're a carrier for an excellent recessive condition, then you'll have a, a small dot Through it. Remember this one cos it can pop up and it eliminates a lot of possibilities. You don't need to think about a lot of this stuff, er, or, or the, the possibility of an excellent recessive condition if they don't have like a dot Through a.in them. Um This, what we mentioned earlier is a constant one relationship if you've got two lines between the mother and the father. Uh And at that point, bells should be ringing saying, oh this is autosomal recessive or it's increasing the chances of an autosomal recessive disorder. Um And finally, mitochondrial diseases. Um So again, this is pretty straightforward as well because there's one key fact that you can remember all mitochondria are inherited from the mother, all from mumsy, all of them are inherited from the mother. Ok. So if they, if, if they, if they ask about 01 mother and all her sons got it and like there, there's one father, the one mother and like um all the Children got this, this disorder from the mother itself and they uh and they're experiencing a lot of variability between them. Then again, alarm bells should be ringing saying that it's mitochondrial. Um II had this endosymbiosis a bit. I didn't really look at that in my first year, but it's just a bit of background knowledge and um the evolutionary parts of mitochondria, bacteria and chloroplasts, uh they were thought to all originate from prokaryotes because they have like similar size plasmids. Um They replicate in the same way through binary fission, er, et cetera. Again, it's a vertical pedigree pattern as you mentioned. So if your mother has it, then all the kids are having it. Um it is very, very variable. This is a classic example of the a question they can ask in the S AQ, why is it variable uh because of heteroplasmy? So again, with this stuff, with, with mitochondria, what happens is that you can have mutated genes within the mitochondria itself. And once you reach a threshold of mutated genes, once you get like more than half me genes, for example, don't quote me on what the threshold is. But if you reach more than half of this, I don't know threshold, um then at that point that mitochondria becomes mutated and you pass on that, you pass on that mitochondrial cell and the, and if there are enough of these mutated mitochondria within the cell, at that point, that cell you call that as like mutated as well. So, because due to random segregation and uh even sometimes non disjunction or like throughout pretty much its reproduction itself, you can lose and you can gain er, mutated mitochondrial genes. Ok. Uh And if you've got more of them, then of course, you'll have heavy symptoms, you'll have severe symptoms. If you've got less of them, you'll have milder symptoms. Ok. So it's all random. Um, so it's just random se that, that, that, that decides how many mitochondria you have in each cell, how many mutated mitochondria you have and within the mitochondria, how many sort of mutated uh mitochondrial DNA you have? Ok. Um So the more mutated mitochondrial DNA, you accumulate, the more mutated mitochondria you have and the more your symptoms, the less the less. Ok. Um So yeah, that, that you just have a lot of variation between um the the diseases. Um an example is lebers hereditary optic neuropathy. Um So yeah, again, you can see on the right over here at the top, the top image, it's showing uh disease, uh phenotype and the threshold for phenotypic um expression. So you can see more muted mitochondria. It means that it's expressed less means that it's not uh at the bottom, it's doing the same thing with, but this time with mitochondrial DNA, um the ones with a cross next to them, you can see a lot of red circles which means that yes, they've got a lot of mutated mitochondrial them and therefore those are the ones that um will, will express the disease. OK. Finally. Um uh So first question, what is the risk of a female inheriting an allele for an excellent recessive condition if her maternal uncle is affected. And I'd like you guys to draw out like the whole sort of thing. Um The, the, the chart with the pedigree diagram if you can. Um But if not, then just answer it, I'll give you guys 30 seconds, I'll draw it out anyway, cos I can't draw it on this one. So, yeah. Um, if you figure it out and just put it in the chart, if not, then don't worry, I'll answer it in 30 seconds anyway. Um, but yeah, please do. There's like it doesn't really matter, just dishon the question, I guess. Um, so yeah, and try and like, use all the correct, um, nomenclature too. Um, so, yeah, it, ok, so I don't think anyone's put anything in the chart, um which is great. Uh If you don't have anything to tell them, don't worry about it. Um I'll give you guys like 10 more seconds just in case just in the hope that someone puts something in the chat. Oh, someone did. Yes, you can have another minute if you want. Yeah, but the guys, if you go at this rate like this might take like 1.5 hours, but I'll do it quickly. I promise you, I'll do it quickly. I'll, I'll, I'll keep, I'll stop you happy. My bad, sorry. Yes. Great, good, good stuff. Uh Leila and Sarah. Lovely, good. Um Yes, it is uh 25%. Again, we're looking at it in the sense that uh first of all, you wanna figure out with this stuff, you wanna work backwards? Ok. So the way I drew it again, hopefully you guys can see this. Um Let me see if you guys can see. Ok, so can you see that? Yes, you guys can see it. Ok, so um If I keep this here like that, this is so cooked man. OK. All right. So that is your proband. OK. So this is the person that we're talking about, this is the, the female that we're talking about. All right, this over here is an uncle that's affected. I've already, I showed you a genotype. It's XY and it's excellent recessive. So this person's called X, the R of the small R and the Y chromosome next to them. OK. This is the person that's affected. Sorry. Um This is the proband and now we need to work backwards. So if this person is affected, if their maternal uncle is affected, then because this person is a male, they inherit their X chromosome from the mother. So we know that this person, so this maternal uncle's dad. So this, this, this lady, the probands maternal grandma, she must have the disease. So I should have called that in, but we must know that she must have the disease. So it should be like that, right? She's got a disease now. OK. So she's got a disease. We've got to assume that this guy doesn't have the disease cos if he did, then um then it'd be like, well, then that's what there was, wouldn't, it wouldn't be a thing. But yeah. Um so she's got a disease. He doesn't. Um And if we did a cross, I did this cross over here. That one, this is the one with the disease. So she's uh this is the, the chromosome, the recessive one, that's the normal one and the xy chromosomes are fine. There's a one in two chance because we know that we're talking about the mother already. So there's a one in two chance of her inheriting or being a carrier of the excellent recessive condition. And then uh we need to do the same thing again for the, the second um for the second, for, for, for the second cross. Uh again, we're gonna assume that the, she's a carrier for the, for the condition. So Xr being the recessive one and X being normal one and then Xy being the probands dad, again, it's a one in two chance because we already know that she's a female, right? So we can exclude all the male, all the male results. So we already know that's a one in two chance of uh her being a carrier as well. And then once you multiply 1/2 times, 1/2 and you work downwards, um you get 1/4 and that's your answer. Ok? Um Hopefully that's what I explained. Hopefully you guys get that again. If you, if, if, if it's a male that's inheriting an excellent recessive condition, you must uh we'll just, just know straight away that the female or the mother must be either. Well, she, I did it wrong actually, she's, she's not a, she's not affected by it, but she's a carrier of it. Ok? You've got to a and no one else is affected by it. This is what threw me off a lot of the time. You, uh, I assumed every single possibility and I was like, what if this, what all this happen? What is this gonna happen? No, with this stuff, you've got to assume that, um, no one else is affected apart from the people that, um, they're talking about, right? So we, we have to assume that the maternal grandfather, grandfather isn't affected and uh the maternal grandma has only got um she's only a carrier of the condition. She's not affected by it. OK. If she was affected, they would have said in the question itself. Um OK. Question two mutation causes some sodium and activation channels to stay closed. Which one is most true? Um This shouldn't take that long. Really? Uh I'll give you guys like 15 seconds. Yes, great. OK. So it is an autosomal recessive condition. It's an autosomal recessive mutation again. Remember, autosomal recessive means loss of function. Um B is just her potential that if you've done a S equation that's to do with like intracellular versus exar ion concentrations and all that stuff, that's all NS equations. That's a newer. Um I think um So yeah, and the ap uh that's like your um absolute refractory. I think that would actually increase in this scenario. Don't quote me on it. And then in vivo lockdown it's actually used to reduce expression of genes. Um It's not used for like uh like a, a loss of function mutation. OK. So hopefully that makes sense again. Remember, autism or recessive means loss of function, autism or dominant means gain of function. Um OK. This is why I need you to annotate but I can't. So now it's looking so dodge. Anyway. Um I'll, I'll try, I guess. Uh OK. So a couple of do this at home with you with like a pen and paper, please. Um, th this is how you get the most out of it and you'll like, walk through it with me. Um Cool. So a couple who are both known to be carriers of a recessive disease, uh have an unaffected child. They want to know the risk of them being a carrier, right? A being a normal allele and a being a disease allele. Ok. So immediately, uh uh I know that they're both carriers. So immediately I'm immediately, I'm just gonna do a cross, a simple cross. Um, and, um, once I do the cross itself, I've got four possibilities. I can, I, um, can eliminate one possibility straight away the, the possibility of this person being affected. So that small, a small a um, the, well, the homozygous recessive condition that's gone. Right. And now I've got three possibilities left. Um, and I need to figure out the possibility or the probability of them being a carrier. So, out of the three probabilities or the possibilities two in, in two conditions, they're the carrier. So the answer would be 2/3. OK. Hopefully that makes sense. Um Again, you guys can see it over here. Yeah, good. All right. Crazy. OK, good. OK. So again, draw this one out guys. Um I think it'll be a lot better. Uh If you, if you draw it out. Cool. OK. Uh A man and his wife discovered that they both have a um they, they, they both have an uncle who is affected by Gaucher disease. Again. You don't need to know what Gaucher disease is. They'll throw you running diseases at you. Um Man and his wife have this gout disease so fine. Uh The maternal uncle, I think on the wife's side and the paternal uncle on the dad's side, um Now they can ask you these questions. I'm drawing it as I go down by the way. So yeah, they can ask you these questions um in the exam and they'll basically just assess your understanding and try and throw you off. OK? I'll try and work with you guys from the start, but I don't know how feasible it will be without like throwing out. Cool. OK. So mine and his wife discovered that they both have an uncle who was affected by Gaucher disease using the pedigree diver in the drop down box, calculating the risk of them having a child with a condition. OK, fine. So um again, wait hopefully. OK. Yeah, hopefully you guys can see um again, that's the diagram over there. Cool. So you've got to work backwards. We've gotta work from the people who are affected upwards all the way to the top and then work down. OK. So always go from the people who are affected and then work your way down. Alright. So in this case, we know that you've got two uncles that are affected. OK. Um and we need to figure out first of all, the inheritance pattern of this condition, right? So can it be autosomal dominant? No, if it was autosomal dominant, then both grandparents. So if you can see over here, these two people over here and this, sorry. Yeah. So here this side, these two people, uh these two people, these two would have the condition if it was dominant all but er it's not OK. So it's not autosomal dominant. Um It's not wi er is it wi linked? Well, if it was wi linked, then the the the the the proband w er would have it. Well, no, if it was wi linked, then the probands dad would have it as well. Um Is it excellent dominant? Um Again, no, it's not. Uh that would be, again a birth patter. You see either the mother or the, well, you see either the grandparents suffering from it and they'd be colored in. So you've got to assume that only these two people are, the ones affected, everyone else is either a carrier or not affected at all. Ok. So what, what's the way that the, the two grandparents can pass it on where it's either excellent recessive or, or similar recessive. It can't do well. And the reason why we can eliminate excellent recessive from this uh condition is, um, if we go back to both sides, you saw that the person over here with the ent recessive condition, um they would have a.in the middle if they were a carrier for it. So we would have to, if, if, if it was an excesive condition, then either one of the grandparents would have like a.in the er well, yeah, a.in them as being a carrier for an extent recessive condition. Ok? Um So, so it can't be that. So it's got to be uh a, a autosomal recessive and it shows as well cos um it's, it's a horizontal pedigree pattern and it's not going down vertically. So if it's, if it's autosomal recessive and you've got two uncles who are both affected by the condition, we must know that both sets of grandparents must both be carriers for it. Ok? There's no other way for these uncles to get the, the condition. They have to both be carriers for them to be susceptible to the condition itself. Fine. So let's take uh the lethargy before Gaucher disease, right? Um And again, the smart thing about this one is because it's got a pretty much symmetrical pedigree pattern itself. You can see down the middle, you can pretty much cut the whole thing in, in half, right? Uh And because autosomal uh recessive conditions don't really affect the sex. Um whatever you do on one side, you can do the same thing on that, on the other side and just modify at the end. Hopefully, that makes sense, right? So we're gonna use the capital G and small G, the capital G being dominant, small G being recessive. Um And I'm gonna start right at the grandparents. OK. So if I do a cross for the grandparents themselves, um, and bear in mind, my next like mode of action is I'm trying to go from, I figured out what the grandparents are. I'm 100% sure that these grandparents have now got both been carriers for this recessive condition. Ok? Um, so I'm 100% sure that they, that they are carriers of this recessive recessive condition and now I'm working down to the proband. OK. So, um, I've done the cross now and, um, I, I'm looking at uh this person and this person, so this person and that person, I'm looking at these two people in particular, the ones that I pointed arrows at. Yes, because these are ones that go directly towards the program. Um, and I've done the cross for each, each grand parent itself at the top. Uh Hopefully you can see that. OK. And with this cross, I can show you that um on this side, you've got a capital G, small G, capital G, small G and both of those people aren't affected, right? So I can already eliminate the small, the, the, the, the homozygous recessive condition. So I can eliminate that already. So now the probability of them being carriers for the condition would just be 203. OK. Cos I, yeah, hopefully, hopefully that makes sense. OK. So again, probability them being haring condition is two or three. And now this is the T bit cos now, after you've got the probability of them being carious for the condition, you now want to look at two random people that have just entered the family tree out of nowhere. Now again, bear in mind, please, please please assume that these people have not got this recessive recessive value at all. You've got to assume that these people are really, this is really, really rare and these guys have like a perfect phenotype of homozygous dominant. Alright, that's what you've got to assume. OK. So now we have to do another cross for someone who's homozygous dominant and someone who's heterozygous. OK. Um And with this cross, we end up having that, we end up with a one in two chance of probability of this person. Um OK. Why is that not looking anyway? Yeah, we have a one and two chance of this person uh being heterozygous for the condition. So now we have one or two chance of the proband and his wife being um, be, oh, well, being heterozygous for the condition itself. Ok. So, or being a carrier for the condition. Um and now we need to figure out the probability of them having a child with a condition. So now if you've got two carriers, you multiply those two, then you've got a one in four chance of the baby having the condition again because you've got two legs and you cross the two legs over. So you get a one in four chance. So now your overall chance would be 2/3 times by 2/3 times by 1/4, which is 1/2 times, 1/2 times by another 1/4. So overall, it would be like 4/9 times by like 1/4, which is 4/36 times by one of the four, which is one of the 36. So if your answer is one of the 36 then you've got it correctly. Ok. Again, I'm gonna try and explain it to you verbally. It's not the greatest if I like show it and talk it, it's not really doing the most justice right now. But um yeah, uh the answer is 1/36. So if you've got that great, um you're gonna go. Ok. So again, work from the people who are affected. Um since they're affected, I know for 100% sure that the both grandparents are carriers of the condition. Um, and therefore the probability of them passing it down would be two of three. Again, remember I eliminate one condition straight away cos they're not affected. So this, the probands dad, uh, and the, the probands wife's mother. Right. They're both, er, not affected by it so I can eliminate one condition and I've got two left. So it's 2/3 for them being carriers. And then again, now I've got to assume that, um, the, the probands mum and the probands wife's dad, uh, are both just randoms that I've turned up out of nowhere and they've got like a homozygous dominant, uh, genotype. They don't have that risky all. Um, and again, if you do that cross, you'll get a one or two chance of them inheriting that sort of heterozygous phenotype, uh, genotype. So now I've got two or three times, one of the two each side so far. So 2/3 down from there and then 1/2 down from there and then 2/3 down from there and one of two down from there. So I've got 2/3 1/2 2/3 1/2. And I do the final cross two extra. Um, there's a one in four chance of two extra zygotes having a recessive, a homozygous recessive baby. So it'll be 2/3 times 1/2 times, 2/3 times, 1/2 times by 1/4. If you times all of them together you get 1/36 which is the answer. I'm so sorry. I couldn't annotate that. I don't know why metal is playing up today. I can't annotate. Um, but yeah, hopefully my dodgy annotation helps. Uh, I, if it does then say yes. If it doesn't then I'll just move on. Um But yeah, cool. OK. Um And finally another walk through uh calculating the risk that individuals. Uh IV four, by the way, IV four means that you always run a generation. Fourth, this is fourth generation, fourth person, fourth generation, fourth person and fourth generation fifth person have an affected son, again, son, not child, son uh for the pedigree child below. Take your own time for this one. You can take a screenshot of this one for example. Um and doing your own time. But um I'll just explain it very briefly, I'll go over it at the end if we need to um o on the book and stuff. But uh in this case, we're again looking at an autosomal uh recessive pattern one because you've got this constant minus line between er generation four, fourth person, generation four and five. You uh so that again means a long breast will be brain. Uh It's, it's, it's autosomal recessive. Um Also it's not really a dominant pattern and the people who are affected. Uh So, for example, second generation number two, his parents aren't affected. Um So one of them should have been at least affected for him to have the condition if he was dominant. So we can rule out excellent dominant, we can rule out widely dominant because er third generation four and five have it, we can rule out um autosomal dominant. And now we've only got excellent recessive and widely er, autosomal recessive left. Again, we don't see that small.in the circle and the, er, so we do, we can rule out excellent recessive conditions and you've only got autosomal recessive left. All right. So again, with this one, you wanna work uh at your nearest point of contact. So you can see in the fourth generation um number one, sorry. Yeah, in the fourth generation, number one, he's affected, but both his parents aren't right. So this must mean that both his parents must be carriers for him to be affected, right? So both his parents must be heterozygous or heterozygotes for him to be affected. So, again, you do a heterozygous cross and then you figure out, um again, I'm looking at fourth generation number four here. Now, um that person's not affected, is he? So you can rule out the affected one and you've got, er, out of three, the probability of him being a carrier would be two out of three cos you've got two heterozygous um possibilities out out of three, nonaffected ones. Ok. So the probability of, uh, number four, well, generation 44 being a, um, heterozyga or being a carrier for this recessive condition is two out of three. Now, if we do the same thing on the right hand side for uh, generation four, number five, now this person, uh, we know that their parent, one of their parents is a sufferer of the condition itself. So they must have a recessive phenotype. Um So they must have uh smaller, smaller, so homozygous recessive. OK. And then again, you've got to assume that number six is um is homozygous dominant because again, we've got to assume that this, that this allu is really, really rare and um like they, they, they're not a carrier for it whatsoever. Again, we can't tell the start of this, but we've got to assume it. So make sure to assume this stuff. Alright. So again, if you do a cross between someone who's homozygous is dominant and homozygous is recessive, 100% all four of those people are heterozygous. So now we've got 100% chance that that number four, generation four, number five is Petrogas and generation four. Number four. Well, they've got two thirds chance that they have. Like. So again, we do a um a whole a, a plot thing. So we do another plot diagram er, in this case we like a, how do you, how do you call it like a cross, I guess. Um, so yeah, if you do a cross, uh, between two extra goods and again it'll come out as, um, so like, I don't know, like capital B, small B, capital, er, P small B and uh, an affected son, there'll be a one in four chance of you having an affected son. Um, well, there'll be a one in four chance one. Sorry, there will be a one in four chance of you having an infected child. Um because there's a son there, you have to multiply that by 1/2 cos there's a one in one in two chance of you having a son. So first of all, you figure out the chance of them having a son, one and two and then you figure out, ok, what's the chance of them? Um being affected by it? You'd say um that would be uh one over um two. So you do 2/3 times by um 1/4 times by 1/2. So in the end, you get 1/12. So if one of 12 is your answer, then you're fine. I'll go over it at the end again. Uh If you guys want on, on the pa few paper. But yeah, if you get one of the 12, then that's your answer. Um I'm doing these along with you by the way. So uh yeah, that I'm I'm trying to use my own logic to try and explain it to you guys. Anyway. Uh finally, OK. There's not much limitation for these, with these, for these bits. So hopefully you should be fine. Um Cool. OK. So now we're on to karyotyping. All karyotyping is, by the way is a seen chromosomes. So now you're trying to see chromosomes. Um I, I've got a picture of a karyotype later on. Uh but we can see that in a bit. Um So yeah, the largest course of early pregnancy loss is uh chromosomal abnormalities. Um I don't know why I put Instagram on there. Why do they inscribing there? Oh, yes. There, there's an account on Instagram called my Medicos Official, which is really good uh for these kind of questions and I actually found this question um on there. So, yeah, my Medicos official if you wanna guys wanna get you on that one. But yeah, anyway, the large cause of early pregnancy loss is um is um um uh chromosomal abnormalities. OK. Uh And we usually use it for um younger Children and for fetuses uh early on in pregnancy itself using either amniotic cells which are basically uh they contain shed like shed cells from the actual baby in the amniotic fluid or uh chronic chronic vous sampling. So, um from the placenta. So the mother, she has those, those cells from the placenta and they're again identical um wi with, with, with, with the same cells from the fertilized egg. So, pretty much you get the same genotype from birth. Ok. Um We'll get onto that in a bit. Uh Again, with typing, you need to know a couple of stuff. So phyto hemotin is basically needed. Uh And that stimulates T lymphocytes to grow and differentiate. You may be asking why we're not doing immunology. Why do we need to know this? Well, when you're karyotyping, um we want to see the chromosomes as clear as possible and this is basically when they're in mitosis, when they're in the metaphase, for example. OK. Uh And COCO is a thing that actually arrests them within the actual met cell. But PTO hematin is a thing that gets them out of G zero, which is a senescent phase and into the cell cycle. All right. Um and gets them dividing, which is what we wanna see. Um Again, G MZ staining is what basically, so that's the stain that we use G MSA. Make sure you remember that. Uh and that leads this G banding patterns. So you can see on the top right over here. Er it leaves that pattern of bands again, get used to the no of this band. So let's say this is chromosome nine. The P arm at the top is a small arm, you call that petite, the bottom one, the bo er the bottom is called the Q arm. It's a long arm. Um The telomeres are at the end and the centromere is the bit that joins the, the, the petite arm, the P arm to the Q arm. Ok. Er, G light. So if you, if you've got a light arm or light band, that means that you've got a lack of, um, well, a lack of condensed DNA. So it's much more open. It's called E chromatin. Ok. So think gu, all that stuff, that slang language. Um, E chromatin. More open, more genes. All right. So more expressions are going on there. So, more DNA. Um and with, uh, with the dark bands, you've got heroin which is like tightly wound DNA, it's much more compact, you've got fewer genes in there. Um And BP HS all that is is it's a way of saying bands halo set. So, um you can see like you, if you use high resolution, you can go like further into smaller and smaller bands. So you can be like, ok, nine P which would mean the ninth chromosome, the P arm, er 22.3. So ninth chromosome P arm, the 23rd, 22nd section, the third bit of that. But you can go like further and further and further. Um, so BS bie just like the, the further you go in the more sort of aberrations, the more like um er abnormalities. So you can see. Ok. Um whole genome sequencing is feasible. Uh It done sometimes in very rare conditions and in research but is it like very practical search for a lot of conditions debatable. Alright. Um the price is really, really high often um and it can only be used really for personalized medicine itself. So uh yeah. Oh sorry. Yeah, again at the bottom as well. This is again, normal patient that you have to kind of learn. Um So again, P petite short arm Q long arm pt being the tip. So ti me uh QT tip of the Q arm is centromere. So that's the bit, middle bit. Um del is deletion. We go on to single, single chromosomal abnormalities in a bit. A derivative is basically just a chromosome that contains extra material duplication is just that bit of the chromosome. Um That's been duplicated either beneath it or in some other place. Uh Insertion is something that's come from another chromosome in. Um does it doesn't have to be the same material as an N A duplication and an inversion is when it's basically just been flipped around. Um And t the translocation, if we do it before the chromosome number, then we know that they've lost or gained the whole chromosome if it's after and they've gained or lost uh a bit of the chromosome. OK. So we get to translocation in a bit. So yeah, uh unemploy, alright. Unemployed is basically just an abnormal number of sort of uh sex pre really, it's just an abnormal number of them. Um uh It's, it, it can be caused for a variety of different reasons. Um The the purpose of meiosis really in general is just to produce these, uh, four genetically different, er, haploid cells because then they can combine and produce that fertilize egg with 46 chromogens. Um, and it does that through, uh, it's like, um, runs the gra and crossing over and all that stuff. Um, but the most common like forms that you'll see would be Trisomy 21 which is also known as Down Syndrome And then things like Turner syndrome, which would be, which is a modest toy, which means that you've got one chromosome. OK. Um And there's many different ways in which you can have unemploy. The main way that we talk about is non disjunction. So this happens early on in early Embron development. It's basically when you have an uneven number of chromosomes in the daughter cells um because of something going wrong with like your spinal operators essentially. OK. So they don't separate correctly. All right. And again, this, this makes common sense really if it happens in meiosis one, which is your first sort of reduction division itself, then all your four haploid cells will be affected and they'll either be, I don't know uh have three chromosomes er or they'll have one chromosome rather than having um two. OK. Um This is after fertilization. Remember that by the way, this is after fertilization. Um So then all cells will be affected if it's in meiosis two. then only half of them will be affected and then they will be fertilized and then they will have either monosomy or trisomy. Ok. Sex pre adelo. Um, that's the one that's most tolerated itself. Why is the most tolerated? It's because of X inactivation, as mentioned earlier. It's this random process that happens mainly in females. Well, actually, no, only in females. Sorry. Um, and you, they basically just naturally randomly, just inactivate one of the X chromosomes. Ok. Um, and in doing so, if you've got that mutated, sort of, um, er, if you've got that mutated, sort of form of extremism and let's say you have trisomy and one of them has a, had been inactivated. Now you're normal, you're back to normal. Again, you've got two left. Ok. Um, so, yeah, again, the low gene content content on the Y chromosome, um, that again means that uh you can disrupt the gene dosage more in males. So, if you've got sex prim unemployed in males, it's a lot worse in females because they've got less genes in males, you'd rather have more genes than less genes all. Um, so because the Y chrom is a lot shorter and a lot smaller, um, uh, it's affected more in males but sometimes even the abnormal X chromosome that's inactivated in females, for example, that can still have effect because X and Y chromosomes, they both have regions called pseudoautosomal regions which act like autosomes. So, even if this X is inactivated, one part of it can still take effect because um it's still acting like an X er like a like an auto. OK? And some genes are still gonna be expressed. All right. Um So that will escape the inactivation bit. OK. So you can see a cty of the hair at the top and you can see how non disjunction occurs in meiosis. One on the left and myasis two on the right. Right. And again, it's just that album and pull of chromosomes which results in that uneven number of chromosomes in the end. Um Cool. So choice between one, this is the standard most common um unemploy itself. Um Yeah. Yes, it is. Um Again, we were talking about the main factor in uh 21. The main factor is maternal on dysjunction and it specifically occurs in meiosis one. So it's gonna affect all the cells, all hopefully you guys are following on. Uh tell me if you're not and tell me if you need to go over anything. Um And, and one key question that will always pop up, that will pop up somewhere. Uh They'll either talk about occurrence of abnormalities before they ask you this question, but it will definitely come up. Why does the risk of maternal nonunion? Why is it increased with age? Um So women with uh women who are older, they're much more likely to have a child with uh Down syndrome. Well, again, follow the cycle the oocyte cycle. So, on the right, you can see the cycle itself. Women are born with a finite amount of oocytes all and they remain in prophase one until you undergo ovulation and um until they go on to like menstrual cycle uh and they end up puberty and stuff. Alright. But then your secondary oocytes that have now escaped uh prophase one are now basically pre before uh well, until fertilization, they're, they're, they're in metase two. OK. And the longer they spend in this form, you've got the increase likelihood of the non dysjunction. So the longer you spend, the older you are, the, the, the likelihood of non dysfunction increases because your spitted apparatus, the thing that actually separates the chromosomes. Uh and the thing if it goes wrong can cause uh an that degrades at the time. So then, then that doesn't separate the chromosomes correctly. Um And then your homolog is chromatid, which is why it separates to make the chromosomes. Um They don't pull apart correctly. OK. Um So, yeah, remember it's a degradation of spindle apparatus, er, because you're just kept in that sort of er, they're frozen in that state for a lot longer. OK. Um Or they're held in that state for a lot longer. OK. Cool. Um And as I mentioned again, uh yeah, but, but, but another thing they may ask epidemiologically, 75% of Down Syndrome babies are still born to mothers under age 35. Again, this is common sense really. Um, it's just because it just purely because, um, women aged un un, under 35 they have more Children. Ok. That's why more babies are born, uh, without the room. Um, if they were older, the, the risk increases. Yes. But there won't be more Children because they'll have less Children. I didn't feel that a lot. Ok. But women under age 35 they have a lot more Children and therefore more of them have Down Syndrome. Uh The women who are older, yes, the risk of Down Syndrome increases dramatically. Um But they're having less, less Children anyway. And therefore in the end meric and discreetly, they won't have as many as people who are younger than 35. Um What about pots? Yes. So the father, there's no sort of unemployed, all that stuff, the, the suicide degradation, all that stuff going on with the father. Um paternal age is not a risk factor whatsoever, but paternal smoking definitely is. Ok. So smoking is a tern risk factor um of, of, of trisomy or monitory uh in particular trisomy 21. Um And again, remember, more genetic information is a lot better than less genetic information. Ok. So trisomy is a lot better tolerated uh than, than monosomy. Trisomy still does disrupt gene expression through, over expression of genes. Uh uh But the cells can adapt to that with monosomy. It, it's barely, not even viable. Like one thing is viable and that's turner syndrome in, er, in females. And again, that's because of x inactivation in males. Turner syndrome is lethal, lethal, er, and by Turner syndrome, I mean, 45 X, um, 45 meaning that I've lost one chromosome and they've only got one X chromosome. Alright. Um, cool. So you remember monosomy is a lot, lot worse than trisomy. Uh Trisomy can be tolerated. Um uh although poorly, it's poorly tolerated but it's compatible with life. Moy often is not even viable with life, right? So, remember that. Um cool. Ok. These are quick. Um These are things, do you, do you need to remember really single chromosome aboral that can occur, deletion, deletions as a result of uh unequal crossing over where I could break in a chromosome, er and it can occur at the ends of chromosomes usually. So, remember the end, so PT and QT being the ends of the chromosomes breaks in those chromosomes and crossing over that can often cause deletion. Uh deletion again is just basically you just lost a bit of genetic material. Ok. So you lost a bit of genetic material, um duplication. Uh That's basically the s er number two, the figure number two over here, you can see that it's the same er gene material that's been Chron er that's been duplicated and it inserted. Um inversion is when that same genetic material is sort of flipped. There's two types of inversion. Power, power inversion is away from the centromere so think um I don't know, Piros. Piros like to fly away. So Paracentric away. Um Perry, I was trying to do something earlier about Perry and Perry. Perry sauce and it didn't really work. But yeah, Peri is around the centromere. So that's an inversion that flips around the centromere. Um Again, these single moralities, they don't really affect the actual carrier itself, but they may affect uh Children uh and the Children may have deletions and insertions and all that stuff. Um Yeah. So these, that's the stuff I remember. Um the same thing with two chro aal. Again, there's two types here. So you can see on the, on, on the left at the top. Um You've got insertion. So all, all, all that's happening with insertion is just that it's, there's deletion from one end. So one chromosome is, there's deletion from one end and then in the other chromosome, er there's insertion. So all er insertion is, is, it's got deletion in one chromosome and um in insertion in another one. OK. Um And then the, the second type is translocation where they basically just switch. So, rather than one game from another place, one goes to one and the other one comes back to that. All right. So there's deletion in both areas and there's um insertion in both. So it's just switching around. OK. Um So, yeah, so two are abnormalities. If they're balanced, then the carriers are not affected. Um But you'll always really have problems in the offspring. You're much more likely to have problems in the offspring offs yourself. Um Why, why is that the case? Why are, are they like not affected as such? Well, it's because um if you're balanced that basically just means that you've got the same like amount of genetic material itself, if you're not balanced, that means you've got extra or less. Alright. If you've got the same amount and it's just been stopped over and you, and you've still got the same amount of genetic material. Ok. But it's in the wrong place where it's the same amount. Um then you'll, you'll be balanced and you'll be fine. Alright. If you've got extra or you've got less at that point and there's been unequal crossing over and stuff at that point. Um, that's known as like not balanced and that could be lethal, could be fatal. Um, but even if you're balanced, it can be passed on to Children. All the Philadelphia chromosome, uh this basically look how to read this stuff. Ok. So it's the same ti know it's translocation. Er, it's saying 922 which means it's between er, chromosome nine and chromosone 22. Q 34 means the long arm of chromosone 9, er, 34 to 34 section and a long arm of Q erone 22 with the 11th section they swap over pretty much. Um, again, this is key, it's big stuff. Alarm Bells. Be ringing when you see nine and 22 think uh fill up for chromosome and think um ch chronic matter of leukemia, there's a lot of protein tins that have been used as a revolutionary drug against this stuff. Ok. Cool. Um Fine. So now you've got different types of um chromosomes. I need to be aware of metacentric. So metacentric is basically when your centromeres in the middle all and you've got like two equal arms of each leg. All right. This is 136 and 19. Cool. Um submetacentric is a centromeres off center. OK. And this is your classic one that we looked at. Uh the, these are the most seromas really um center is off center and it's asymmetrical and you've got this QR which is long and the pr which is petite or short and then you've got acrocentric. Acrocentric is basically when the centromere is really, really close to one end, pretty much. You've got pretty much no QR it's very tiny. Um a very, very short pr and a very, very long QR. OK. The, the very short pr is also known as a satellite structure. It doesn't really um in like it's not really involved in actual sort of genes and stuff, it's involved in the background. Er that's why we have satellite structure. Um and that's chromosomes 1314, 1521 and 22. All right. Cool. OK. So Robert 30 translocations. This is what uh a lot of like examiners love this stuff. Um This is looking at specifically acrocentric chromosomes. So the ones which got a very, very long QR and a very, very short pr so it's usually between 13 and 1414, 15 and 1421. You don't need to remember this. Just remember the 1314, 1521 22. Don't remember the pairs. Just remember 1320 1521 22. These are action ones. Ok. Uh There's nothing special about representing translocations. It's just, er, specific chromosomes that you're talking about. Um, again, it's usually silent but your Children can be affected. Uh, and it's lethal if unbalanced again, as I, as I said, um, if they've got extra, er, genetic information or they've got lack of it then it's unbalanced. Uh And, um, it can be lethal. So, again, on the right, you can see different ways of writing, um, this, this, this, this, uh, this Robertsonian translocation. So it's a translocation between um, 4, 14 and 21. So, first of all, we want to start off with how many chromosomes are there? 45 in this case, why they're 45. Well, um, there's been a translocation of the long arm of uh 2021 chromosome to the 14 chromosome. And, um, they've, they've, they've, well, they've sort of exchanged between 14 and 21 they've sort of exchanged uh, their, their, their long arms. Ok. Um, but in doing so, and in exchanging these long arms. What's happened is there's short satellite structures. They've pretty much just gone to the bin or they've gone like they, they, they've been dumped. Ok. So now you've lost that one chromosome, that one, that one structure which would have been made by two satellite structures. Hopefully, that makes sense. OK. So I'll try and explain it again. Uh 45 because you've lacked on chromosome Y. We'll explain it a bit. It's Xy cos you can see Xy over here. Um So it's male, it's Rob. Rob, you, you can say Rob Robertsonian, but I'd stick with at, OK. And it's 1421 because the long arm of the 14 has been swapped with a long arm of the 21. OK. And in that process of swapping them both that one satellite structure, er, in the, in the, in the long arm, well, in the short arm of Q. Well, well, no, in a short arm of 21 and the short arm of 14, er, has been lost and that would have counted as one chromosome. So that's lost pretty much. Ok. Um And you can see now that 14 looks a lot bigger because it's got the, the, the long arm 21. Um uh So, yeah, hopefully, hopefully that, that makes sense. Um Yeah, so with ations you end up losing um I crazy in my back. Ok. So, er, deletion of duplication syndrome. Um again, uh this is the kind of stuff just need to really look at it and understand it really uh and somewhat memorize it. Uh microlesion are basically things that you can see er in very high recent resolution banding. So this is stuff that you can't really see through karyotyping. You might need fish for it, fish stands for uh fluorescent in situ hybridization. And that allows you to see structures in a lot more detail that can see micro duplications and microdeletions really well. Um So that's not karyotyping as such. So at the top, the top picture, you can see Williams syndrome, which is a deletion. Ok. Deletions again, aren't handled as well as duplications. Um But yeah, you can see the top deletions. It's a seven q 11.23 deletion. What this means is it seventh chromosome, long arm and it's section 11.23. So it's the specific band that's deleted all phenotype of a person with Williams syndrome. They've got a long filtrum. The filtrum is basically the baby between the upper lip and the nose. They've got a longer uh a short term nose, arched eyebrows, supravalvular aortic stenosis. All that means is to say that your aorta is pretty much just narrowed. Um and a cocktail personality means they're quite outgoing. Alright. The opposite is below. Uh You can see this sort of um duplication of here. The beha well, the display autistic behavior, dilatation of aorta, flat eyebrows, uh a very broad er, nose and a short build from this time. Um And again, the duplication, you don't need to know why. But yeah, it's handled a lot better than your deletion is all right. Cool. So, question three. I promise you guys, I'll rush through it. It won't be that long left. Um But yeah, how would a 47 X deletion XP 11 K, a big person tolerate the chromosomal imbalance. Um How would that work? Anyone in the chat if they want to t in, if not, then don't worry, I'll skip through this question. Isn't worded that correctly. Like anyway, um if I was to reword it, I'd say 47 X XX. So triple X. Um but yeah, assume from Mexico. No. Uh Sure. OK. Um So again, I if it's a 47 X, so again, as we c 47 you know, that's the extra chromosome, you've got an extra chromosome. OK. Um There's a deletion in the X chromosome itself and specifically within the, the short arm 11 section. So P 11, um how do they usually tolerate this imbalance itself? Because it says 47 X, you've got to assume that they're saying there's one extra X chromosome itself and this deletion in the X chromosome itself has been um tolerated through random x inactivation. It happens early on in the embryonic stages. Um And, and one of those X XX that is inactivated and uh if the extra that is inactivated has that deletion on it, then it won't be expressed and it's a lot, it's a much milder phenotype. Um, a and it would be tolerated like that. Ok. So it's a random process. Uh, it's complete activation of the abnormal extremism. Ok. So in these cases just find buzzwords, uh, and go towards them all. So it would be d, the D is the answer. Ok. Um A can't really occur. Well, a, a could be a possibility because introns don't really code for actual, like, genetic stuff, like genes of the last stuff, but they're still responsible for a lot of the background stuff. So, yeah, BS is not possible. And c uh it's a random process. Not a, on one that happens on purpose. OK. Um How would decreased methylation affect the understanding on the chromosome? QR uh I'll give you again, like 30 seconds of this if you guys have it. Um, in the chat, if you guys wanna put something down, guys don't worry about it. Like it's, it's, it's a lot, it's just beer. Um But yeah, OK. This is stuff that they'll pick up like sometimes cos people don't really read about methylation and stuff. But yeah, it is the thing. So no one, no one, no, doesn't matter if you're wrong. Uh uh OK. So, so put a fine. Um I hear it. I would have said the same thing if I was, if I didn't plan the session. Um, no, I actually think it's doing the session itself and I looked back during your problem notes. I'm not sure which one it was. Uh, the answer is actually, um, deep. So what? Mm. No, no, it's not actually c again, if the answer is actually d um, again, I'd know why it's ci, know why. I don't know why you guys thought it, it could only be either AC or D really, um, fine. Yeah. But the answer is ser d, OK. So methylation, methylation itself that causes like more condensed DNA. OK. If you've got more condensed DNA, you're gonna have uh hematin hematin is one, hematin is a dark one that, that I talked about a a couple of sides back. Hold on. Um Good. Yes. So when I talk about heterochromatin, that's the one that's compact. That's, that's condensed, that's the one with fewer genes that's dark, ok? That's heterochromatin. Um What's happening here is that you've got methylation is methylation has caused that that is the fact that you need, you need to know. Alright. Methylation causes condensation. It causes um increased sort of like uh like like compaction, all that stuff. Ok? Um If you've got a decreased methylation going on, that means that there'll be less of that compaction, there will be less of that conation occurring, it will be more open instead and there'll be more genes being transcribed, there'll be more transcription occurring and there'll be a lot more open, it will be a lot more light. OK. So there'll be, there'll be a lot more echt OK. And that's why you have much more lighter bands all because the DNA becomes more open. So methylation. He forro dark bands, no methylation. Um Euchromatin, more DNA transcription, unwinding, openness, lighter bands. All. Hopefully you guys know a distinction now. Um Yeah. OK. I'm pretty sure II saw methylation somewhere but um if it's not on your spec, then don't worry about it. Um But yeah, cool this off guys. Thank you. I appreciate the um enthusiasm. Uh Cool. OK. So now we're on to normal pregnancy scans. Um Again, this is, this is something that I struggled with a lot because I thought it was just pure memory and the way they explained it to me was just pure memory and pure rote learning, which I hated. So now I'm just gonna try try and take you through like a little journey of there. Um OK. So with normal maybe um I II hopefully everything's fine really. Um but you start rather start with uh two den stands that are non invasive. OK. Um But help narrow down a lot of stuff and that, that helps you pretty much create this flow chart for you to go on to the rest of this stuff. OK. So you can have a, a nuchal er scan. Uh A nuchal scan happens between 1 to 14 weeks. Um Yeah, sorry. Yeah. A mucos is between 1 to 14 weeks of gestation. Uh you can date the actual baby itself uh whether you've got multiple pregnant pregnancies. Um And if this, for example, you feel chromosomal abnormalities like Down Syndrome. Ok. How do they figure out the chromosomal abnormality is Light Down syndrome? Well, uh the thickness of the fluid at the back of the neck. So you can see in the bottom picture over here, you've got increased nucal translucency, more thickness of the back of the neck, specifically more than three millimeters that signifies an increased likelihood of chromosomal abnormalities. Of course, you have to check that up and do like some other more scans and all that stuff. We're down to that uh to like fully um what do you call it to fully uh lock that in. But yeah, cool. So that's one of them that can happen, right? Uh between 1 to 14 weeks of gestation really, really early on. That's a nuchal translucency scan. OK. Then you come to a mid trimester scan, which is between 2022 weeks of gestation. OK. So think about the timeline. So right at the start nuchal mid trimester, this is a bit different because he's looking at structure abnormalities in the heart, the brain, the spinal cord, the face, the kidneys and the abdomen. So he's looking at things like spina bifida. I'm pretty sure if you, if you guys have heard of the spinal bifida, if not, let's search it up. Um it's like a condition where um I think like the, the, the, the, the what is it? I'm not sure already, I'm not sure. But yeah, I know spina bifida was definitely one of those conditions that has picked up in the mid trimester normally scan um because of the structural abnormality and had something to do with the spine, um maybe the spine and the foot. I'm, I'm not sure. Yes, but I remember from last year. Um But yeah, cool. And now if this nuchal transition is scan and the, the, the MTA the mid trimester anomaly scan, if they detect some sort of abnormality or increased risk of something going on or if they've got of this family has had a previous child who's um had the condition before um or there's a family history of it, then we go on to prenatal testing. Alright. And prenatal testing is basically looking at first non noninvasive testing. OK. So you can have really two types already. You can have N I PD and N I PT. All right, not NY PDN in I PD. OK. So, noninvasive uh the parental diagnosis and noninvasive, sorry, noninvasive prenatal diagnosis and noninvasive prenatal screening. Uh sorry, testing. OK. So we'll start with N I PD. First N I PD happened on a lot earlier than N I PT. Um Again, you're looking at DNA fragments in the mother's plasma. Um They're shared through um the, this DNA coming from the placenta which is the same again, same DNA as the baby or. Um, so you just use that cos it's representative of the baby itself. Um, it's fetal DNA, it's cell free fetal DNA often, but it can be with the cells as well and it's DNA fragments that you're looking at. Um, so when you're looking at an excellent condition, then, er, you do N I PD uh fetal sexing as well and you basically detect for an S RY gene, key gene S RY, it's on the Y chromosome. This tells me, er, if they've got a Y chromosome and if they're male or not. Ok. And if I, if I'm looking at X chromosome, er, if I'm doing testing for like an X chromosome or, or extensive disorder, for example, and I see that yes, we've got the S RY gene. I'm going to go on to prenatal testing. Why? Because males are much more likely to have uh an excellent condition because they've only got one X chromosome. Alright, cool. Hopefully that makes sense. There's a key called logic over there. Ok. So you do the, the testing, then you do fetal sexing through N I PD, fetal sexing sri gene, then prenatal testing. All right, then you go on to N I PT. So N I PT again, is not diagnostic. N I PD is somewhat diagnostic. Um but it's not like N I PT is not um it, it, it's, it's more of a screening thing. Uh It's usually used for unemploy. So again, T 13 is Patel syndrome. T 18 is Edwards and T 21 is of course Down Syndrome. Um Again, if you meet all the risk factors, then you have this N I PT screening, uh which is basically just again, quite late on. Um And it's again for chroma abnormalities. Um The limitations of N I PT and N I PD is that if you've got multiple pregnancies, then you don't know whose fetal DNA is and who's like who, who, who, which babies are linked to. Um If you've got a higher BM, I, then um you can't really be done as a mother. You can't really do N I PT and N I PD. Um And even after this stuff, even it is non noninvasive, but you still may need invasive testing later on. OK. But the benefit is that you've got no increased risk of miscarriage because it's noninvasive and um hopefully your number of missed tests uh reduced, but of course, there is a still a possibility of it happening. Um So that's a limitation. OK. So uh yeah, you can see a clinic over here. One of those rich ones, private ones about um uh the fetal DNA metal DNA and N I PDN I PD. Um I haven't really seen many questions on them, but it's just like there's the distinction between the two. OK. So after you've got a solid known risk, whether that's N I PDN I PT or Nucal or MTA or um your family's got risk, all that stuff and depends on how much money you have, I guess. Um you can go on to C VS, which is chronic vous sampling or amniocentesis, right? C VS happens earlier. Uh It can be either trans undoubtable or transvaginal. Um In this case, you'll see that you're again sampling the placenta because again, the placenta shares the same sharing material as the baby um as a fetus. But there is a 0.5% risk of miscarriage infection and uh recent sensitization. What do I mean by resensitisation? There's a pure link to HD FN is human disease of the fetal newborn. I think back to your hematology here. All right guys. Um So if, for example, I'm doing this procedure right, transabdominally or trans. And I cause this mixing of blood, let's say, for example, the mother is rhesus negative and the baby is rhesus positive. So Rh positive and I cause this mixing of bloods. I certainly because of this risk and I cause a missing mi er this mixing of blood. Now the baby's Rh positive blood will go into the mother and the mother will think what is what on earth is this? This is some like this is some um external stuff. Let's let me create antibodies against it. So now she creates hell antibodies against this Rh positive blood from the fetus and now this means that this baby is fine. But the next time she has a baby, if that baby has a uh Rh positive blood, she will have a lot of Rh positive antibodies and it will go and attack the blood through the placenta. So it'll go and pretty much attack the baby's blood through the placenta, um which will cause a lot of harm to the baby, which will pretty much kill the baby. Um, and it may also cause damage to her as well. Uh There's a lot more information on that in hematology. Um, so, yeah. Ok. Er, amniocentesis is, er, ha happens in the 15th weeks, it happens a bit later on, er, in this case, you getting a fluid sample from the amniotic sac which is around the baby itself. Um, same risks but less risky. What on earth was talking about that? Ok. I think what I mean by that is basically, um, because you're doing centesis later on, it's less risky. It's much more stable and you're not actually uh attacking the placenta, you're going towards the anergic sac. All right. Um, so that's why it's, it's a bit less riskier. Ok. Uh, and you've still got the same risks as a miscarriage infection rus. But um, the, the, like the risks are a bit lower. Ok. Um, so for monitoring disorders, we talked about karyotypes. Uh PCR again, the gold standard that we use is CG HRA, again, it's something that you need to know, memorizes a bit. Um So the CG hra is looking at er, microdeletions and micro duplications as imbalances in chromosomes. Ok. Um And if this comes up as positive, then you must test the parents and carriers and you can create a whole family tree, you can do genetic counseling, all that stuff. Ok. Um And the prenatal exom R 21 uh that's basically when, again, it, it can, uh when your fetus has significant structural abnormalities, it's like the 20th week of pregnancy really. Um If it's been picked up by a mid trimester normally scan, uh then you do this exom, you take the DNA from the fetus, the ecze is a, there's a coding region and you basically just co uh you test for that and you test for that exoneme the coding region um by taking DNA from the fetus itself. So that's quite a high risk as well. All right. Um Cool. So this is stuff that you just had to remember this. I've, I've had the main points really. Um But yeah, so the main thing, thing about invasive testing aes and um uh C vs, those are two main ones monogenic think karyotype PCR CG hra sorry, er think gold standard and then prenatal exom R 21 think of that further down the line 20 weeks. Um And if there's a structural abnormality. All right. Uh OK. So question five. again, 30 seconds. Um 36 year old pregnant woman is admitted to an antenatal ward requiring invasive testing. So it's already narrowed down her options. Her previous pregnancy resulted in a miscarriage and she's previously uh and she's particularly worried about this happening again. Um So which prenatal diagnostic test should be offered? All right. Um So what prenatal diagnostic test should be offered? An invasive one? I've tried to highlight all the main information. I don't know if I already hit the mark or not. Um Please do ask, I'll send out like any sort of, uh, I'll fill out my anky deck to you guys, er, later, but mine's pretty washed is not the greatest, but yeah, I'll send it out anyway. Uh Any answers. Ok. So that was a possibility. It was either C vs or amniocentesis. All right. Um And either of them would have been fine. Um But if I was being picky, I'd say um go with amniocentesis because it's slightly less, less risky because it happens a bit later on. Um uh And therefore you've got less risks of like infection, miscarriage reces. Um uh because it's because the baby's more stable and you're later running pregnancy itself and you're not um going towards the placenta. Therefore, there's less risk of sensitization and criss cross and exchange between the mother's blood and the baby's blood. Um to the am amniocentesis is slightly less risky. So I would have said that, but CVS is also fine. All right. Um But Yeah, if you wanna be sure about it. Less risk. Amnio. All right. Amnio equals less risk. OK. Cool. OK. This is the last section guys. Um After this bit, I'll ask a couple more questions in a quarter. All right. Um Cool. So S NPS, single neide polymorphisms, all these are single base pair changes base pairs. The base doesn't mean like cytosine, guanine, adenine thymine. Uh You've got single base pair changes in the DNA sequence that occur at specific points in the genome, right? So let's say for example, you've got a cytosine replace with all that stuff. Ok. Um That can occur in different places between different people, but we use S and PS to help us as epidemiologists, researchers and doctors to figure out um what specific like swapping or what specific S and PS cause the disease. All right. Er, it's not the same as disease causing mutations particularly because uh sometimes you just find them, er, and they don't do you any harm? All right. And they are actually occurring, they're not things that like happen for a reason. Ok. So it's not like with sickle cell, for example, you have that swab that you heard in the C first CSI. All right. Um Something like that. Ok. So um this S and PS can help identify genetic differences that affect pharmacogenomics, which you, you also look at, I think during your course. Um and it creates this Manhattan plot that you can look at the bottom of it. Um uh And it helps identify disease susceptibility, uh response to treatments uh and precision oncology as well and pre precision precision medicine, which will, which is kind of the future rate. Um So we figure out um S and PS through genome wide association studies. All right. What we do is we get a group of patients, uh a group of a, let's say 100 patients who have the condition and a group of patients, 100 patients who don't have the condition. Ok. Bear in mind that these people might be misdiagnosed. So that's one ation already. OK. But um hopefully they're not. Ok. So there's people who have the condition, people who don't have the condition, we analyze their genome, we find similarities between them, we analyze their genome, we find similarities between them and we compare the two and once you compare the two, we find oh cytosine in this position is really, really high for this disease. But over here it's very low. So this might be a marker that we can target and we can use for pharmacogenomics and diseases, the worst stuff. Alright. But the problem is that there may be over 10 millions of these all, there may be like 10 millions, 100 millions of these, like these single sorts of um polymorphisms. So the way scientists do it is that they've grouped uh them together. So they group nearby single polymorphisms. Uh in chromosomes uh through short time and repeats. So they call them short time and repeats and they group them together and they'll be like, ok, if these set of, if this set of short 10 repeats is high in this disease and it's low in people who don't have the condition. Then um at one point, if it's statistically significant, we can say that, yes, this is, uh this is, this is causing the disease, right? Cool. And you can see this at the top as well. So you can see it disease specific S and PS and non disease S and PS um patient DNA, nonpatient DNA and how they compare it to and then they'll create like a ma clot uh at the bottom and the large the line at the bottom. So you can see it on here as well. Oh sorry. Um The larger the line at the bottom of here uh the more significant this SNP called a short 10 and repeat it. Alright. So remember short 10 and 10 and repeats grouping them together and S and PS. Alright. OK. So there's loads of limitations. Um I'll run through this really, really quickly, don't worry. So let's say, for example, you have a very, very rare S MP. So you have might have one S and P like a very, very rare 11 finding that's causing this whole uh disease like with sickle cell, for example. Um So that could be a limitation of genome wide association studies because you can't often like find that, find those S and PS even if you group them together because they're so rare. Um uh a and it may not really be one, by the way, it may be several of these rare ones that are all causing this disease independently. Ok. So there might be a thymine over there or adenine over there or like a guanine over there that's all causing them. So we have to figure out all of them like um independently, then combine them together and then we can make sense of, of this. All these individually are causing this disease, ok? Mis inheritability. So miss inheritability is huge. This is a this is I'm trying to, I'm gonna try and explain it the way I thought it was. Alright. So it's it's the gap between um heritability of like a certain trait that you can figure out through like twin studies or family studies um or lineages versus what you find in an actual genome wide association study. OK. So let's let's take height for example, alright. Um through family studies and through all this stuff, you can do a lot of statistical analysis and you'll find that height is very much a gene factor, right? And uh let's say 80% of it is heritable by heritability. I mean factors that are passed down from one generation to another. And um these affinic attributes that I can attribute to um, genetics. OK. So these are, these are factors that I can attribute to genetics. So let's say there's an 8% chance that height is, um, is a factor that is down to genetics. OK. And I'll figure this out through loads of like uh parent studies and like uh twin studies and all that stuff. Right. And now I try to do the same thing with S and PS. So I find really, really tall people on one side and really, really short people on other side. OK. Obviously, I won't be able to like show the same 80% of the level um of heritability uh in a G in a genome wide association study as I have in like family studies. OK. So that gap between II could maybe get like 20 20%. OK? So that 60% gap between what you found in like family studies and that heritability and what you're trying to find using S NPS er is what we call missing heritability. Alright. Hopefully I'll explain that. Well, if not then um yeah, asking the end or like set up a video one, I guess. Um but yeah, again, as I mentioned, rare arrogant and sometimes they also may be gene gene interactions, let's say you're doing a gen association study and you find this thymine and you find loads of individual S and PS. But um it's like one gene only works um with uh with interaction with another gene A and A and like, those are all acceptable. And in a genome wide association study, you can't really figure that out. You're only looking at specific ones and you're looking at differences. Ok? You're not looking at like the interaction between genes that's called epistasis. All right. Um, misdiagnosis, as I mentioned earlier. What if in the genome wide association study, 50% of the people who are meant to have the disease, they don't actually have it. And the doctor was just a bit like off his head that day and diagnosed them in incorrectly. Ok. Um So yeah, and you can also sometimes underestimate heritability. So you can underestimate heritability in terms of um like height, for example, within like family studies. So there's quite a lot of stuff, some challenges include statistical significance, the sample size, the larger, the better and ethical considerations, of course, um um like consent and all that stuff uh and diagnosis um and the consent unless someone's genome er which is, which was quite big when you think about it. Um So, yeah. Ok. What's the time due to the idea that single genetic variations found by genome wide association studies cannot account for much of the heritability of diseases. All right. So this is again looking at um how S and PS and Genome Association Association studies don't tell the full story. They only tell some of the story. A lot of it is in the ch please. Yes. Great love you missing our ability. OK? Wait, good stuff. Um And finally I'm gonna whiz through the principle. Um Here a lot, I've got some questions afterwards for you guys. So don't leave, please. Uh But yeah, uh shout out er Trix. She's er a second year at Kings. She helped me out with this stuff. Um Again, the highly that principle, all that's looking at is you wanna figure out your allu and your genotype frequency within the ideal population. OK. So there's a bunch of maths for this. Um It's a bit like uh quadratics back in the day really. But er so once you know these two formula really, you're, you're pretty much done. OK? Um So P squared can stand for ho well, it, it stands for homozygous P which is usually a dominant condition. All Q squared is homozygous Q which is usually a recessive recessive condition. Um Q is often recessive but it doesn't really matter like which one you use for which uh you can use Q for recessive and P for er dominant or other way round. It doesn't matter. And PQ of course, er means hely, right? If you've got one thing dominant, one thing recessive, that means heteros. OK. So I'll do a quick example with you guys if you take cystic fibrosis, for example, uh what inheritance spatter is, cystic fibrosis. Hopefully someone puts it in the chat. Um But yeah, we'll take it as someone put autism or recessive? OK. Yeah. Er Anyway, CF is an autosomal recessive recessive condition. Again, remember it's the loss of function of that CFTR channel loss of function condition. Um If its prevalence is one in 2500 births, then you can say that Q squared which is homozygous recessive. Uh The probability of that happening is one of the 2500. All right. So you can figure out Q by doing a square root of that. Once you figure out Q, you can figure out P by doing P equals one minus Q and then you can figure out P squared which is a homozygous dominant frequency. So some people who have er homozygous dominant genotypes and uh two PQ, two PQ is carried, remember it's not just PQ, it's two PQ. Alright. Two P QS are, are people who are heterozygous and they are carriers. OK. Assumptions within the ideal population. Of course, this, this could never work, right? Because every single population out there um has some element of migration, has some element of new mutation. Always look at bacteria, for example, very, very rapid um has some element of random mating and has of course element of selection, natural selection. Alright. So you've got to assume these, ask you a question on assumptions and how do you, how do you want the principle? Just remember these five and you should be fine. Um And yeah, again, uh as I was showing you uh you guys earlier, the whole normal balance thing. This is not, this is, this is this picture of your hair has nothing to do with the hardy we principle, by the way, um this is just to do with chromosomal abnormalities, which is more imperial based really. Um But again, look, so I was looking at normal er chromosomes, you can see normal Chromos chromosomes on the left, you can see balanced ones on the right. Again, these are the ones that have not lost or gained any new genetic material. They've got the same amount of material, well, the same amount of white, the same amount of yellow as before as normal. Um but they just got it replaced in different places. The unbalanced ones are the ones that have got too much white or too much yellow. Alright. So hopefully that makes sense. Ok. If you've lost or gained generic material like you have over here, too much white, too much yellow, that's unbalanced. If it's balanced it, it will be normal or it'll just be like the same amount of genetic material but it's swapped, swapped over like different chromosomes. Ok. So you, you'll still have the same amount. Alright. Um Cool. So hopefully hardly that would make sense. Um Oh dear. Ok. Uh well this is a highly armed question. If any of you uh guys wanna take a screenshot of this um uh and do it and then put it in the chart then please do. Um I'll send the, I'll send the answer out uh, in a bit. I might have to do it myself. Um, again, uh, sorry about that. But um, yeah, cool. Uh I'll go on to the next question anyway. Ok. Hunts. All right. We'll do a quick one on Huntingtons because it's probably big one. a proband again, guys join you can is good practice. Alright. A proband, a 25 year old male, he has Huntingtons. Alright. With 44 C 80 repeats from the H TT gene and he's got an unaffected partner. Forget that last bit. Do a what's the probability that their first child will inherit a Huntington's disease? Ok. First of all figure out, well, I told you earlier, hopefully you guys know what Huntington's is and and its inheritance pattern. Alright. Um, hopefully you guys know Huntington's inheritance pattern. If not let it out, you're allowed to. Um, actually I'll just tell you guys, uh, it's, it's autosomal dominant. Alright. So it's a dominant condition. Um So what's probably that is first child with an Eric. Huntington's someone put it in the chat. Yep. Good. 2.5. And uh, what's the probability that the second child would get? This question's all on the board, by the way, their second child, they probably do their second child getting it. No. Ok. And they are, you might, you should have said like 0.5 again pretty much. Uh, but yeah, you got the right answer, don't. Right. Um So this is an effect like e each child have the same problem of getting the disease. OK? It doesn't affect from child to child. It's not something sex rated or it doesn't matter like like that. OK. So just uh stick with your guns pretty much. OK. So this is the concept I haven't explained to you. Question B explain the concept of dominant anticipation and how it may impact future generations. If you guys have learnt it, you should have learnt it. Um You guys can play in the chat. If not, then I'll explain it to you. Um Hope you guys learn it. Mhm I'll give you guys like 15 seconds if you guys learn to, you put it in chat. Dominant anticipation. Anticipation is a key word here. Um Just, just put it down the list so deep. No. OK. Fine. So, um, with Huntington's, Huntington's is an autosomal dominant disorder. OK. Yes. Yes. Yes. Good. Nice, Mohammed Le good. Uh Age of onset as earlier. That's great, great stuff. Um Why is age of onset earlier? How age of 17 patients gets low? How? Yes, it does. Good, good looking nice. Um Yeah, so you a as you go down generations pretty much, uh what happens in G gamma gamma genesis itself is that that C A repeat, that training period that repeat, that basically gets longer and longer and longer. The more generations you go down the greater I repeat it, the longer I repeat it is um it basically leads to uh increased age of onset, increased severity uh as you go down. Ok. So let's say uh uh granddad inherited it at like 60 years of age. Then pops, he will inherited it at like 40 then the kid will get it at 20 because that C repeat is getting longer and longer each time, each in each gamut all as you go down the generation. Ok. So its impact your generation by this being. Um, you, you'll, you'll get it earlier and it'll be more severe. Um, and, uh, yeah, all right. Uh, what ethical considerations should the genetic counselor discuss with a couple regarding testing for Huntington's disease in the embryos using preimplantation, genetic diagnosis? So this is something that again is part of your genetic testing thing. Um, I didn't really talk about EGD as such. Um, but, uh, this is just looking at again, if someone's confirmed to get Huntington's, they'll go through PGD rather than genetic testing and stuff. So they won't really undergo, um, pregnancy and stuff. They still go through PGD. Uh, any ethical considerations that you, you guys can think of, um, is part of the effect. So I'll just put it in there. Yeah, screening is actually one of them. Um, uh, the screens up there as well. Again, compliance and all that stuff. Uh, it matters. Um, I was thinking more like the whole ethical side of, um, would you select against the embryo that like, let's say, for example, it did pop up as, yeah, positive, whatever it is. Um, or, or screening all that kind of stuff, it, it came up as positive, um, which ethically think about selecting against an embryo that could develop the Huntington's later on. So let's say you came up that this guy, this guy will get Huntington's, um, uh, would you, would, you, would you stop having a baby? Would you not go through with it because this person could have like, er, 100 years later on? So, are you selecting against people with this, with disabilities later on? And their quality of life? And there's a whole argument against it. So think about quality of life, think about selecting against people with the possibility of having disease later on as well. Um, so yeah, again, there could be a few psychological impact on the parents as well that you can talk about. But, um, yeah, cool. Ok. I'm gonna draw this one out. You guys, uh, I'll give you like two minutes to do it. Um, both questions. Nine A and B. Um, so yeah, take your time, draw it out. Um, and write the answer to b when you, when you get the answer. Ok. And, um, make sure you know what inheritance by cystic fibrosis is. I told you this like two times, um, Huntington's was dominant cystic fibrosis is and by the way, they may actually just make you, like, um, draw out this thing in like the exam and just take a picture of it. They did that for a while on us once. I don't. November. Mm. Oh, yeah. You guys already done it. Ok. I was doing p um, yes, you guys are right. Mhm. Ok. This is quite simple stuff. Really. What they'll do now is that they'll, they'll basically, um, what do you call it? They'll, they'll complicate it a bit more by. Yeah. Ok. So they, they'll, they'll complicate it a bit more by. Ok. They ask by diagram, by the way, uh make sure you have the consent when it's marriage. I didn't draw it the best, but that's the affected proband, I'll draw arrow towards that and then that's the unaffected system. Alright. Um uh, the answer is 2/3 again, it's Heterozygous Cross and this system is un, is unaffected, remember? So that affected, um GEO gets, gets done out immediately and you've got two, heterogynous options left, heterozygous options left. So it's two out of three. yes, other thing they might do the same thing over here but what they'll do is they'll either they, they'll, they'll put in something known as like um, a European risk factor or like AAA known risk factor. Uh, and the best factors for that would be your po um lecture itself by James Gardner on it. I think, I think it was James Gardner. Yeah, it was James Gardner. Um, he did a great, er, p, like tutorial on like European risk or like, er, risk that comes in from elsewhere. Cos this, th this, they'll be like, ok, one in 22 people are known to be carriers of this cyst, er, this cystic fibrosis, for example. And then they'll throw that in to try to distract you. Um, uh, and you have to take, you have to take that in. Uh, you have to take that, that, that, that, that data in for people who aren't part of the family and who are like, um, who, who are marrying you in. So you have to include that in your final calculation. So that's where they can, um, sort of throw you off a bit. So just go over that lecture editorial. Um, first of all, it's a geneticist. Just take pictures of chromosomes, determine chromosomes component of an individual. Uh, how do you image chromosomes basically? All right. So this should be like 10 seconds, guys, you guys? Oh, I imaging chromosomes, imaging chromosomes. Yes. Mohammed. Yes, later. Um, no, I honestly I can't that I might have made that up. I don't know what ideogram is. Um, I think it's a thing, I don't know. But, uh, yeah, it's, uh, it's not, is it, is it, is that a thing you do everything? Is it, is it, you see, II didn't know. I didn't know I was a big, um, I thought it was K karyotyping because this is like this imaging of current today. Um But yeah, have you guys learned about Ingrams? II II, never learned about IMS uh R TBC R is amplification of DNA. Next gen sequencing is just um that, that, that, that's a lot quicker and that's for like diseases in particular and stuff. Um And that, that, that will like figure out your whole J make up really quickly and that's not specifically chromosomes, chromosomes is carroty. Alright. Um So yeah, unless I'm completely wrong with the IMS is the thing, maybe I'll set you up later guys. But yeah. Um ok, so some file tips from a trying to make three paper for me. Um I did the paper last year because there's a, there's some stuff that come came up. Ok. So again, excellent recessive recessive pedigree diagrams. Um make sure you go over that. Um if you see a pedigree diagram, er where it is, it, it's not like, so it mainly affects males and it's not that vertical. So it's more like horizontally, it skips through a couple of generations, but it mainly affects males. Then you're thinking yes, it's ex recessive and of course, if they put that little.in the circle as a carrier and you've got this female carrier then you know, of course for, for certain that's actually recessive. Um uh So as I mentioned, yeah, I if, if you see males were affected but some generations were skipped, then you think that, yes, it's actually excessive. If it was wi linked, then every single male would be affected. Um, if it was actually dominant, then that would again be very much vertical, uh affecting a lot of generations. Um, er, there would, there was an M CQ type on T 1421. So again, 1421 were the, the, the genotypes that I talked about over there as well previously. Um uh Again, it was Robertsonian translocation when you see 1314, 1521 22 think Robertsonian classifications and think a lost for chromosomes sometimes as well because those two short p arms, those satellite structures, there's petite arms, they get lost. Um So you end up having 45 chromosomes rather than 46. Um So yeah, again, trans and uh there was a question about initial prenatal testing for an ex ex recessive condition again, when it comes to ex recessive conditions. Um er your gender matters, gender matters a lot because males are much more likely to get it all. So, um if they're testing for an ex recessive condition that it has happened before in the family or something like that, uh you want to first figure out what gender is this child? If this child is male and they've got the S RY gene er on that Y chromosome, um then I can go on with pre pre prenatal testing because I know that males have an increased likelihood for the rec recessive condition. OK. Um Because they only need that one mutation on that X OK. Females need both. All right. Um uh So yeah, again, CFF DNA, all that means is cell free fetal DNA. OK. So this is DNA. They can get uh from the placenta through amniocentesis or um CBS. All right. Uh Cool. Any questions popping in the chat guys? Um Please do fill in the feedback form. You'll get like a personalized sort of certificate uh through to your email if you guys do so. Um for beer on fifth Jan, uh I'm not sure if your uni staff and I don't think it should, but we've got another hematology session, same as this one. Pretty much, hopefully a lot shorter. My bad guys, sorry. Um uh Again, for just uh a lot of students in general, a lot of uni students, a lot of uni in, in particular. Um and I per in particular, but in general, um that'll be by another second year. Uh It'll be on hematology, a lot of questions for you guys to join, answer on the fifth of January. Um uh in January, uh we'll start a whole like BRS and biography theories and I'll be doing endocrinology, a lot of high stuff there as well. So please, if you come along uh follow us on Instagram beer. Um We're uh if you have any questions about joining Bema getting involved. Um and how to help out and like how I can help you and stuff. Then please, if you do free to, uh, email me, um, I'll be helping out on the med P crash book as well. So if you guys want any particular stuff before your actual exams for the new mos, then tell me, um, uh, I will be sure to in that stuff in. Um, so, yeah, great. Thank you very much guys. Uh Please be filled in the feedback form. Uh, you get your own cer certificate and stuff. Um I hope you guys enjoyed, um, I hope it wasn't too, too long. Um And yeah, I go, I'll, I'll see you around for the fifth of January and good luck with your exams. Uh, revised Smart and Revised Heart, but revised Smart. But, um, yeah, in a bit.