Hi, and welcome to office hours for unit four. This is actually the first office hours that we're recording for this second session live, so, I'm your TAA for the course, Bridgette. This, of course, is your professor, Matt McGue. >> Hi, thanks. >> And we're first going to touch on some questions remaining from unit three since we didn't get to address them last week. We're going to start with one from Rachel, and it's in unit three, module a. A simplified example of meiosis was presented. Is the meiosis one stage, the, one that is random where the daughter nuclei are first formed? Or is it meiosis two that is random? Or both? >> Okay, well, this is a question I think that. Actually people on, in the discussion forum. >> Mm-hm. >> Gave a very good answer to. But I, I thought it would be good just to touch on some of these here as well. Because not, of course, not everybody looks at the discussion forum, although it's a good place to look. I think there's a lot of good discussions going on, and I appreciate that. I actually brought a picture. So, this is kind of, you've primed me for this question. Just to try to make this very concrete, because the picture I gave in the lecture was not the greatest picture. The randomness that underlies Mendel's first law, the law. Segregation is really, takes place in meiosis I. >> Mm-hm. >> And as illustrated in the, in the figure here, which you're probably not seeing. >> Mm-hm. >> Is we have an organism with three pairs of chromosomes. Let's say, the red chromosomes are coming from the mother and that organism's mother. And the blue from that organism's father. During meiosis one, and actually it's at meta phase stage of meiosis one, the homologous chro-, chromosomes, the two number ones, the two number twos, and the two number threes align. They pair up. But the orientation, what, which pole they actually are on, what side of the cell, so to speak. The, the mother or father's chromosome one is on is a random event. And it's that random pairing. That actually underlies Mendel's first law. >> Great. So, do you see any randomness in stage two, or is it just predominately in stage one? >> The randomness I was referring to was in stage one. I guess the other thing that I should mention, that I don't think is actually illustrated, but it's illustrated actually, in the slide. Is that when homologous chromosomes pair up, there is an opportunity for exchange in material. >> Mm-hm. >> Between the homologous chromosomes, between the two numbers ones, and so on and so forth. And, in fact, that's normal. That typically happens, so. >> Okay, great. Moving on. This next question comes form Patrick. And the question is, although covered in the unit three office hours video. I still don't get why additive gene effects are the only ones that pass down phenotypes to offsprings, offspring. When the additive effects were first described I, thought non-Mendelian traits like height were being described. So were the additive effects used by biometricians only non-Medel-, Mendelian traits? Also, the fact that some traits are clearly Mendelian. And non-additive, yet clearly heritable also confuses me. >> Yeah, that's a, that's a good question it's, it's kind of a complicated question so let me try to briefly unpack it. One of the, the things, one, one hang up students can have when they're first introduced to the polygenic model. And the bio-metric components added to genetic factors and what not is trying to relate that back to Mendel, Mendelian genetics. So you take something like Huntington disease. Which is not additive in the Mendelian sense of not being additive. >> Mm-hm. >> That is it's an autosomal dominant disorder, right? >> Mm-hm. >> Nonetheless there's, as, as the question asker points out, there's obvious. Parent offspring transmission. So how does that relate to the bio-metric notion of additivity, when we have Mendelian dominance? What I usually tell students it best, is to try to keep the two terms separate. What's mean by non-additivity in the Mendelian sense,. And what's meant by non-activity in the in the polygenic model, sense. In the case of Mendelian dominance like Huntington disease, in the polygenic model a, a, a locus like that would actually generate additive genetic variance. Even though it's completely dominant. So, it's, it, maybe that sounds a little bit confusing. That's just the way it is. A, what I try to emphasize is, what, what geneticists mean by additive genetic variance, is the component of genetic variance that's shared between parents and offspring. So dominance, oddly enough, can, Mendeley dominance, can actually generate some similarity between parent and offspring, obviously. Therefore, it can generate additive genetic bearings as well. >> Great. And now, we're going to start our questions for Unit 4. >> Okay. >> And we'll start off by just talking about basic structure of DNA. And the first one comes from JC. And the question's video 4b refers to mature RNA. What is meant by mature messenger RNA? >> Yeah. I'm sorry, if I didn't define that when I went through. So DNA is transcribed into RNA, messenger RNA. And that then. Forms a template for the synthesis of an amino acid sequence, a protein. What's meant by, when it's first transcribed, both the exons and the introns are transcribed. Mature RNAs after the introns have been excised out, spliced out, and so, ma, what's, wh, when geneticists use the term mature RNA, they're just talking about the RNA sequence that's ready to be translated. All the other material has now been spliced out. The next one is I read about extra chromosomes, and they always seem to be located on 21, 18 or 13. Is there something that makes these chromosomes more susceptible to be doubled? >> Okay, this was also a question that was asked, answered, I think quite nicely on the forum. >> Mm-hm. >> But it's a, it's a great question. It comes up a lot. And actually again, this one you kind of warned me about. So I bring a little slide to remind me of what's going on here. So in live births, aneuploidy right is inheriting, for humans, other than 23 pairs of chromosomes, other than 46. So in, in live human births, there's about, I think it's about one out of every 300 births. Has an aneuploid condition. Most of those involve the sex chromosomes, X and Y. There are three conditions of live birth that involve the autosomes, and the question asker is correct. They're, chromosome 21, which is Down Syndrome, 13 and 18. And so, what here she is asking is, well what about the other chromosomes? Why don't we see Trisomy 1 or Trisomy 2? In fact, probably all those other trisomies, and actually monosomies as well, occur, but they're not viable. They are associated with early fetal loss. >> Mm-hm. >> And what's actually shown in this table here it's, what's reported here is that one out of, these are based on various studies, but one out of every 300 births is aneuploidy. But. Up to about 35 percent of early fetuses are aneuploidy. >> Oh, wow. >> And what happens is early fetal loss is actually associated with aneuploidy. And when you look at those early fetal losses, what you see are other chromosomal configurations. So you see. Trisomy maybe 5 or, or, or 12 or other and even maybe some monosomies. Which are very, very rare are not normally compatible with, with life. Or, if, if a baby was born with monosomy other than one involving the sex chromosomes, they probably wouldn't live very long. Most of the aneuploidy, it, and now scientists have actually studied this, most of the aneuploidy is coming through the mother's eggs, not the father's sperm. >> Hm. >> That actually, if you study mother's eggs they actually carry a very high burden of aneuploidy. Most of that aneuploidy, if it actually results in a fertilized egg, will be associated with early fetal loss. In fact, most, probably, early fetal losses aren't even, people don't, mother's don't actually know they were pregnant. >> Mm-hm. >> Maybe it was a delayed period or something like that. So aneuploidy probably exists with all the chromosomes. Most of those are going to be associated with early fetal loss. The vast majority of early fetal losses I shouldn't say a vast majority, but a very high percent, I don't know if we know it's the majority, but a, a very high percent, anyway, are associated with aneuploidy. The reasons for the ones that are compatible with life, presumably, chromosome 21 is the smallest chromosome, so it probably has the fewest number of genes. So, there's greater tolerance for having three copies of those genes. Maybe similarly with 18 or 13. It's going to depend on what genes are there, what's the implications of having three copies of those genes. >> Mm-hm. [SOUND] We have a question from Madeline, and it is, I was hoping you could go into a little more detail about how the switching on or off of one X chromosome in women affects their health. If one X chromosome is turned off randomly in females, and the active X chromosome contains a genetic defect or harmful mutation, does this affect the health or behavior if the defect is present only in certain cells? >> That's a great question. So, right, so eh, in women, in females, they have two X chromosomes, sometime early in fetal development, one is randomly turned off. >> Mm-hm. >> But at that time, I, I don't know how many cells there are, but I'm sure they're millions if not billions of cells. So different cells, because it's a random event, different cells are going to turn off different X chromosomes. So if you're a woman who's a heterozygote carrier. >> Mm-hm. >> For some recessive disorder. Some of her cells will express the mutant allele and some will not. And whether or not that has medical implications, really depends on the distribution of those random events. kind of like the calico cat sort of example, and I have actually have a picture here or two of Bridgette, becuase I like this picture. This is an X-linked recessive condition called ectodermal dysplasia. There are various genetic forms of ectodermal dysplasia, this happens to be an X-linked one. It's recessive. So, and what you're seeing one of the, the symptoms of ectodermal dysplasia is a loss of sweat glands. >> Mm-hm. And so, what the students are seeing in the slide is the gray area on the women here are where heterozygote carriers for this particular mutation, where they've lost their sweat glands. So, presumably in the gray areas that the chromosome, I, I'm sorry, the cells with the non-mutant version of the gene got turned off and so only the mutant was there and they don't have, for all the daughter cells that derive from those cells, they don't have sweat glands. And, actually what's kind of interesting here is the last pair here of women on the right are a pair of monozygotic twins who have the disorder, they're, they have, they're heterozygous. They're carriers for it. And you can see that the pattern of sweat gland being, loss of sweat gland across their skin, differs for the two monozygotic twins. That's because the inactivation of that occurs after the twinning event. >> So interesting. That's so incredibly interesting. >> Oh, I, one other thing I should point out about this, though. So and it, and it gets maybe more directly to her question. If you take a disorder like Duchenne muscular dystrophy. >> Mm hm. >> Which is an X-linked recessive disorder, overwhelmingly, the majority of people with Duchenne muscular dystrophy are male. Right, its an X-linked recessive. But you do have women that do have Duchenne muscular dystrophy. Again, it's going to depend upon which X is inactivated in which cells and where they're distributed throughout their body. Usually women that have Duchenne muscular dystrophy have a, a less severe form of it though. >> Interesting. And this a question about kind of the assumptions about shared genetics. I and this question is coming from Felix. And it's why is it assumed that adopted siblings share no genetics? Wouldn't the expectation be higher than 0% for two random individuals? Considering there are many copies of each gene in the global gene pool the expectations should be considerably higher, in fact, if there'd be only two alleles for each loci and the shared genetics of two random individuals should be 50% on average, so so why do we assume 0%? >> Okay, so, this is a great question. It's it kind of relates back to the Mendelian versus additive, dominance question. And it's, it's, it's a little bit diffi, bit difficult to explain with words what's shown mathematically, but let me try. First of all, right, over 99% of our genomes are the same. So he's, he's not, Felix is not asking about the, that 99%. He's asking about the less than 1% where we vary. >> Mm-hm. >> Where, where differences in our sequence exist among different people. And he's right, if you take one locus, let's, let's say the ABO locus, maybe I have, I have O blood type, maybe Felix has O blood type, we're not genetically-related, at least we don't I'm sure we don't have anything. >> You never know. >> Yeah so let's assume we're not genetically related we're not genetic-related, but right, of course, we can share our O blood type. >> Mm-hm. >> The, when, when we say in genetics that dizygotic twins, for example, share 50%of their genetic material, that's really, kind of a convenient shorthand for us to say that they're sharing 50% of their segregating genetic material, and, and even that's a little bit of a shorthand. The, maybe, the way to best understand this is what Felix indicates in his question, is that if we take one locus, Felix and I might have the same O blood type. But as we begin to get multiple loci, it begins to get less and less likely that we're going to share alleles across that unless we are related. >> Mm-hm. >> In a polygenic system what we're talking about is the effect of not just one locus, but many loci, so as we begin to go over many, many loci than only people who are genetically related are likely to share alleles across that, across those loci at greater than chance levels. >> Mm-hm. Great, I think you actually explained it out phenomenally well without being about to explain it with math. >> Okay, well we'll see. I don't know, we'll see. >> All right, moving onto Prader-Willi syndrome, Angelman syndrome, and Williams syndrome. >> Okay. >> So in Lecture 4G, you said about 15 to 20% of people with Prader-Willis, Willi Syndrome had two maternal chrom, chromosome 15s. And 10% of people with Angelman's syndrome had two paternal chromosome 15s. In Prader-Willi, are the two maternal chromosomes two copies of the mother? Are the two copies of one mother's chromosomes or is it two different copies from the mother? >> You can get both. Let's just take Prader-Willi syndrome. You could, and the same thing would apply to Angelman syndrome. You can get both. That is, okay, so what's happened, you, you have two maternal 15s and no paternal 15, right? So, presumably, early in fetal development, one imagines that there were three chromosome 15, two maternal and one paternal, but somehow the cell threw off the paternal 15. In most cases, it's two different maternal 15s, but there are examples where it's the same maternal 15, a duplicate copy. >> Okay. >> But usually it's a different one. You can have both, though. >> So both are possibilities but generally they're [CROSSTALK]. >> And I don't, you know maybe the question, too, is getting at, is there, are there clinical implications of that? There may be. Because, and, and I think in a question I know is coming up here maybe it's the last question you have in this sequence. Is if you have two maternal 15s, then right, you're going to increase the likelihood that you express recessive conditions. So, there might be clinical implications of having two two copies of the same mother's 15 verses two different mothers' 15s. >> Mm-hm. >> It might be a little bit more risky to have two copies of the same 15. Again, most of the time it's two different 15s, though. [NOISE]. And this next question is, When are Prader Willi syndrome and, Angelman syndrome detected, and are there any effective treatments? And also, a similar question from somebody else asks the same about Williams syndrome,. >> Williams syndrome. >> So, if you want to just get to all three of those. >> Okay, so when are they detected? So, certainly if, if, a mother had amniocentesis or whatever, prenatal diagnosis, it doesn't have to be amniocentesis anymore. I would think that in most cases they would probe for copy number variance now, I'm not 100% sure because I'm not a clinician, they certainly probe for anti ploidy. They may also probe, they can't observe right, something where you're missing a couple million bases of DNA. That's not large enough to see something missing under a microscope. They actually, so they can't, in a normal karyotype analysis, they, they can't see it. But if they're doing CNV analysis is part of a prenatal diagnosis, it would be picked up then. I assume probably, most cases are not picked up then. Why would they be picked up postnatally? There are probably, most cases would be picked up in infancy at some point, for various reasons. First of all, pediatricians are now fairly familiar with these common, relatively common, I think each one of these occurs one out of 10,000, one out of 20,000 births. So they're relatively common, most pediatricians know about them. They know about their phenotypic presentation. Oftentimes they have distinct effaces. Or, like, something William's Syndrome, they would have the aortic stenosis, so that, they might be picked up for that reason. Prader-Willis, Willi Syndrome, I think I might have mentioned this. Ironically enough, Prader-Williams Syndrome have feeding problems early on. >> Mm-hm. >> And, they would be identified for that. Usually, the, the thing that leads to some sort of genetic testing. Is the, is what clinicians call failure to thrive, that the child's not developing in the typical way. They're not meeting milestones, or in the cause of Prader-Willi they're having a difficult time taking in nourishment. And pediatricians know that if a child is failing to thrive in that way, one thing they probably should do is check. Their genetic background, in particular, for things like copy number variance. >> Are there any effective treatments for any of them? >> Yeah, so there are, they're not cures, for any of these conditions. There are interventions that are targeted to specific features of that condition. So, right, of course, for Prader-Willi-Syndrome, right, parents are going to try to control access to food. >> Mm-hm. >> They're treated with hormones to try to build up muscle strength, so that they become more active. William Syndrome, conversely, is, if people watch the film, you can see that people, that parents try to take advantage of their great musical interest. >> Mm-hm. >> Hey try to, also, build on their great verbal strengths. So, there are, let's say, interventions, or educational programs that are targeted to the unique features of each one of these syndromes. But there are no medical cures at this point in time. Maybe in the future, maybe there'll be genetic interventions, but they don't, certainly they don't exist now. All right, our next question comes from Cynthia. And she says, ehy do you get duplications and deletions in certain genomic regions? >> Okay so, this was the last [LAUGH] one that, that I made a slide for or that I took a picture. So, there are certain regions of the genomes the regions of chromosome 15 from Prader Willi Syndrome that, it might not sound that common, but, right, one out of 10,000, one out of 15,000 births, is deleted for that region. So it's recurring. Why does it recur? It recurs because there is an unequal crossing over that occurs in that, that's why I showed the-. >> Mm-hm. >> Mei, one of the reasons I wanted to show the meiosis one slide. During that meiosis one, when the homologous chromosomes align. >> Mm-hm. >> And here in the picture I know, you, you can't see this Bridget. It's not the only mechanism that underlies copy number variance. >> Okay. >> It's the easiest to understand, and it may be the most frequent. So, what's happening here is, there's two chromosome, let's say 15s. >> Uh-huh. >> This is the case with Angelman and Prader-Willi, that are lining up here in meiosis 1. And, but they're misaligning, and they're misaligning because the region y here is flanked- >> Mm-hm. >> By two regions labeled x. The x are two segments of DNA that are highly, highly similar. And they're probably high, they're probably duplicates of one another. So, when the two chromosomes line up, they should actually line up perfectly. The w with the w, this first x with that x. >> Mm-hm. >> The y and so on and so forth. But because the two xes are very similar, sometimes they misalign. And when they mis-align, and you get a recombination, the recombination will end up with a duplication of x in this one, or I guess it's y. I'm sorry, [LAUGH] it's my, I can't-. >> Doesn't make any difference to me. >> Okay. >> [LAUGH]. >> A y, and then a, a deletion of y there. >> Mm-hm. >> So, it's the features of the DNA surrounding the region that's either duplicated or deleted. In this case, there's, there's DNA that's highly similar on each side of the region here, in chromosome 15. And because it's highly similar, when the homologous chromosomes align in Meiosis 1, they sometimes misalign. Our next question comes from Phil. And he asks, can individuals will Williams syndrome see that their drawings are poor representations of the targets they were asked to copy? >> Yeah that's a great question Phil. So you wanted, so so they're asked to draw a bike and, and what an individual with Prader-Willi, I'm sorry, with Williams syndrome, will do is they'll draw the parts of the bike, but not integrated into a whole. And so the question is, when they look at that, and maybe they're asked to actually copy a picture of a bike, so they don't have to even recall what a bike even looks like. They'll have difficulty doing that, they'll, they'll put the different parts. Do they see that their picture doesn't look like the, the original target. People with Williams syndrome have a difficulty with reproducing spatial objects, and then integrating the parts and the whole. They don't actually have a problem in, in seeing it. >> Mm-hm. >> So they can see that the dis-integrated picture that they're producing doesn't look like the original target. [SOUND]. >> This next question comes from Bishanka. And it's, in Prader-Willi syndrome and Angelman syndrome, the professor mentioned that 25% of cases an entire chromosome is missing, and the other one is actually duplicated. In this case we know that the syndrome happened because the part had not imprinted from that particular parent. What about other parts of the same chromosome that has imprinted from the wrong parent? Is there any disorder associated with the other parts, or does it not matter which parent these came from? >> Okay. Bishanka, was that? >> Bishanka, mm-hm. >> Okay, that's a good question and, and I guess I didn't really explain this well when we were talking about imprinting. It may be, I'm, although Bishanka is asking about, Prader-Willi syndrome and Angelman syndrome, it might be easier to answer the question, with respect, to Williams syndrome. So in William's Syndrome, you have a deletion. But it doesn't matter whether that deletion is in the paternal chromosome or in the maternal chromosome. But in Prader-Willi and Angelman Syndrome, it does matter. So why is that, why does it not matter in William's Syndrome? It doesn't matter in William Syndrome because the William Syndrome deletion region does not have imprinted genes. Imprinted genes are genes in our genomes that are differentially expressed depending upon whether or not we inherit those from our father-. >> Mm-hm. >> Or for our mother, from our mother. Some of our genes are only expressed if we inherit the gene from our father. Some are expressed only if we inherit them from our mother. In fact, most of our genes, it doesn't matter who we inherit it from. They're both expressed from the, the father and the mother. In the Williams Syndrome region, there are no imprinted genes. In the Prader-Willi, Angelman's syndrome region, there are imprinted genes. Some genes in those regions are only expressed if you get them from the father. So if you don't have the father's chromosome, you don't express those genes, you end up with Prader-Willi Syndrome. Other genes in those region, in that region, are only expressed if you get them from the mother. You don't have the mother's region, you end up with Angelman's Syndrome because, you don't express that gene. It turns out that I think the estimate is about 1% of our genes are imprinted in this way. So you can go and there'll be big chunks of the genome. Where it doesn't matter who you're getting that gene from. You'll express both the mother's and the father's. >> And that takes us to our last question for this this office hour and it comes from Erin. And she says, My son was recently diagnosed with a 4Q deletion. And so this class and especially this unit has been really helpful in understanding what that means, so thank you for that. >> Okay. >> So, related to that, why is it that people who have the same missing genes can have radically different phenotypes? Can this all be explained by early environmental differences that cause different epigenetic effects? So, for example, on the 4Q 32 terminal deletions, you see many but not all kids have the following, heart problems, small jar, or cleft palates. >> Mm-hm. >> Fingers and toe anomalies, seizures, autism. You see a really wide range of severity, intellectual disability, behavioral problems and feeding problems. So, just as an example to get to this question. >> Okay. That's a good question. There are various factors. That can account for differential presentation of individuals that are inheriting a deletion or a duplication. It could be either. But let's, I think she, is it a she? >> I think it's a she. >> She is asking about is a deletion so let's talk about deletions. If you're deleted, let's say like in Williams syndrome, several million bases of DNA. First thing, first reason why you might have different presentations is, it isn't always the same, same exact region that's being deleted. >> Mm. >> They, they overlap. They highly overlap, but sometimes the regions are a little bit larger, sometimes they're a little bit smaller. Sometimes they're covering these genes. Sometimes they're covering another set of genes. There's kind of a core set of genes that are always deleted, but there are other things going on at, at [SOUND] the boundaries as well. So, it's not, it's, it's, although we intend to talk about it as if it's the same exact region. In fact, it's not always the same exact. So, that's one explanation for differential presentation. A second probably important explanation for differential presentation is this. If you only have one copy of a segment of your DNA, then the allele you have on that one copy becomes really important, right? Most recessive conditions we inherit are rare. You have to get two mutations to express, something like phenylketonuria, right? >> Mm-hm. >> But if you only, if it only requires one mutation. Then it would be more common. When you have a segment deleted, all of a sudden it gives an opportunity for those relatively rare recessive conditions to be expressed, because you only have that one copy. >> Mm-hm. >> So and a second reason for the differential presentation is to, it depends on what alleles you have in the segment of DNA where you actually have it. >> Mm-hm. Maybe you have some recessive, deleterious recessive genes there that normally wouldn't be expressed. Because you'd have some, you'd have the, the non-mutant on your other. But that you don't have the other copy, they're all of a sudden expressed. Finally maybe genes in other regions of, of your genome are impacting or interacting with what's being expressed in that region. So, there's a lot a genetic reasons why you might get differential presentation. I would think the most important ones, at least in, in the terms of the way geneticists are thinking about it now, is not overlapping regions of, of deletion. And also, unmasking the expression of rare dilitarious recesses in the single copy of DNA you have. >> Interesting. Okay, well that that concludes our unit for office hours. Get your questions in for this next unit and we'll see you next week. >> Yeah, thank you very much.
