The Science of Everything Podcast - Episode 147: Genetic Mutation and Repair

Episode Date: August 31, 2024

Here we survey of the causes and consequences of genetic mutation, including a discussion of mechanisms of endogenous and induced mutations, rates of mutation, types of single nucleotide mutations, and the phenotypic effects of mutation. We also discuss various mechanisms for detecting and repairing genetic mutations, including base excision repair, DNA mismatch repair, nucleotide excision repair, double strand break repair. We conclude with an examination of large-scale chromosomal changes, including deletions, duplications, inversions, and translocations, unequal crossing over, with a brief look at polypoidy in plants and aneuploidy in humans. Recommended pre-listening is Episodes 34 and 35: DNA Structure and Function, and Episode 44: Cell Division. If you enjoyed the podcast please consider supporting the show by making a PayPal donation or becoming a Patreon supporter. https://www.patreon.com/jamesfodor https://www.paypal.me/ScienceofEverything

You're listening to The Science of Everything podcast, episode 147, Genetic Mutation and Repair. I'm your host, James Fodor. Now, in this episode, what we're going to do is discuss how genes and genetic material become mutated or changed over time and the various mechanisms that the body has developed to correct and repair those. So specifically, we're going to look at different types of mutations and their causes, the effects that they have on DNA sequence,

and then the various repair mechanisms that have been developed. So we're going to talk about base excision, repair, DNA mismatch repair, nuclear-tight excision repair, and double-strand brake repair, so four different mechanisms. And we'll conclude by discussing large chromosomal changes. So these are sort of bigger changes to the genome, including deletions, duplications, inversions, translocations, and unequal crossing over.

So recommended pre-listing is episodes 34 and 35 when we looked at DNA structure and function. That will be quite useful to understand the basics of DNA structure and function for this episode because we're going to be talking about quite a lot of detail with regard to the kind of biochemistry and cellular biology of some aspects. Another episode that will be helpful is episode 44 on cell division, particularly when we discuss chromosomal changes, many of which relate to the process. of cell division. So without further ado, let's get started and begin by talking about types and causes of mutations and a natural point to start there is by asking what is a mutation.

So mutation is an alteration in the nucleic acid sequence of the genome of an organism. So the genome is the set of all genetic material that an organism has. Genetic material consists of DNA nucleotides, which are joined together in a long sequence. The sequences of DNA code for the proteins that are essential for the biological functioning of that organism. So when there is a mutation or an alteration in the nucleic acid sequence of the genome, then that means that there is either a loss or some sort of corruption of the information in the genome. And that's usually deleterious. We'll talk about that aspect in a little bit, but usually that's a bad thing because essentially the information that is coded there currently,

serves it usually it serves a purpose, at least if it's coding for a gene. And therefore, if that's modified or altered in some way, it usually means that there's going to be some negative consequence for the organism. So certain proteins won't work correctly or won't be produced in the right amounts or at the right times and so forth. So that's a fairly intuitive idea, right? If something's working at it, if you mutate it or change it in some way, that's usually going to be a bad thing. mutations typically result either from errors in DNA replication, which we'll talk about it a bit later, or from damage to the DNA caused by some kind of external mutagen. And we'll talk about some examples of that at a moment.

So there's sort of two main types of mutations those caused internally or sort of externally induced. And mutations may or may not produce detectable changes in observable characteristics of the organism. So this is the phenotype of the organism, observable traits or characteristics. So many mutations won't change to phenotype. Some will. And it depends where the mutation is and the type of the mutation, which will go through in more detail. So first of all, let's get some idea about how often do mutations happen. So let's talk about mutation rates.

Mutation frequency refers to the number of occurrences of a particular type of mutation expressed either as a proportion of the cells in an individual or as a proportion of individuals in a population. It's important to understand exactly what the kind of denominator is here, whether we're talking about mutations per cell or per organism or per population and over what period of time, because different sources will sort of quote different types of measurements. Mutation frequencies vary substantially between different organisms. It's also important that we make a distinction between germline mutations

and somatic mutations. So germline mutations are those that occur in gametes. So these are essentially sperm or egg cells. That's important because any mutations in a germline have the potential to be passed on to the next generation. Somatic cells are all of the other cells in the body. Mutations in somatic cells can have an effect on that organism while it's alive, but won't be passed on to offspring.

So there are different mutation rates in the germline compared to somatic cells because the body has to be extra. careful in preventing germline mutations because these will be passed on and will have evolutionary effects as opposed to somatic cell mutations which which won't. So in humans the germline mutation rate has been estimated to be about 0.3 times 10 to the minus 9 per base pair per year, which is a bit of unintuitive unit. Mutation rates are typically measured per number of base pairs in the genome per year because we're talking about things that happen over a period of time, right? So you have to specify what interval you're talking about. So for example, if we assume that the average age of

a father is about 30 at the time of conception, which is sort of when the clock starts. So that's when the gametes will be formed. So when you are conceived and as you develop, your gametes will form early in the development process. So roughly at the time of conception or shortly afterwards, that's when the gametes that you carry are formed. You know, they're precursors, right? The initial cells, and then you count down up to the time when you conceive. And so the time between one conception to the next effectively represents the generation time of that organism. So that's the timeline that you want to consider when you're looking at how many mutations happen from one generation to the next, how many mutations will be passed on from generations. And so

for average father's age of about 30 years and the size of the, known size of the human genome, about 30 mutations per generation are expected to be passed on one father's gametes then to your gametes. From your father's gametes to your gametes. And I've been talking about father, by the way, because the mutation rate in the father is most important rate, the determining rate of the overall inheritance of mutations. So the crucial thing here is that 30 mutations per generation is a very small amount, given that the size of the human genome is something like 3 billion base pairs long.

Only 30 mutations in that whole sequence in a 30-year time span is really quite impressive, and that goes to show how effective the repair mechanisms are. Somatic cells, by contrast, they keep accumulating mutations throughout the whole life of the organism, not just from one conception to the next. And the rate is much higher. It's something like 100 times higher than germ cells. So that means that each semantic cell will accumulate about 150 mutations per year. That 150 mutations refers to each cell in your body.

So the total number of mutations will be very large. But most of those mutations will only affect one cell or maybe a small number of cells, if it's still an actively dividing cell type. So it is very important to make this distinction between whether you're talking about germ cells or somatic cells, because mutations in each have very different consequences. So let's move on and talk a bit about. some of the causes of mutations. So, you know, where do these mutations come from? As I indicated before, there's two main classes, spontaneous mutations,

so those that happen due to essentially mistakes in endogenous biochemical processes, and then induced mutations, those that are caused by external causative agents. So let's talk about some of the causes of spontaneous mutations. Most of these are biochemical in nature, so it's when something goes wrong in one or more of the different biochemical interactions that occur, you know, as part of metabolism. So one example is depurination. So this is the removal of a purine base from DNA, leaving it without a base for parent with. You may recall that there are four different DNA bases, so that's ATGC, and each of those consists of a five-membered ribose sugar

connected to a phosphate group, which provides mechanism for connecting up the different adjacent bases along and forming a chain, right, along the DNA molecule. And then there's a base. And this is what differentiates the four different nucleotides along the DNA, the A, T, and the G, and the C. So deep purination means that a purine base, so that's one type of the basis, is lost. And so it doesn't have a base to pair with. And that effectively means that in the DNA chain, there'll be, you know, the DNA is a double helix, so one side of the helix won't have anything to pair to. And that obviously represents a problem for the structure. It will be imbalanced and part of the information is lost because it's actually that sequence of different bases, the AT, D and C, the order of those

along that double helix that provides the information about what the DNA codes for. So if you lose that, then you lose genetic information. So a similar process is deprimidation. So that's basically the same thing as depurination except for the other type of nucleotides. So that's when the perimidine nucleotides lose their base. So therefore they're not able to pair with anything. D-amination is a process whereby a normal base interchanges instead of pairing with the typical A to the T or G to the C, it instead pairs with an atypical base. So this tends to cause bulges or improper shape of the double helix. There's also something called a tortimerism.

So this is when a base is changed by repositioning a hydrogen atom, altering the hydrogen bonding pattern. The hydrogen bonding is what connects the base pairs together. so the A to the T or the G to the C, right? They're connected by hydrogen bonds. And totalomerism is effectively when orientation or the shape of some of the atoms in one of the nuclear-tide pairs is altered, so it sort of moves around or reshapes, and that means it can't form the hydrogen bonds properly. So that leads to incorrect base pairing. Again, that tends to result in structural deformation of the double helix and a loss of genetic information or corruption of genetic information. There's also something called slipped strand mispairing, which is interesting.

So instead of one nucleotide being off, which is the previous examples we've been talking about. So what happens during DNA replication is that the double helix sort of unwinds and unzips and splits into Dnachers into separate strands. One of those strands will be copied. That's the template strand. And then after the copying is done, it will re-associate back with its complementary strand and, you know, wind up the double helix again. But in slip strand mispairing, what can happen is that if there's a repetitive sequence along the DNA, so the same set of nucleotides in the same pattern over and over again, there can be a slippage. So the two strands that should line up properly, instead there becomes a kink in one.

Because the way to think about it is if there's repetitive DNA, there's multiple ways of matching the two strands together. And so instead of sort of two strings pulled taut lying next to each other, one of them will be kind of bunched up forming a little loop and then comes down again and runs along next to the other strand because there's multiple ways in which the two strands can pair next to each other because of the repetition. This can't happen if the two strands don't have any repetition because there's sort of only one way for them to line up next to each other. But repetition can result in these different ways of associating. And so this leads to improper association of the of the two strands with each other, which can lead to a variety of consequences, some of which

will look at when we look at chromosomal changes. So these are examples of some of the spontaneous mutations that can occur. Don't worry too much if you didn't quite get all the details of the exact biochemistry. The point is just to illustrate that there are many reactions that are recurring in the complex biochemistry, and if things go wrong because of a misplaced hydrogen atom here, or an enzyme acting in a slightly inappropriate way, cutting off part of the molecule over there, then that results in changes to the actual structure and sequence of the DNA. And so that happens at some rate just spontaneously. That's just, you know, the nature of chemistry is that there's many reactions that can occur.

You know, some of them are quite unlikely, but they'll still happen some proportion of the time. So those are the spontaneous mutations. Now let's have a look at some of the inducing mutations. So this is, of course, by some external agent. Let's start by talking about base analogs. Base analog just means it's some chemical compound that is structurally similar to the standard bases, the ATGNC, that are involved in standard DNA. If these are present, they can be inappropriately incorporated during the process of replication. This can then often result in mispairing or miscopying of the DNA later down the road.

Nitrous acid is another mutagen, so this is a deamination. agent. So this causes nucleotides to switch because of deanimation. We talked about that just before. This involves changing a normal base to an atypical base. And what it tends to do is it results in transitions of an AT pairing to a GC pairing. Effectively, the way it usually happens is that one base will be modified in some way and then it will mispair. It will mispair to a normal but wrong but wrong base. And then the repair machine, we'll see, oh, we've got a mistake here, this base analog or this incorrect compound shouldn't be there, so we'll take it out. But then because it's already, sort of the harm's already done, it's already been paired with the wrong thing in the other strand,

the new nucleotide that's added back in replacing the thing that shouldn't be there is the wrong one. And so this is a common mechanism that can occur, essentially that there's something is incorporated that shouldn't be there. It leads to mispairing. The foreign agent is removed, but the mispairing remains, because Another type of mutagen are called intercalculating agents, so things like Ethidium bromide, acridine orange, and profylene molecules, they can actually insert between DNA bases, and that can cause things like frame-shift mutations, so this is sort of what I talked about before, where the DNA molecules sort of move relative to each other, and so you

get skipping or duplication of nucleotides along the DNA. UV light is a mutagen, so people are probably aware that the sun can cause cancer, well, this is why because uv light that is in the sun is high enough energy to disrupt the bonds between some of the nucleotides in DNA molecules and particularly what it tends to do is distort the double helix by forming thymine dimers so if you have two if you have two t's right the thymine nucleotides if you have these near each other a reaction that can be effectively catalyzed by uv light or at least the energy for it provided by UV light, forms the two thymines into a dimer,

which actually forms bombs between the two nucleotide bases, which shouldn't be there. So this causes a disruption in the, and distortion in the structure of the double helix, which, of course, is a problem. Then there's ionizing radiation. So ionizing radiation is radiation that is capable of removing the electrons from an atom. So UV lights, at least mostly not ionizing,

though it is relatively high energy. Ionizing radiation is kind of the next level up, so x-rays and gamma rays. This can create free radicals, which are molecules that have unpaired electrons. Because of that, they're very reactive, and so free radicals are generally quite dangerous. I mean, there's a certain number of them that are in the body produced by endogenous metabolic processes, but you generally don't want too many of them around because they're very reactive and they can cause a lot of damage to other molecules. Essentially because they're so reactive, they tend to go around and,

react with everything that they can find, producing some sort of strange and unusual byproducts and disrupting the structure of DNA and so forth. So ionizing radiation can have this sort of double-wammy effect. It can directly break a double strand of the DNA because it's high enough energy to actually break those bonds. Or it can create free radicals. It can ionize a different molecule to create a free radical, which then in turn does damage to the DNA. These are just some examples of mutagens. There are many, many different chemicals. and also physical processes like light, which have mutagenic effects. There's a very simple test that's used to determine whether something has the potential to act as a

mutagen. It's called the Ames test. And it's quite a simple assay. What it involves is you take a special strand of bacteria, which require the amino acid histidine for their growth. So they can't grow, or they can sort of barely just survive, but can't expand. They can't. They can't multiply to any significant rate. So that in order to grow significantly they need histidine to be added to their culture. So what you do is you grow them in a plate that lacks histine or just has like the bare minimum amount so they can just barely survive but they won't expand over the. So then what you do is you place a little pellet or some extract of the chemicals that you want to test on the on the plate. So you culture the plate with the

bacteria, you don't give them the histinion that they need, and then you just put a sample of the chemical on there, and then you incubate it, and you see what happens. If effectively nothing happens, there's minimal, in other words, if there's very minimal growth of the bacterial colonies, then that's a negative result, and what that means is that the chemical that you've added hasn't mutated the bacteria, or at least it hasn't mutated the bacteria to any appreciable extent, because they're still acting normally, that is, they're still not growing. If, on the other hand, you see that the culture has begun to spread across the plate, that indicates that there's been a mutation,

and now the bacteria are capable of producing their own histidine, and so they don't need it anymore, they're able to grow despite the absence of histidine. And the only way that that's possible is if there's been a mutation, which has reverted them to the phenotype, where they can now produce that themselves. They have the right enzyme. I'm not sure exactly what that mutation is,

but it doesn't matter for our purposes here. So the point is, if you see a new phenotype like that, that's an indication of a mutation. That's evidence that the chemical that you've added is acting as a mutagen. It's caused that mutation, allowing the bacteria to then acquire this new phenotype. So that's a simple test for determining whether something is a mutagen. It should be stressed that just because something is a mutagen doesn't necessarily mean that it's dangerous to people. It just means that it has the potential genetic mutations.

there are further questions about, say, dosage and exposure and other aspects that are very important for assessing the overall risk. Okay, so now let's move on from the types and causes of mutations and talk about the effects of mutation. So regardless of, you know, exactly how the mutation happened initially, what does it do? I've spoken so far in fairly vague terms about damaging the DNA molecule or corrupting or disrupting the information stored. in the genome, but how does this actually work? Well, again, if you're not familiar with this, then go back and listen to the episodes where I talked about DNA structure and function, but the key point is that the information in the genome is stored by the linear sequence of nucleotides, so AT, and C. If you change that sequence of nucleotides, you change the information

encoded in the genome. Now, much of the genome does not actually, does not actually code for genes. There's a lot of other material in there as well. It's repetitive or structural or doesn't seem to serve any known function. And so mutations in those non-coding parts of the DNA don't necessarily have as big effects. But if you do change the nucleotide sequence in a coding part of the genome, then what that means is that the amino acid that's coded for by that gene will potentially also change. And that then has the potential to affect the phenotype of the organism. So that's the basic idea. You change the sequence of DNA, you change, if it's in a coding part of the DNA, then that changes

the protein that's coded for, which then changes phenotype. Typically for the worse, though, again, not necessarily for the worst. So let's look at that in a little bit more detail. The simplest type of mutation is called a point mutation. And many of the ones that are, the types of mutations that I've been talking about, such as those induced by spontaneous mutations, like deep urination and deperamination and stuff like that, those typically lead to point mutations. And a point mutation is just when a single nucleic acid,

is changed or altered into a different one. So an A could become a T or a G, a C, or something like that. Now, there are other types of mutations as well, and particularly we'll look at larger scale mutations when we get to large chromosomal changes at the end of the episode. But for the moment, we'll talk mostly about point mutations. So point mutations come in a few different types, because you can change a single nucleotide, but depending on how you change it, like what you change it to, that will determine what the actual effect is, are on. the phenotype. So first type of point mutation is called a silent mutation. It's called silent because you kind of don't see it, right? I mean, you can still, you'd still know what

happened if you sequenced the genome, but otherwise you wouldn't know about it. And the way this works is because the genetic code is degenerate, what that means is that there are multiple codons. So codon is a sequence of three nucleic acids in a row. Multiple codons code for the same amino acid, because there are four times four times four, which is 64 different codons, but only 20 amino acids, that means that there must be degeneracy. That is, there must be some codons that code for the same amino acid, which means that sometimes you can change a nucleotide, which changes the codon, changes that sequence of three letters, but it won't change the amino acid that it codes for, because it just happens to be a different codon that codes for the same amino

acid. So for example, A-A-G, that codon codes for the amino acid lysine. A different code on, A-A, also codes for the amino acid lysine. So if you change that final G to an A, that's a point mutation, but it's a silent mutation because the amino acid that results is the same. So silent mutations usually don't have any effects on phenotype. I think in certain cases they can because sometimes there's sort of, let's just say there's subtleties there, but generally they don't have any the phenotype the protein will be the same and then the phenotype of the organism will be the same. Now here's another possibility. There is a special codon which is called the stop codon and that codes for the process of translation. So when the information on the DNA is converted into messenger RNA

the stop code on tells that process essentially to stop, meaning that this is the end of the transcript for the protein. Obviously it doesn't go on forever so it has to be an endpoint. The stop stop codon says, we're finished now. A nonsense mutation is a point mutation which results in a premature stop codon. And it's called nonsense because typically if you insert a stop code on too early in a gene, then that means that the resulting protein product is going to be incomplete and therefore usually completely useless. Hypothetically, maybe if you inserted a stop code on a couple of amino acids early, then maybe

you'll be able to get away with it if the few amino acids of the protein are not essential. Sometimes they might be clipped off anyway. But in general, if you just throw in a stop code on halfway through the protein, well, you shouldn't expect a functional product, right? It's just going to be half a protein. And half a protein isn't half as good as a whole protein. It's typically useless. So that's why it's called nonsense.

It doesn't code for anything kind of meaningful or useful biologically. So the next type of point mutation is called a mis-sense mutation. of an odd word, but what it means is that it codes for something, it doesn't code for nonsense, it's just not the right thing. So hence, mis-sense instead of nonsense, right? And what this means is that there is a change in the codon which results in a new amino acid. So instead of a silent mutation, which changes the code on, but to the same amino acid, a mis-sense mutation changes the code on, but to a different amino acids. And this can be broken into two sort of subclasses, conservative and non-conservative. A conservative mis-sense,

mutation basically means that yeah the amino acid has changed but it's similar enough so that the function will be similar so there will be some change in function of the protein but no not too much typically whereas a non-conservative mutation or it's a completely different amino acid with completely different by chemical properties and so that may have a significant effect on the function of the protein so those are some different effects that point mutations can have on the DNA sequence I should also mention frame shift mutations those tend to be much more catastrophic, a frame shift mutation is caused by the insertion or deletion of a number of nucleotides that is not evenly divisible by three. So if you delete three nucleotides from a gene,

what that will mean is that you will remove a single amino acid from the resulting protein. Now, that could be important. It may not be important depending on amino acid. but it's actually worse if you only remove one nucleic acid because if you take away three nucleic acids from the DNA that means that only one amino acid from the protein will actually be removed and so most of the protein is still the same but if you take away only one or two nucleic acids from the DNA that means that the whole the whole what's called reading frame of the gene is changed

because now instead of counting sort of from one two three and four and so the first three are a codon, this next three are codon and so forth, now the whole series of counting is off. So all of the codons will be misaligned. This means that the DNA will code for something completely different than what it originally coded for, and often the result will be nonsense. So frame shift mutations are usually extremely deleterious, and typically you won't get anything even remotely similar to the initial result. So that's why insertion or deletions are particularly dangerous, much more dangerous than a, a point mutation that just modifies the single nucleic acid. Now, beyond these different types of point mutations or the sort of

bichemical effects on the DNA sequence, there's also, we can also think about the effects of mutations more at the phenotypic level. An amorphic mutation is one that results in a complete loss of gene function. This is also called a knockout or a null mutation. So this would typically happen as a result of a frame shift mutation or a nonsense mutation. It just completely disrupts the phenotype, complete loss of gene function because you don't get a viable protein product. Hypomorphic mutations result in a partial loss of gene function. So maybe it's lower protein production rates or a mis-sense mutation resulting in a protein product, which works, but not as well as it typically does.

So it impairs the function. A hypermorphic mutation is one that actually increases normal gene function. This is also called a gain of function. This can result from many causes. For example, if a mis-sense mutation happens to improve function of the gene in some way, as it can do, it's unlikely, but it's possible, then that can result in a hypermorphic mutation, a gain of function. Another possibility is that duplication of genes. We'll talk about how that can happen a bit later. That can result in increased gene expression.

So there's many ways that gain of function can happen, and this is one of, gain of function is one of the mechanism. essence by which evolution happens because if there's a gain of function that is beneficial for the organism that will be selected for over evolutionary time and therefore become more prominent in the population. There's also something called ectopic expression. So this is when a gene is expressed, so it's a regular gene that's expressed, but in an abnormal place in the organism. So this can be caused by disease or it can be artificially produced to help determine the function of a gene by activating it in an abnormal position. This is often done, for example, with research in drosophila, so fruit flies, they'll activate genes in abnormal positions on the, on the fly's body, and sort of see what

happens. Okay, so that brings us to an end to the first part of this episode. So we've talked about what mutations are, the causes of mutations, and the effects of mutations, both at the sort of sequence level and at the level of the phenotype of the organism. So now we're going to talk about some of the repair mechanisms that are used by cells. And specifically, there are four different types that we're going to go through. Once again, the biochemical detail is too difficult to explain and really beyond the scope of what I want to convey in this podcast. So I'll talk, I'll try to explain it a little bit, but I just want you to get the sense of how it is in general terms that the cell is able to identify and correct mutations, because it's not like, it's not like that there is a conductor

that there who's sort of looking at the DNA with a magnifying glass and then, ordering different molecules to go and fix things. It's all done as a series of chemical interactions. So you might wonder, how does that happen? Well, here are some ways that it happens. The first repair mechanism that we're going to look at is called base excision repair. This typically is used to repair small non-helix distorting base lesion. So often this will be used to repair a single point mutation, so a single nucleotide.

Perhaps that's been inserted correctly due to an area in transcript. or perhaps due to a base analog being inserted, or due to one of these spontaneous mutations like depurination or depramidation or something like that. So any of these things that results in kind of one base being off in some way. And what happens is that there are special enzymes called DNA glycosylases, which kind of are constantly moving along the DNA and keeping an eye on things. And when they detect an abnormality in the double-examilases, in the double helix that's caused by an incorrect base insertion or some other

or some other mutation, that can be detected because it changes the shape and the structure. It's sort of literally the double helix will be the wrong shape in that place because it's abnormal. The glycosylase is able to detect that and then remove the aberrant base. So this is why it's called base excision. It detects the abnormal base and removes it. And that leads to what's called an AP site. which is basically just an empty site. There's the backbone is there, but there's no base.

So there'll be a base on the other strand, but it won't be paired with anything. So it's like a lone base. And then what happens is that other enzymes come in. They recognize that, oh, there's a site here that doesn't have a base. It should do. So then it takes out the sugar phosphate backbone, and then phosphate airstase comes in and adds back in the missing base. And it's able to do that because,

remember that you've got the double helix structure, the complementary strand is still there, and so the enzymes are just able to add back in, oh, you know, this is a G on the complementary site, so it should be a C here. This is why I sort of talked about before. If the complementary site has already been altered through some other process, then this will still result in a mutation, because basically the repair will happen, but it will happen after the complementary nucleotide has also been altered. And so the slower this correction takes place, then the more likely it is that there will be a mutation that's sort of locked in anyway. But that's a fairly simple overall process. A more elaborate mechanism is called DNA mismatch repair. And this typically occurs

after DNA synthesis. DNA synthesis is not a perfect process, so it results in some mistakes. mismatch repair is often used to correct those mistakes. So there are mechanisms by which the cell is able to distinguish the old strand from the newly synthesized strand. This appears to relate to methylation of the DNA molecule. So methylation, it results in just sort of adding small carbon and hydrogen groups to the DNA molecule, which goes sometime after synthesis. So basically the cell tags in a fairly simple way. It tags the DNA molecule.

So it can distinguish the new copy from the old version. And essentially the assumption is, or the assumption built into the, biochemical process is that when there's a mistake, the old copy will be the correct copy. And that's reasonable because the old copy is the one that's been around longer, and therefore it's less likely to have, at least it's less likely to have a mutation that's resulted from synthesis. I mean, it may have accumulated mutations in other ways. But with this particular type of repair, it's focused on repairing damage resulting from synthesis.

and so the one that was most recently synthesized is most likely to have this damage, right, because it hasn't had to repair yet. So the way it works is that you have enzymes which are able, again, to detect the incorrect pairing of bases as a result of the mismatch. That's why it's called DNA mismatch. It's able to detect the mismatch in bases after synthesis, again, by bulges and distortions in the Helic structure or in the pairing of the nucleotides and then once the enzyme detects this sort of bulge or these these imperfections it then recruits a bunch of

other enzymes to form a complex and this is where it differs quite considerably from base excise from basic excision repair because instead of just removing the one nucleotide and then adding back in the correct one it actually cuts out a whole big section of the newly synthesized strand remember if there's a miss pairing of nucleotides you don't necessarily know which one is and which one is incorrect. So the assumption here made by this system is that the one on the newly synthesized strand, the one that's not methylated, that will be the incorrect one. And so it cuts that out, not just that nucleotide, but in a sort of a long stretch downstream with that as well.

And then DNA preliminaries comes in and essentially redos the job. It redos the synthesis job. So it adds in all of the nucleotides according to what the complementary strand stipulates. So it's basically like, oh, we did a bad job here. We're going to rip all these out in this region and then do it again. So the key difference here between basic excision repair and DNA mismatch repair is basic decision repair doesn't have to worry about which strand has the mutation because it's sort of obvious, right? It's a type of damage where you can tell which of the nuclear tides shouldn't be there, typically because it's an aberrant form or it's a base analog or something like that. So you can just rip that out and replace it. Whereas DNA mismatch repair, all the

the cell is able to determine directly is that there's a mismatch, but you don't necessarily know which one is the correct one. So the assumption is made, well, the unmethalated strand will be the newly synthesized one, and therefore it's probably the one that's wrong because there was probably a replication error. So we'll just rip out that whole region and then do the replication again, essentially. Nuclear-tide excision repair is kind of similar in that it involves ripping out one of the, like a segment of one of the strands of DNA, and then synthesizing it back again. The difference here is that instead of responding to errors in DNA replication, nucleotide excision repair typically takes place in response to damage from ultraviolet light,

particularly those adducts. So these are the thymine dimers that I mentioned that can be formed by UV light coming in and forming these aberrant bonds between the adjacent thymers. that results in a big sort of bulky bulge of the double helix structure, which can be identified by special enzymes, again, that are looking for this. When it finds one of these, it records other enzymes, it cuts out that region and replaces it, again, with whatever is appropriate given the complementary strand. So again, it's easy to tell which is the aberrant strand and which is the correct one here,

because one of the aberrant strand will have the bulky adunk on it, and the other one won't, right? So the cell doesn't have to worry about distinguishing them here. One of the most dangerous types of damage is a double strand break. I haven't really mentioned this so far. We'll talk a little bit more about this in the final section of this episode. Double strand breaks happened when both strands in the double helix are severed. So when you have, for example, replication of the DNA or transcription for that matter, the two strands come apart.

And if you cut one of those strands, then there'll be a cut in. one strand of the DNA. This happens, for example, during DNA mismatch repair, nucleotide excision repair. One of the strands is cut, and then it removes the nucleotides in some region of one strand of the DNA and then replaces them back. In double strand breaks, both strands are cut. It could be either at the same place or select slightly off, out of step, one strand, slightly upstream or downstream of the other, but in a similar place. This can happen spontaneously, such as reactive oxygen species or by ionizing radiation. So both of these basically chemical or physical damage

from high energy species or high energy radiation can cause this. It does take quite a lot of energy, but it can happen. And as you might imagine, it's very dangerous because it means that if there's damage to one strand or one strand's been chopped or something, well, then the template strand can be used to repair and fix it. But if both of them have been cut, then that whole chromosome effectively has been chopped in two

and that's obviously a big problem you need to fix that so there are actually a multitude of mechanisms for fixing double-strand brakes and the precise details are still being studied is my understanding two main mechanisms I've just mentioned to repair double-strander breaks are non-homologous end joining and homologous recombination and these involve very different mechanisms so non-hemologous end rejoining is sort of the simplest method that you might imagine. Well, if the double strand has been broken, say, by ionizing radiation, let's just

bring those two ends together and ligate them back, essentially glue them back together. And that's, that's more or less what happens with non-homologous end joining. Enzymes are recruited that detect these ends of the DNA that shouldn't be exposed. And they're like, hmm, this doesn't seem, right? These ends shouldn't be exposed to the solution here, because ends of the chromosomes, especially wound up and there's proteins that protect them and so forth. But if you just sort of chop right in the middle there, that's going to expose the ends that will start flopping around, and that sort of novel chemical environment will attract these enzymes that then attract further enzymes that help to, well, that licate, that basically sew up the gaps on both sides, so both of the,

both of the strands. So that's quite a simple method, but it's not the only method that the cell uses. It also uses more complex methods when needed. The more complex method that we'll discuss here is called homologous recombination. Homologous recombination is quite complex to explain. The major advantage of homologous recombination is that it actually doesn't just assume that the two loose ends belong back together. Because for non-homolegous end joining, the ligase just sort of assumes, well, these are two ends, let's just sew them back together. But it's possible that some genetic material has actually been lost there, or added for that matter. That simplistic process has no way of checking.

So my understanding is that this is the advantage of thermolumatial. recombination is that it's more complex, but it does more checking because what it does is it actually uses Homologous chromosomes or remember in all cells except for gametes there are two chromosomes that have the same information So you have two copies of each chromosome except for the sex chromosomes and so these are the two chromosomes that have the same information are called homologous chromosomes So what homologous recombination hence the name is what it does is that it uses information from the homologous chromosome. So basically it says, oh, we've got a cut here. Let's bring along the buddy of this chromosome, because that should be a good copy, an unmutated copy of the genetic information here. And so it uses that information to sort of

synthesize one strand of the, like one half of the broken piece and then the other half of the broken piece and sort of sows them together in a more complicated way, more similar to DNA synthesis and crossing over, right? Again, I won't try to explain it without a diagram, but the point is that it actually uses homologous synthesis of the complementary strand from the homologous chromosome, which then allows the cellular process to check that these two ends actually belong back together and sew them together in a way where it ensures that they are actually sort of complementary and belong there. So the point to emphasize there is that there are multiple mechanisms that the cell uses to correct

these different types of repairs, even double-stranded repairs, which are quite difficult. There are sort of simpler methods, and then there are more complex methods which use more kind of cross-checks. And a lot of what it comes down to is enzymes, which are constantly on the lookout for structural defects or chemical environments which shouldn't be there, like a cut in the double strand of the DNA. When those molecules detect this, they recruit other molecules, enzymes, which perform repair mechanisms. usually these repair mechanisms results in removing the aberrant genetic material or like the aberrant bases or nucleotides and replacing them based on the complementary strand or in the case of DNA mismatch repair the newly synthesized strand which is assumed to be the correct one in the case of a double-stranded break where you don't actually have a complementary strand because both of them are

being cut through you can just sort of go ahead with the simple method and use non-hemologous end joining and just sort of hope that those ends belong together, which often they will, but maybe you've lost some material there. Or you can use the more complicated method of actually recruiting the homologous chromosome, bringing that along and then using its extra copy of the gene sequence. So the cell is very efficient with its use of information, and there's a reason why multiple copies of the same information are stored, both on complementary strands of a single D molecule,

and then also with the fact that we have two copies of, all of our chromosomes, except for the Y chromosome if you're a male. Okay, so let's conclude this episode by talking about some of the larger scale causes or types of mutations called large-scale chromosomal changes. So the chromosome is a package of DNA, along with associated structural proteins, which stores some or sometimes all of the genetic material of an organism. So you can think of the chromosome as basically a very long DNA molecule, wound up and packaged with proteins. I talked about the structure in previous episodes, so again, I'll refer you to those for more

detail here. Humans have 23 pairs of chromosomes. So 22 of those are called autosomes. They are chromosomes that always come in pairs that are essentially identical and contain most of the genetic material that we need. And then there are two sex chromosomes. Females have two X chromosomes, and males have one X chromosome and one Y chromosome. Males and females both have 46 chromosomes in total, 44 of those are autosomes, two copies each of the 22 pairs, and then the two sex chromosomes. A chromosomal abnormality is any missing extra or irregular portions of chromosomal DNA. So this is at a higher level than we were talking about previously when mostly we were talking about point mutation, so a single nucleic acid or perhaps a few in a row. But here now, when we're talking about chromosome 11 abnormalities, we're talking about very large sequences of DNA.

So a single chromosome may have hundreds of millions of base pairs, the largest ones do. So if substantial fractions of that chromosome are either deleted or duplicated in some way, then that could be thousands or even millions of base pairs that are altered in some way, typically moved around or cut or pasted, right? So this typically results in much more substantial changes in phenotype than occurred just by changing a single or a couple of nucleic acids in one protein. Although that's not necessarily true either. It's not always the case that the number of nucleic acids affected directly corresponds to the magnitude of the phenotypic change. But overall, you would typically expect that changes across larger numbers of nucleic acids are going to have bigger changes to the phenotype. So let's talk about some sources of chromosomal abnormalities and what effects they typically have. So deletions.

Deletions involve the loss of genetic material. So the smallest case we talked about before is the loss of a deletion of a single nucleotide. Losing a single nucleotide will result in a frame shift mutation, which is often quite dangerous in itself. But you can even have entire pieces of chromosomes or even entire chromosomes that are deleted. deletions typically involve two chromosomal breaks, so in other words, a double-stranded break. You have to break it on both locations in order for it to be fully deleted, otherwise it will just be kind of ligated back again. And this often occurs as a result of ionizing radiation. Deletions occur at different magnitudes, so introgenic deletion is a deletion of a small number,

or relatively small proportion of nucleotides within a single gene. That can damage that gene, but it typically won't affect anything else, or at least not much. Deletion of small segments within a gene is typically not reversible. So we talked about like basic position repair and DNA mismatch repair, which can repair single nucleotides that are damaged. But if you delete a large segment, or even a fairly small segment to be honest, but within a gene, then there's usually nothing that can be done about that because there's no complementary strand to use and the damage is too extensive. There's also multigenic deletion, which can remove anywhere from dozens to thousands of genes. The latter would be a large proportion of the whole chromosome, and this results in very

severe phenotypic changes, obviously, because you've lost large amounts of gen 8 material. Now, in humans, if any single chromosome is missing, that results in a non-viable embryo. So that does happen periodically where, due to errors in DNA synthesis or in cell divisive. vision entire chromosomes are missing, the result will be a non-viable embryo and that will be spontaneously aborted fairly early in the process. So humans can't survive without both copies of all 22 autosomes. There's only one chromosome that you can survive without as a human and that's the Y chromosome. And we'll discuss a little bit as to what that can look like if you are missing a Y chromosome but don't actually have two X chromosomes. So deletions are usually

quite harmful, especially if we're talking about a whole chromosome or large. proportions of it. The opposite of a deletion is a duplication. So this is when genetic material is, well, duplicated. Again, this usually is the result of errors in DNA synthesis or particularly in cell divisions. We talked about one cause of this a bit earlier on of DNA duplications can be if there is a frame slippage during synthesis, where typically due to repetitive sequences of DNA, one of the strands become sort of misaligned relative to the other, and then you get this loop of sort of non-matching material, which has been effectively inserted. So one way this can

happen, if you imagine that there's a template strand that's being used as the template for DNA replication, and it's, you know, the machinery is moving along, and the replication fork, and it's adding new nucleic acids. Now, imagine there's some sort of problem, and the enzymes get dissociated or they get moved in some way and then they try to return to their position and continue the replication. But one thing that can happen is if there are repetitive sequences in the DNA, the machinery can return to the wrong position. So they think that, oh, this is where we need to pick up. But actually, if they go, if they accidentally go backwards and match up to a region that looks like where they should be, but it's in fact a sort of a previous copy of the same thing,

then they can inadvertently copy the same sequence again. And this will result in a sort of a loop of the newly synthesized strand, where it doesn't have anything to pair with because it's been duplicated. And again, this happens largely because of repetitious sequences where there's sort of multiple places where the two strands can pair with each other. So this is one way material can get duplicated. Another cause of duplications is unequal crossing over, which I'll talk about a bit more in a moment.

So whatever the reason, duplication of genetic material can lead to extra copies of the same gene appearing in the genome. And this can lead to phenotypic changes because it can change the level of expression of a certain gene, for example. So having extra copies isn't neutral because it affects the amount that something is expressed. It can also change where it's expressed in the body sometimes. If the genetic material is placed in a different chromosome, it can affect based on how much that chromosome is activated or deactivated in certain locations, it can affect how much that gene is expressed or where in the body it's turned on. So even extra copies of the exact same genetic material can have significant effects on phenotype. Generally, not as much as a deletion of a large section of a chromosome, but still they can be quite significant. So I've already alluded to this, but a translocation is when part of a chromosome becomes detached and then moved and placed in a different location.

So it's not duplicated or deleted, but it's moved around from one chromosome to another. So ends of chromosomes can sometimes become detached and placed on different chromosome. There's another phenomenon called inversion where you have a piece that breaks off, rotates 180 degrees, and then adds back on. So in this case, you have no overall change in genetic material, and typically it doesn't result. in any abnormalities because all of the same genetic material is still there. However, if the break point occurs within an essential gene, then obviously you're going to get a lethal mutation there because that gene will be chopped in too now.

So there's lots of complex things that can happen, deletions, duplications, inversions, translocations. The important point is that all of these can have substantial effects on phenotype. Generally the most dangerous is going to be a large-scale deletion because you're actually losing genetic material, but all of the others can have significant effects as well. one of the major mechanisms by which these large-scale chromosomal changes can occur is through something called unequal crossing over unequal crossing over is a type of error that occurs during cell division so what happens during cell division is that first of all each of the chromosomes duplicates so there's a so there's a process of DNA replication

and each chromosome, you may recall, if you've familiar with this or listen to a previous episode, each chromosome goes from being kind of like a sausage with the centromere at the center, so like a line with a bulge in the middle, to looking like an X. And the sort of center of the cross of the X is the centromere, and the two sides to the X are the sister chromatids. So they are just copies of the same material, and what will happen is one of the sister chromatids will go to one of the daughter cells, and the other will go to the other daughter's cell.

Crossing over is a process that occurs where by the two homologous chromosomes. Remember, there's always two apart from the sex chromosomes. Each chromosome has a pair, a buddy, and each of them should contain essentially the same genetic material. There may be a couple of mutations here and there, but it should be more or less the same. What happens is that the homologous chromosomes line up, and they sort of pair up with their body along the center of the cell during mitosis, and they kind of exchange genetic material. is called crossing over. Crossing over is important because it's a source of genetic variation. But the way crossing over is supposed to work is that if you imagine, just to simplify things,

region four of this chromosome, it swaps out for the same region four on the homologous chromosome, like the buddy, right? So the same regions are supposed to swap out for each other. So all you're doing is swapping the same region of the same chromosome, but from one of the homologous pairs to the other. So that's what's supposed to happen. So when there are cases of heterozygote alleles, so an allele is a variant of a gene, so if one of the homologous chromosome is one or the other and the other has the other allele, that's an example of heterozygosity. Crossing over can have effect on the distribution of alleles and things like that.

And so it's a source of genetic variation and novel genetic combinations, and it has various benefits in that respect. But the point is, crossing over doesn't always go as it's supposed to. Crossing over isn't supposed to change the overall amount of genetic material. It's just supposed to sort of shuffle it around a little bit, but keeping the order the same within each of the chromosomes. If crossover goes wrong, this can result in one of the daughter chromosomes that eventually ends up in one of the daughter cells. It can have extra copies of the same region of the chromosome. because instead of essentially what's supposed to happen is there's a swap.

You know, one of the daughter chromosomes gets region four of its pair, and then in turn hands over its region four, and so there's a swap. But if the swap doesn't happen correctly, one of the daughter chromosomes can end up with two copies of the same region, and another will have no copies of that region. Or you can also have inversions where it gets a copy of region four, but it's inserted the wrong way. So that's like the inversion that we talked about before.

or it could get the copy of that region, but it's somehow stuck on the wrong part of the chromosome. So there's all sorts of things that can potentially go wrong. And these are one of the major sources of these large-scale chromosomal abnormalities is the unequal crossing over. There are other sources as well, like we talked about how ionizing radiation, for example, can lead to deletions of large segments of genetic material because of double-strander breaks. But unequal crossing over is one of the major causes of variation.

in there. Now, I was explaining before, as many of you would already know, that humans have two copies of each of their chromosomes, except again for sex chromosomes in men. And I said that humans have 22 autosomes, so that non-sex chromosomes, two times 22, making 44 the whole. The number of distinct autosomes, so non-sex chromosomes, in an organism is called the monoploid number. So in humans, that's 22, right? You have 46 chromosomes in humans, two of them as X chromosomes, and then two copies each of the 22 autosomes. So the monoploid number is 22. Most animals are diploid, which means that they have two copies of each of their chromosomes. The number of chromosomes varies dramatically between different species, but most animal species have two copies. So they're called diploid. There are a few animal species, mostly insects, from what I understand, which are monoploid. So they only have one

copy of their genetic material. And usually that relates to a completely different mating cycle that humans do. Human gametes are monoploid. They only have one copy of the genetic material, but the actual organism itself is deployed. Now, I mentioned this because what's called polyploidy, which is having more than two copies of the chromosomes and more than your standard too, is quite common in many types of plants, especially flowering plants. And this is due to a combination of natural causes or selective breeding. And it's actually quite interesting because polyploidy in flowering plants has been a major source of agricultural progress for many millennia.

It's been observed that polyploidy in flowering plants often leads to an increase in the size of the actual cells in the organism, as well as the size of the fruits, and often the size of the plants as well. So everything's bigger. The cells are bigger, the plants get bigger, the fruit gets bigger. presumably this is due to an increase in the overall quantity of the expression of different proteins without changing the ratio of expression and this is important it turns out that if you change the ratio so if you add in one extra chromosome then that's deadly for pretty much any species

or at least highly detrimental likewise if you delete a whole chromosome that's usually deadly or highly detrimental and for humans it's always deadly if you delete a whole chromosome but if you add in a copy of all chromosomes, then that turned that to be much less dangerous. And the reason is because if you increase everything by 50%, then the ratios are all still the same. So you'll get much the same result. It's just, well, at least in many flaring plants, it's bigger. Everything's bigger because you have more of all the relevant proteins, right? So the important point here is that the ratio of different gene products is very important. So it's not just what information is there, it's also how much of it is there, which affects how much it's expressed relative to other things. So many flowering plants, about half of all flowering plants are polyploid. So some of them are triploid, meaning they have three sets of chromosomes, but mostly they're tetrapload, which means they have four sets of chromosomes. So this is double the amount of genetic material compared to humans. Now there's an interesting difference between triploid and tetroploid plants. If you think about this, tripleploid doesn't really make very much sense.

Now the reason for this is because think about what happens during cell division. As I mentioned, during the process of mitosis, there's first duplication of all of the genetic material. So each of the three copies of all of the chromosomes will be duplicated. But an important feature then is homologous pairing for the chromosomes. But you can't have homologous pairing if you don't have pairs. If you have sets of three, then you'll have two and one left out. Two is company three is a crowd, so to speak. And what this means is that triploid plants can be entirely healthy.

and often quite like large and vigorous relative to diploids, but they will produce sterile gametes because this homologous pairing during meiosis is not possible because you don't have pairs, right? So triploids are very useful for development of seedless varieties of fruits. So particularly a common, normal type of cavendish bananas that you buy from from a shop, they are seedless, and that's because they're triploids. So they can't conduct homologous. That's, pairing of homologous chromosomes because they have three instead of two, and therefore they're seedless and infertile. Likewise, seedless watermelons, it's the same thing, they're also triploid. So a seedless variety of a flowering plant is often because it's triploid, and that's been selectively

bred. Tentroploids, by contrast, have four copies of each chromosome, and so in this case, you can have a pairing of homologous chromosomes, where you just have two pairs, right? And so tetraploids typically are fertile. And even goes more than that. So, you can't. A hexaploid organism has six copies of each chromosome. And a good example of this is wheat. So standard wheat is hexaploid, and by analyzing its genome, scientists have been able to determine that wheat has resulted from fusion of the genomes of three distinct ancestral organisms, each of which were sort of vaguely wheat-like grasses,

but were over many thousands of years selectively bred by humans to form. larger and tastier varieties. So wheat is what's called allopolypoid, which means it is a combination of genetic material from different organisms. So it's actually three different genomes kind of in one. Obviously three closely related species, but many types of flowering plants are able to cross-pollinate with similar but different species,

and that was the case for ancestral wheat, so resulting in this sort of hexaploid combination of three different species in one. There's also what's called autoploid, which is just all the chromosomes come from the same ancestral species. So polyploidian plants is, I think, quite an interesting phenomenon. It helps to explain some of the unique properties of plants, such as seedless varieties and the effects of selective breeding on the size and robustness of the resulting plants and fruits. Now let's finish up by just talking about some of the, what happens when you have large chromosomal changes particularly in humans. So I was just talking about polyploidy, which is when you have multiple copies of the entire set of chromosomes. And as I said, that at least in plants is actually

fine because it doesn't change gene ratios. It just means you have more genate material, so you'll have more expression of everything. So polyploidy is not necessarily a problem. Polysomi, on the other hand, is when an organism has at least one more chromosome than normal. Not an copy of all chromosomes, just an extra copy of one chromosome, or maybe two chromosomes, but not all of the chromosomes. So usually polysomy results in abnormal phenotypes. And most types of polysome in humans are fatal, so results in non-viable embryos. There are only a few exceptions. So there are many different potential types of polysomy, depending on how many extra chromosomes one has. The most common trisomy is when you just have an extra copy

of a single chromosome. When this happens, as we talked about with triploity, again, that's when you have an extra copy of every chromosome, trisomy upsets the segregation of chromosomes during meiosis, and so results in infertility. The general term for any abnormal chromosome number due to fractional changes in the chromosome number, so that is either extra chromosomes or fewer chromosomes, but not extra copies of the whole. set of chromosomes, just like an individual chromosome added or missing. That's called aneuploidy. So polysomy is when you have more than you should, and then there's terms for when you have less than you should. So for example, the monosomic has one chromosome missing. So I mentioned before,

monosomics and nullosomics for humans are not viable, at least for all human autosomes. There is the exception of the sex chromosomes, which I'll come to in a moment. So the point is that in humans, aneuploity is mostly fatal. There are only a few known aneuploity conditions which are viable in humans and sort of not surprising because we kind of need all the genetic material we have, it's all important, and likewise having an extra copy of a chromosome results in ratios of gene expression that are substantially off what they should be and that also results in major problems. Remember that many genes code for proteins that are transcription factors and they essentially control how much other genes are produced.

So if you have extra transcription factors, that means you have extra a whole bunch of other genes that you now have in the wrong ratios. So you can't just throw in, it's like you're making a cake, right? You can't just throw in 50% more of arbitrary ingredients and expect the result will come out well. It's the same thing when it comes to chromosomes. You can't just arbitrarily take out one copy of a chromosome, we'll add in extra copies, or even segments of chromosomes, and expect the result will be very, will be very much. viable. Most of the time it is not. Or when it is viable, there are significant impairments. So I'll just talk briefly about a couple of conditions of human and employee, which do result in viable organisms. So Turner syndrome is probably one of the best know. So this is monosomic

condition where there is only one X chromosome. So no Y chromosome, but also no homologous X chromosome. So this is the only case of a human chromosome where you can lose one effectively. You can either the Y chromosome or one of the X chromosomes, and that's referred to as Turner Syndrome. So this results in sterile females with short stature and certain carousic features like web skin at the neck and shoulders. It's fairly rare, one in 5,000 female births. An example of a trisomic condition is Kleinferter syndrome. So this occurs when you have a male genotype of xY but also have an extra x chromosomes. So two x chromosomes plus a y chromosome.

So that's why it's trisomy because there's actually three chromosomes instead of the normal two. This results in a sort of tall, lanky, mostly phenotypically male build. and also mental retardation, and Turner syndrome and Kleinferter syndrome are both sterile, as I mentioned before. There's also a condition called double Y syndrome, where there's a single copy of the X chromosome and also two Y chromosomes. This one is actually normally fertile, not entirely sure why. I understand that the extra Y chromosome is simply not transmitted. It's sort of redundant, probably because the Y chromosome is so small. It's sort of able to just slip by, so to speak, the mayiosis process.

and fertile gametes are still produced. So males with double Y syndrome may not show any particular symptoms. And that sort of makes sense, right? Because the Y chromosome is by far the smallest chromosome. It only contains a very small number of genes, like 100 or so, all of which relate directly to male reproduction. So an extra copy of that is just not likely to have a very large effect. There was some research, there were claims,

claims back in the 70s and 80s that males with double Y syndrome had elevated levels of testosterone and as a result of that were particularly violent and aggressive and so forth. Subsequent research has demonstrated that there doesn't appear to be any evidence for that, and it was largely the result of prejudice and bias and then amplification of those initial reports. So you can look into that if you're sort of interested, but I just mentioned this in case people have heard about this because it has been, this myth has been spread in some popular media about the sort of double Y syndrome and male aggression, but there isn't really any evidence that there's higher rates of aggression or really any significant differences in phenotype between

double Y and the regular male genotype. And the final example of human aneuploidy, which I think is pretty much the only viable human trisomy, in autosomes. There may be a couple of other very rare ones, but this is the main one. Trisomy 21, so trisomy because, remember, there's three copies of the chromosome, instead of the normal two, and 21 refers to the number of the chromosomes, and it's the major cause of Down syndrome. It's caused by non-destruction of chromosome 21, so basically that means that there is an error that occurs during cell division, where the chromosome doesn't, the cysticromatis don't break apart properly.

and so you went up with two copies of the chromosome instead of just the one. And it's interesting that even just a single extra copy of one of the smallest chromosomes results in very substantial phenotypic effects. Indeed, that's probably why it's one of the very few examples of a viable human trisomy condition is precisely because it's one of the smallest chromosomes, which means that the impact in terms of skewed ratios of genetic material, it's still very significant, but it's less than any of the other. So if you have trisomy in any of the other chromosomes, it's not viable. So let's just sum up what we've talked about today. We've talked

about the, we've talked about genetic mutation and repair going through the types and causes of genetic mutations, including the causes spontaneous mutations and induced mutations, and they're sort of underlying biological mechanisms. We talked about the types of. about the effects on the DNA sequence of point mutations, silent nonsense, mis-sense, mutations and frame-shift mutations, and then we talked about the effects of mutations on phenotype. So that's the amorphic, hypermorphic gain of function and ectopic expression. I then talked about the different repair mechanisms that the cell has. Basic excision repair, DNA mismatch repair, nuclear-tight excision repair, and double-strand

break repair. The common factor there being that there are a variety of enzymes that are constantly screening the DNA, especially after DNA synthesis. to detect abnormalities in the structure and bulges and things like that. When those are detected, enzymes are recruited which remove various parts of the DNA, either single nucleotides or entire segments, and then add back in the removed nucleotides based on whichever of the strands is identified as sort of the original strand, or the one that doesn't have the damage, it's used as the template for repair of the damage strand.

That's more difficult than double strand break repair because there's a cut across both strands, and so there's two different mechanisms that we talked about. Non-Homologous end-joining, which is the simple one, you just sort of glue them back together, and homologous recombination, which brings in the buddy homologous chromosome to provide a template that actually checks that, yeah, that the two ends actually fit together in this particular way. We then talked about large-scale chromosomal changes, so including deletions, duplications, and inversions and translocations, typically resulting from unequal crossing over, and we talked about also changes in chromosome number like polyploidy in plants particularly

and then aneuploity when you have an extra copy of just one chromosome or a deficit of just a single chromosome and we talked about a few of the small number of human aneuploity conditions which aren't always fatal so tonus syndrome Kleinfordis syndrome double y syndrome and trisomy 21 the major course of down syndrome so i hope you found this episode interesting If you want to support the podcast, you can do so in a number of ways. You can leave a favorable review on the aggregator of your choice. You can become a Patreon supporter. Just Google Science of Everything podcast, Patreon. Finally, you can make a one-off donation. You can, to my PayPal, just vods12 at gmail.com. Another thing, if you're interested, you can also send me an email and

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