Copy number variation and the secret of life - with Aoife McLysaght

this evening I'm going to talk to about evolutionary genetics and give you some of my insights on evolutionary genetics but I'm going to start with a beautiful quote from a very well-known geneticist called dobzhansky and he wrote this in an essay which was in reply to some creationists who couldn't understand how evolution could possibly make sense and of course he said that nothing in biology makes sense except in the light of evolution a really beautiful phrase a really beautiful sentence and is it's extra beautiful I think because it has many many layers of meaning to us so if you think about like why do I slated islands have species of plants and flowers that exist only on those islands and nowhere else in the world this is explained by evolution and no other way why do viruses and bacteria quickly evolve become drug resistance of course it's by evolution how come if a scientist observes and agna does work in mice we learn something about humans this is only because of evolution in fact evolution is the only way this biology makes sense because without evolution there's no such thing as biology without evolution you have Micro biologists who are studying bacteria of entomologist studying in sexing of zoologist studying animals you know botanists studying plants but there's nothing to link them except evolution so there is such a thing as biology there is a field of biology and it's evolution that links them all and even further you go well how come there are so many wonderful and beautiful and weird varieties of life on this planet from the archaea bacteria that can live in the boiling water of deep-sea the thermal vents to ants that form social colonies to funguses that can infect the ants turning them into zombies that so they start acting in the fungal interest to the extraordinary stinging spiky cuddly animals that exist all over the world and of course to humans who have evolved and figured out a system for making sensible of this so the thing that links all of these of course is evolution but even deeper than that underneath are linked by genetics all forms of life have the basic fundamentals of genetics so everything has DNA with the slight exception of RNA viruses that I only mentioned for the occasional patent but so am that every living thing has DNA and that DNA is basically the same and it works in basically the same way everywhere so when I first got interested in genetics as a student part of what made me interested and really got me excited is not that it's a field of study it's an approach it's a way of looking at the world and you can look at anything in the natural world using a genetical approach and so these amazing forms of life have evolved and this has happened at the genetic level this has happened because genes evolve and genes change and so it's worthwhile briefly just saying what is gene right so and I can actually argue indefinitely with genetics colleague colleagues over what is a gene so it's not it's it's maybe it's a little trade secret that we can't fully agree and there might be different definitions for different purposes but one definition of a gene that works very well an operational definition is that a gene is a piece of DNA so it's a bit of the DNA that makes a protein so that's one way we can think of a gene and proteins are all throughout your body and so keratin is protein in your hair and your skin and your nails and there's a gene for that so there's a gene that within the four letters of the DNA has the code to make keratin so it's a piece of DNA that's dedicated to making keratin then of course there there are lots of other genes so they're in your blood you have hemoglobin which carries the oxygen in your blood that's actually there are two genes which make the different parts of the hemoglobin which combined together to carry the oxygen in your blood so these are physical structural things and also insulin so insulin is another protein which is coded for by a single gene so we have genes in our body and they typically have a job to do so we can think of them that way and we can think of a gene as a piece of DNA that makes a protein but that's a simple definition that belies a lot of complexity underneath so we're pretend for a moment that this straight line I've drawn here is a piece of DNA so we're to start thinking about what a gene would look like here so and and I'm even simplifying as I do this but let's just say these yellow bits here are the bits but have the the letters the ACTG letters correctly organized and in the pattern and in the way that will mean that they code for the particular protein of interest so that's the first thing that's the first layer of complexity is that the letters have got to be in the correct sequence that's what we talk about a DNA sequences the sequence of letters along the DNA because DNA is made up of these components that we we symbolize with letters but as you can see here I've drawn this with gaps in the middle and this is the way most of our genes look so a lot of our genes of all these interrupting bits so not only do we need to have this correct sequence so the correct bit that's going to make the right kind of protein you need I'm sorry you need a start signal which makes it start at the right place you also need to make sure it stops at the right place so we need some signals this big big big long enormous DNA molecule has to be read in the right places and then we need to cut out these bits actually so we need signals which will it tell the machinery of the cell where to cut these ads so we need other stuff here so this is already starting to look a lot more complicated and I am simplifying grossly then we have M R up beside the gene we have the signals that that when and where to turn on so when and where if you think about your body right so you in every cell of your body you have identical DNA it's the DNA that you got in that first cell of you which was the fertilized egg right so just had whoa you know you had a single copy a single cell with that DNA and every cell in your body has the same DNA yes the different cells of your body don't look the same right so you've got liver cells skin cells heart cells nerve cells brain extraordinary material these contain the same DNA but they're not doing the same things so what they're doing what's happening is different genes are being turned on and off different times and places for different times during your development different times in response to environmental signals and then different places the difference different parts of your body so even though I've grossly simplified I think I've given you a bit of a flavor of the fact that genes are complicated right they're very complicated but DNA is simple right DNA is only made of four letters that's the way we symbolize it anyway so there are four parts that get combined to make DNA it's very very long but it's simple and this is kind of where the magic happens right because the fact that it's simple it's in a sense DNA stays simple when you think about it this purely chemical level it is simple no matter what's going on at the other level doesn't matter that some of those AC T G's are a signal for when to when the gene should be turned on it doesn't matter that some of those AC T G's are a signal for cutting out the intervening interfering bits in the gene that doesn't matter at the chemical level of DNA because it's just these four letters and this makes it kind of magic because it means it's easy to copy DNA right it's easy to make more AC T G's because you just make more AC T GS and the simplicity how the simplicity of copying DNA is entirely independent of the message it contains and I think I don't know but I think this might be part of what Watson and Crick we're thinking of when they so proudly declared that they had discovered the secret of life because they had just discovered the structure of the DNA molecule right so they had figured out the double helix and if within that double helix there are pairs that go across if you imagine this as a rope ladder or something like that you got the two ropes and you got the the rungs on the ladder each rung is two letters put together of these ACTG and it's always G with C and it's always a with T so if you know there's an a here you don't even need to look it's a T over there right and they very very cheaply wrote a line in their paper when they when they publish this and they just said it has not escaped our notice that this structure implies a copying mechanism so they kind of simultaneously teased everybody that there was something more there and claimed precedence on the idea but it does imply a copying mechanism it is the correct mechanism because the DNA can pull apart got to half ladders and you get in whole new when formed on each side and so it's simple you can make more DNA very simply because all you need to know is what letter is there and you put the correct one there and it doesn't matter how complicated it is and this is a secret of life I think because it means that evolution can happen things can get complicated based on this very simple simple foundation so the thing we see copying genes duplicating genes so you can get an extra copy of a gene is easy and so if you think about this like a bit like a telegraph or something like that right so the telegraph system is very simple it doesn't matter if the message you're sending is by some milk or if the message is fermat's last theorem the synth the mechanisms of transmitting that message is simple regardless and it's the same thing with DNA so the mechanism of transmitting the message remains simple no matter how complicated the genes get so when we're thinking then about evolution and how did things get complicated how did we get all these wonderful forms of life how do we get all this diversity well it requires new genes right so we need to get different genes and new genes and genes are complicated so how do you get a new gene so where the new genes come from well they can come from other genes so the simplest way to get a new gene is to copy an old one and so the simplest way of getting all of this complexity right all of this cut here don't cut there begin there and there turn on here but not there and only then all of this complexity the simplest way to get this is to copy an existing one and to tweak it and so we see in evolution is that there's a really really powerful and important process which is evolution by gene duplication so I've made the gene even simpler here because it only looks like it's a tiny tiny bit of DNA this this blue bit here but so if you imagine you've got a gene so it's just a piece of DNA that codes for a protein and has all those other bits that need to be there that get things cut out at the right place and turned on and off at the right place and then that can get copied and immediately of course when it's copied there are two identical copies so you don't have anything new yet but what you do have is raw material so you got the raw material to start doing something really different so start making things better start making new things and start getting some more diversity and more new functions going on so this is an idea that's been around in evolution for a while actually because it was a problem units it is it is challenge to think about how do you get something so complex and it was really only when it became possible to sequence DNA and sequence whole genomes so genome is the total DNA of an organism that he could really start seeing that there was lots and lots and lots of copies of genes and it's very easy to see because as I already said we can represent genes as these letters ACTG and so that means it actually makes it really easy to to work with genetics and computers because computers are pretty good at storing text and you can compare text and so we can when we store a genome sequence a DNA sequence we always store it as this big long thing of the letter is ACTG and in fact that M page I showed you earlier which was the printout of the letters that actually is a photograph from the Wellcome Trust down the road in London where they have printed out the entire human genome as this text I think it takes something like over 200 volumes over 18 shelves or something like that and it's about six point font so it's really really long but I'm but you can do this and you can store the DNA this way and you can compare it very easily so when we look in the human genome we can look for genes that have the same you can do a pattern matching on the letters so you know you can find that they look very similar and when we do this we see there are lots and lots and lots of duplicated genes in our genome and lots of them are really quite important so if we think about some of the senses we have one a sense we have that's a really very important sense is our sense of smell and I think we're not necessarily that conscious of it we have a very sophisticated sense of smell not as sophisticated as some other mammals because we've neglected it a bit we've we're not using our sense of smell as much as we could but if you ever get a really bad cold so that your nose is really blocked up or you actually just hold your nose while you're eating you'll realise how much of what you think is taste is actually smell right so there's a lot going on there and in our genome in our DNA in the human DNA if we look at this and we look at the letters and we compare them we can find that there are over 900 olfactory receptor genes so these are all they would have started out as identical copies but through changes in the DNA small little changes they became slightly different so they're still they're still detecting odor it's still responding to odor but slightly different odors so you suddenly have a large repertoire of different odors that you can respond to so in our case we've got about 900 but I'm also saying here that many of them are now non-functional so over half of them and so this is another thing that we can see in terms of evolution another process which is can be summarized I suppose as you that or losers because and if you imagine and once people stopped using their sense of smell so once our ancestors stopped using the sense of smell there's no survival advantage for the guy who has the gene to smell that thing who never bothers and the guy who doesn't have the gene and you know there's no survival difference right so and because there's a certain and attrition I suppose you know the mutations happen and unless there's some selective advantage to for the guy who keeps the gene then that mutation where the gene has been effectively rendered non-functional will just persist and stay so this is what happened so we no longer sniff each others but when we meet and other certain other ways we don't use our sense of smell and you can see this so this is this is actually visible in our genome so even though at some point in the mammalian ancestry these genes have got duplicate and duplicated and duplicated again to make lots and lots of these genes we've lost some of them and dogs have lots dogs have lots more than us so that data you know you would not be surprised it means very clear anybody who's ever had a pet dog would know the dogs have a very very fine sense of smell so but there are other ways and there are other very nice examples of how duplicating a gene has been really really powerful in evolution so this is quite obviously a very accurate drawing of an eye I think everybody must agree and the pink bit there the back is supposed to be the retina okay and so if we look more closely at a bit of the retina there are basically four kinds of cell in the retina so one of them is roughly rod-shaped so it's called a rod cell and the others are variants of the cone right so they're cut they're conical for the cold cone cells and these are these are this the cells that respond to light in your retina right so this is of course very simplified again because there are nerves are connected to the brain and there's a whole transduction of the signal to the brain where it's interpreted but just at this very basic level there is a response to light and that's because these different cells have different light-sensitive pigments which again are coded for in genes so there are genes which code for a light-sensitive pigment so the ROG cell has an opsin so we call them these these M light-sensitive proteins are called Upson's and it's been called rhodopsin which is rod ops a nice and this is basically for black and white vision if you imagine in terms of the evolution of vision it's really really extraordinary so it has gone from basic basic simplicity of a light-sensitive patch more than likely or even if there's a or a portion of a cell even that could be light-sensitive so this basic ability to detect light to something that can tell the direction of light something to start focusing an image and then finally in our sense of our vision is quite a sharp and we can not only say things in shapes and in focus we can see colors and so the color comes from the other cells so these cone cells there are three kinds or there's defined by whether which of the genes is turned on in them so again this is another example of different genes getting turned on and off in different places right so there's the blue one so we just call it blue because it responds to short wavelength light then there's one that responds to medium wavelength life and one that responds to long wavelength light which is roughly red and so you think about the spectrum the spectrum of life so we quite arrogantly call this the visual spectrum of course it's visual to us but I'm you know insects and birds can see UV and there they actually have other options which are sensitive in the UV range but so what we see in our DNA is that so we have this rhodopsin this one gene but then we have these different color sensitive ones and they are quite clearly quite obviously when you look at the DNA they are copies of each other that have become slightly modified so you start out with basic a basic ability to detect light and then it becomes diversified so genes complex genes get copied and diversified and so what we see here is that the blue one is on what we call an autosome which is an ordinary chromosome right so where the x and the y are the special chromosomes the sex chromosomes so the blue ones they're on an autosome and they're red and the green are on the X chromosome so you probably know that colorblindness is much more common in males than in females and this is because these red and green jeans are on the X chromosome which means that males because they only have one X basically only have one shot at getting a correctly functioning copy of each of these genes whereas a female can inherit one faulty copy from one parents but get a working copy from the other parent and not be colorblind but so these are beside each other on the X chromosome and they are really very similar in terms of their DNA sequence when you look at them they're very similar and they also respond to quite similar wavelength of light is not very different in the wavelength and the blue gene is much more different it's a much older gene it's been changing for longer so it's got more changes in it and it responds to them to this quite different wavelength of light so this these red and the green are quite a recent a duplication and it's actually within the it happened within primate evolution and it happened after the New World monkeys split from the old world monkey so if you look at South American monkeys South American monkeys typically only see two colors so that's because they have only the blue and then they've got one gene on the X chromosome and so they might have one that's kind of sensitive in the green range or they might have one that's kind of sensitive in the red range and and this actually so they only have dichromatic color vision so we've got our three colors which allow us to see three colored genes which allow us to see millions of colors and these monkeys can only see thousands of colors I think but there's something special that happens there as well because in the case of their females again they've got two x chromosomes so if in a given population there are some individuals who've got what we might call a green sensitive gene and others they might have a red females have a real chance of getting one of each from either parents so in these species and in howler monkeys in South America the females are very frequently have trichromatic color vision and what we think happened in our own evolution as well that it used to be like that it used to be that there was one gene with two versions so you get either the red version or the green version so the same way that you might get you know if you think about the color or hair color or these kind of things you've got alternative versions so it used to be there was one gene with two versions and then when the copy happened when the copying happened and each one kind of got fixed and like photographic fixing I suppose in the different place so this is so we get two copies that do what they old one used to do so this is part of how we get our color vision different animals that live in different environments have different color vision genes so mammals that live in deep sea like whales have a lot more discrimination in the blue range so they've got a lot of words we have got one roughly blue or we might call the blue range these are mammals that live in deep sea have acquired new genes that have diversified and they're sensitive in the blue range so really makes sense in terms of evolution so another the last example really that I'm going to give you of duplicated genes are the globins so globins are genes that carry so that well their genes that produce proteins carry oxygen and so we've got two major classes of globins so one is myoglobin which carries oxygen in your muscles and the other is hemoglobin which carries oxygen in your blood so these are again so there's an original gene which is coding for protein that can carry oxygen and a duplication occurred which meant that they could specialize in two different areas and in fact a hemoglobin is actually so the protein is made from two different genes because there's an alpha and there's a beta which come together alpha B globin B 2 globin come together and make the hemoglobin so again this is another example where we have this duplication creating this raw material to get new diversity so we can see this really finally at the gene level and with the hemoglobins something else that really special that happens so nobody can remember it but we all started out in our mother's womb and at that point we were complete we dependent on our mother for everything right so for all nutrition and for oxygen and the it the placenta is a marvelous tissue and a lot goes on in the percenter but the blood doesn't mix right the blood gets very close there are very very fine membranes in the placenta that means the blood can get very close but it never mixes so you know you're not necessarily the same blood group as your mother and you that's that's okay because the blood doesn't mix them therefore there's no clotting problem but the oxygen needs to be transported across this percenter and there are no policemen there telling it to go across it has to happen chemically it has to happen naturally so there are other globins that have been created again by duplications and these ones are specialized not to a place but to time right so the time along the bottom here the first part of it is the age of a fetus after PO after conception and after birth we start counting weeks old okay and so what you see in this graph here is you see there are different kinds of globin so the alpha globin this big one is it stays more or less constant but the beta globin that we all have as adults is basically absent we're close to absent in the embryo instead there is a different kind there there's a lambda right so they're just arbitrary names but this is a different globin again created by a gene duplication but that has specialized to the fatal stage and what's special about this is that it's got a higher affinity for oxygen than the adult form so if you just imagine the blood is coming into close proximity there's a tiny membrane in between them there's part of the placenta and just by pure chemistry like a stronger magnet the oxygen gets drawn over into the baby's blood just by the fact that this fetal hemoglobin has a higher affinity for oxygen is like magic it's wonderful and so the and this all has to happen recently of course because mammals are kind of a recent evolutionary invention other animals don't do something so peculiar they lay eggs and that it go down with its own business so what we see then so what we can say so far is that gene duplication really happens a lot it's happening all the time in terms of evolution so the recent ones are really really starkly clear because when we look at them we can see the DNA is almost identical and but then it's been happening for much much much longer it's been happening all throughout evolution so we can see that this really really important happens a lot and has contributed many genes to our genome but there's another way we can think about evolution as well and it's a way of interpreting the patterns of evolution and there's a nice little story that helps explain this philosophy so em in terms of how can we look at the patterns of evolution and understand something about the genes how can we understand something about the genes so yes this is supposed to be a drawing of a plane I drew it freehand congratulations me and that new thank you and that is a photograph of man called Abraham World during World War I remember was a statistician and and during World War two he was called in by the Air Force to help them because they wanted to reinforce their planes but you don't just slap a hole out of extra metal all over your plane it's first of all it's going to make the plane harder to fly it's going to become too heavy and it's the war you know everything's in short supply and so the story goes that Wald was given the job to examine the distribution of bullet holes on the planes returning from battles so these records but red dots are supposed to be bullet holes and the story goes they said to him you with your statistics you examine the distribution of bullet holes look at all the different planes find those parts of the planes with lots of bullet holes and that's where we're going to put the extra metal because you know we got to use it wisely and so apparently what happened is that Abraham Wald said well I'll take the job but you got your logic completely backwards so if we imagine a scenario right so these are our planes that are flying and there are bullets coming up hitting them the bullets in there shooting up in the sky but they're not able to target one part of the plane or another right they're happy if they hit so the bullets are going up relatively randomly and where they hit the play is relatively uniform but some of the planes get shot down right so some of the bullets are going up randomly hitting relatively uniformly but some of the planes can't fly anymore with that bullet hole so what Abraham Wald said was said okay well then if we look at this distribution of bullet holes we say instead what I'm really interested in is in those planes returning from battle where do we never see a bullet hole or where do we hardly ever see a little hole because they are the ones that have been hit and haven't returned right so by looking at where you basically see nothing you actually can make a very significant observation so you think there's nothing happening but that's actually because the change the did occur there the bullet hole I made the plane not fly and the exact same logic applies to jeans so we can look at a Jean so we can look at say alpha globin and we can look at alpha globin in human and a mouse and we can look at alpha globin in chicken and we can look everywhere and we can look at where has this gene changed so we can line up can print out the eight letters the ACTG and we see that some of them are completely the same and some of them have changed and we use this logic I say okay if it hasn't changed and if it hasn't changed since chicken that's been quite a lot of time and if there's winds region then there's been you know half a billion years or so of evolution and there's been no change it's not because the bullet never hit is because the plane couldn't fly right because the gene can't work with that change and so when we look at something like hemoglobin then so this is the way we draw proteins through these beautiful ribbons and and the different colors are the Alpha and Beta parts when we look at this and we look at the pattern of evolution over a huge number of animals which it represents a huge amount of time we do see lots of changes in the genes but in this center part we see hardly any and so this means that we have with this evolutionary logic we can say this looks like it's an important part of the gene and when you add in the knowledge of biochemistry to this actually this is the part of the gene that carries the oxygen so the rest of the gene just the rest of the protein just need to be roughly the right shape it needs to be soluble in water so that it can stay inside the cell but apart from that it doesn't really matter but this part this is the business end so we can see we can use evolutionary patterns we can look at the way genes evolve and without having to do another experiment we can understand something about the gene we can understand something very important is going on alright so this is a really really powerful thing in evolution to really really and it's a really really useful philosophy and I'm going to come back to that later but before I do that and there's another thing that I'd like to tell you about vertebrates us and so the animals that include fish and birds and then you know lizards and tortoises and they you know mammals which includes rhinoceroses and mice and human beings it's an extraordinarily diverse group of animals so our history is only about 500 million years which sounds long if you're a politician sense or even if you're a historian but in terms of evolution it's not a very long time and other similarly old groups of species don't have anything like this diversity so it's really really special and and so there'd been debate actually for a while about what could be the origin of this huge diversity what would give enough raw material to start out to evolution happen in so many different ways and in so many different places and so and the idea that came along which was first just a theory and was later proven by the data is that instead of it being gene by gene duplication so duplicated gene that something happens you beget another gene that something happened there was a total duplication of everything so we call this size I think I said already this word for your total DNA is a genome so it is possible to duplicate the entire thing all in one go it's actually very easy to happen because you imagine and at the for the formation of the egg and the sperm what happens every individual has two copies of all their chromosomes one from mom and one from dad but the egg and the sperm have one copy that's the one you're going to pass on so it's very easy mistake to happen in terms of the cell that that has two copies instead of one so you got so you get that you get a double there for a moment you can get a double from dad and all of a sudden you've got extra copies of everything so this provides new raw material and it's better or it's more powerful than just the gene by gene duplication because you pick eight whole sets so things that work together so just getting one on its own is not really very useful right now you've got that whole set of genes that work together in a pathway like a pathway that can do something like produce vitamin C which we used to be able to do and so you know you can get this whole set of proteins that work together and you get the entire set and now instead of having a gene to work with you're a whole entire set of connected parts to work with and so this is a se ona and this is what our ancestors looked like impressive right and and so this so what we now know is this duplication happened and it happened again so you know one became two became four so this times four equals us and I have chosen a human being not at random here and because this is Sumer owner and he is responsible for a lot of these ideas a Japanese man who wrote this book in 1970 but evolution by gene duplication and I think he's possibly not well known outside my field but he's an extraordinarily influential person in my field and really had kind of it's not really fair he had all the good ideas I think for them so he was he was were the first ones who talked about this and when the human genome sequence finally became available in 2001 this was the first chance we had to test this and it's kind of funny because then you know normally in biology we learn about humans by studying mice or by studying some more other organism but in the case of genomes the human genome was the first one of the first complete genome of all the vertebrates so actually by studying humans human genome we learned about all the other animals but this is actually something that I was in I'll do it in my PhD we looked at the human genome sequence when it came out and we looked for evidence of this and it turns out that Ono was right so in early early early on in the vertebrate lineage around about 450 or 500 million years ago our genome doubled and doubled again giving a vast amount of raw material for evolution to work upon so had all the complexity all the right bits in all the right places just waiting to be changed to do something new but that's all kind of historical isn't it that's all ancient evolution but what about now what about the diversity in this room and so none of us and I don't think they don't see any identical twins but let's say none of us are completely identical genetically even identical twins will acquire some changes over the years so you know what does human genetic diversity look like now so if we think about two people there are two main kinds of difference we can talk about so one would be a difference in the letters of the sequence so you know where I have here I've got the highlighted in orange a little difference in the letters of the DNA sequence and these are common and but even more common is a difference in the number of copies of some bits of sequence so it turns out this is just a really really easy mistake to happen when DNA is being copied when it's being copied to be passed on to the next generation or even when it's being copied as your body grows it happens really really often that we get different numbers of copies of the DNA so this really easy mistake to happen is the most common kind of genetic diversity so within this room I don't even know what the numbers would be there's going to be lots and lots of people who are going to have three copies of one gene and somebody else only has one some people have two copies somebody else will have none right oh this is going to be this is a really really common kind of diversity so every healthy person carries lots of genetic variations so if you want to think about it that way we're all mutants we're all some kind of mutant at least at some of our genes and most of the time that doesn't matter right so this is there's a lot of Tolerance in this I suppose you know you can say that we all can carry lots of genetic diversity and most of the time there's no consequences when you look in healthy people there are lots and lots of genetic variations and the plane is still flying right so this doesn't matter but sometimes the plane gets knocked down it's shot down so there are some cases for having more of a gene so too much of a good thing and causes something to happen so a very famous example I think a well-known example is trisomy 21 which is an extra copy of chromosome 21 and this leads to Down syndrome so this is an extra copy of a perfectly good chromosome so it's a perfectly good a perfectly normal chromosome but too much of it causes a disruption so it's an imbalance in the cell so some genes are just sensitive to the relative quantities right so they got to have things in the right amount not only and there has to be not just the right place with the right relative amount in the cell so Parkinson's disease and there's more than one way more than one add genetic insult that can cause Parkinson's but one of them is having an extra copy of a particular gene so you normally have to one from each parent if if an individual has three copies of this gene then they are much more likely to get Parkinson's and they might get us in their 50s if somebody has four copies of the gene instead of two they're likely to get Parkinson's in their thirties and so this is very sensitive Alzheimer's as well is cool it can be caused by extra copies of a particular gene there are also certain genes that when they are present in a good gene but in the wrong amount can cause developmental delay a lot of neuropsychiatric conditions are also recognized to be caused by the wrong amount have a perfectly good gene so schizophrenia and autism but also certain forms of heart disease many different kinds of cancer also are linked to this so this is a really common kind of variation most of the time it's just fine but some of the time it's causing a problem so if we think about what might be happening when we have too much of a good thing we can think about the normal and the too much scenario so first cases let's just say the normal amount this is a scale drawing of a protein and three proteins and so let's say this is the normal scenario we've got a certain concentration of this protein in the cell but when you get an extra copy of the gene you've got a higher concentration just of this genes and this is the only thing that is increased in isolation if you just get a duplication here and that can lead to this clumping up through an aggregation and this is what's happening in things like Alzheimer's and Parkinson's so these are characterized by plaques which are clumping up aggregates of proteins so this seems to be down to a high concentration of the protein which means these proteins that normally would manage to kind of drift away from each other or if they did occasionally meet and stick together in something the cell could process and deal with you get a high concentration it's happening a lot it's happening too much and the cell can't cope anymore so that's one way that the the wrong amount can have an effect on the way a protein works and there's another way and that is because that is to do with proteins that work together so I already gave the example of hemoglobin where there actually it's not just one protein it's the Alpha and the beta that come together and that's called a protein complex it's when proteins join together to do something so in this case I've got a red yellow and blue protein which are separate and in order to do their job whatever that job is they need to come together and form this complex together so the thing that does the work is the joined up bit right that's the active thing that's what you need so let's imagine a scenario where one of those duplications happens and it copies the red okay so now what's happened is we've got one extra copy of red and when this protein starts assembling a bit of yellow binds to red a bit of blue blue binds were red and now we're stuck right so all the red is used up but we don't have any of our final active complex so in these cases well these genes that work together they need to be they need to stay balanced right so we've got a balanced scenario and a gene duplication makes it unbalanced and when we look at these cases of disease and these different one of the things you see is it's not so simple as just one gene being copied actually because when you think about the DNA it's a big long string and there are lots of genes all in a row so you get a big chunk can get duplicated and the problem then the question the challenge is to say well which one of these is the problem because if you're trying to do anything if you're trying to understand a condition of trying to understand a disease you first of all need to know what it is that you're dealing with you need to know what is it what is this that I need to reduce in order to regain a normal scenario so lots and lots of genes are duplicated and we don't know which one so we think well maybe we can take an evolutionary approach to this so we come back to our idea of the planes and the planes that get shut down and the planes that manage to fly anyway and we can think about evolution and this gene duplication process is happening not just today in all of us but it has been happening all throughout evolution so we can think back on evolution we can look back over it and we can think about well what are the patterns we see not just of letters changing within a gene but of whole extra genes being copied and retained or whole extra genes being copied and we never see it because the plane doesn't fly right so we can think about then what do we expect to see what are we looking for then so if we're thinking about these balanced ones for a moment what we're saying is one thing is that this one by one duplication is just a no-go because the one by one duplication upsets the balance within this system and that disrupts us that it doesn't work anymore but if you could possibly achieve it simultaneous duplication of red yellow and blue would be okay right but yellow and blue might be completely different in completely different places in the genome so achieving that simultaneous duplication would be kind of complicated right but if it was to happen it would work because even though the amount has increased the relative amount hasn't they're still balanced and then we remember that actually there is a kind of special balanced duplication that did happen in our history we had this back 450 500 million years ago where everything got to placated which is guaranteed to be balanced right so got if you duplicate everything you duplicate all the components it's guaranteed to be balanced so we get duplicated and everything duplicated again so for these dosage sensitive genes these ones that need to stay balanced this is okay so this special kind of duplication is okay this everything at once but the other thing that we see and in our genomes today is that a lot of those genes that were once upon the time duplicator got lost again same way that we've lost our factory receptor genes same way we've lost other things like vitamin C biosynthesis genes if you're not using them we lose them so a lot of these genes that were duplicated way back then have been lost again so there's actually only a small fraction of our genes that are still in this situation this balance thing so means it's actually a smaller search space for these interesting genes so this ends up being useful for us so then if we think about that what are we looking for what's our pattern what's our special thing that we want to find on the plane well then for these doses sense of genes we say okay this special balance duplication which is the whole genome duplication is a special unique opportunity to duplicate those so not only will they be that's okay they'll also tend to be retained after that because you can't lose them again because we've used them again now you're unbalanced but ordinary genes that aren't sensitive to the amount that will they'll be gained and lost doesn't matter they're going up and down all the time so that's so that's loads of bullet holes but our dosage sensitive genes will happy retained after this special big duplication and they won't have any other kind of one-by-one duplication so there won't be any bullet holes so when we look at the genome of humans and mice and rats and dogs and horses and cows and we can compare chickens and fish in all of these all these are available we can look and we can say which genes have stayed steady over this whole thing where there's just one copy all the way in all of this vertebrate history and which other ones are going up and down so we're looking for these tell-tale patches in the genome where there are no bullet holes and when we do this we find that it really does work very well so and this is showing you a chromosome 21 and I'm going to explain this in more detail but and so if we think again about trisomy 21 so this is an extra copy of chromosome 21 so this is a particular particular mistake that can occur in the copying of DNA having an extra copy of this chromosome this can happen for the other chromosomes as well it can happen for chromosome 1 2 3 4 but we don't tend to see it so trisomy 21 Down syndrome is the most common human trisomy it's about one in 500 1 in 800 live births and this is not because it happens more than the other trisomies it's actually because it flies better than the other trisomies right the other ones occur but we never see them because they don't survive so actually if you're going to have an extra copy of a chromosome 21 is the one to do so it because it has the least severe consequences and when we look at the human genome and we ask we look at this pattern and we say so where are the bullet holes and where are these genes with no bullet holes no duplications over all of the break history what we find we get a list of these genes and the chromosome that has the smallest number of these is chromosome 21 so this is completely consistent with also having the smallest effect of having an extra copy of the chromosome right so the most tolerable one is chromosome 21 and so in this picture here what I'm roughly showing is so the line at the top is the whole chromosome and I've just labeled some of the genes on it and those ones they're labeled in black are the ones that our evolutionary analysis said are the ones that look like they are dosage sensitive there they have to be balanced right so when we look without we don't think about any kind of a disease or any other kind of information brought into it always say is what is the pattern of evolution no other information then we find that these 40 genes on chromosome 21 and the ones are the little green dots beside them which you can just about see are the ones that people who study dance syndrome think are linked to dance syndrome and Down syndrome is complicated it's a syndrome it's got a lot of different things going on and it's got different severity from person to person and so there are more than one gene there's many genes in fact involved in this and these are the these are the first ones that have been identified and proposed to be at genes involved in Down syndrome but it's also at the same time clear that they're not the only genes so what we said was in this analysis we said that actually we propose that these other genes we identify purely in terms of evolution purely by the absence of bullet holes we say that these are also good candidates and part of the reason we're confident is because we found again without deliberately searching for them we found again all the ones that were almost all the ones they were found by other people doing all the painstaking work with patients and looking through and looking at how the genes operate in the cell so this works so this evolutionary analysis works and not not only that we also look to the same thing in terms of these duplications involved in schizophrenia and autism as well and when we look in with an evolutionary analysis we can find that there is a relationship between the way genes evolve in terms of the duplication and whether a new duplication in human beings is linked to some of these conditions and so and this is we think a really really powerful approach to understanding the way these genes work which ones are important where are those weak points so in terms of the weak points in the plane where are the weak points in our genome and so if we think about then what we have seen so what we can say is well and these duplications are really really common so when something is really really common not seeing it means something right so when something's happening really really often this most common kind of variation in human populations so the failure to see it means something it's not just that it's not there and so that this is really really common in terms of evolution and really really common in human populations actually creates a really powerful setup for understanding this better and then so we also see then that some of these genes are really finely dosage sensitive that if you change the amount even by a small amount it seems which does seem like a small amount to have normally two copies of a gene and then having a third copy will upset things then they this disrupts the finely balanced processes in the cell so there is so much to such a thing as too much of a good thing and and so and then the I suppose the insight and then the hope comes from the fact that fact that these genes are dosage sensitive influences the way they evolve and it influences the way they evolve in characteristic and predictable ways so we can start we can get genome sequences and there are loads and loads of genome sequences now right so it's no longer a problem to sequence a genome they're been sequenced for lots and lots of different organisms and this is all informations is all input that can help us understand what are the constraints what are the weak points in the genome and so then if we think back then to this quote data I started with nothing in biology makes sense except in the light of evolution well then we see many many more ways in which this is true we can also say actually evolution can help us make sense of biology so by thinking about evolution by thinking about the way genes evolved we can understand what are the parts of the gene that are doing the work what are the parts of the genome that are really important and are frail to the perturbations so I hope I've given you a bit of a sense of what it means to study evolution and some of the power that there is in an evolutionary analysis thank you you you

Channel: The Royal Institution

Views: 159,699

Rating: 4.7977014 out of 5

Keywords: Science, Ri, Royal Institution, Science Communication, Education, Genes, Genetics, DNA, Copy number variation, Cancer, schizophrenia, Duplication, Disease, Inheritance, Autism, Variation, Mitochondrial Disease (Disease Or Medical Condition)

Id: BJm5jHhJNBI

Length: 53min 34sec (3214 seconds)

Published: Tue May 27 2014