Genetics of Complex Disease - Lawrence Brody - Buy Bentyl

Genetics of Complex Disease - Lawrence Brody

Genetics of Complex Disease – Lawrence Brody

By Bryan Wright 1 Comment May 11, 2019



so I name's Larry Brody i'ma wear a couple of hats in the genome Institute one thing I do is I do human genetics research mostly looking into birth defects and cancer susceptibility and metabolites so that's my research hat I also run what's known as the division of genomics in society which is an extramural program that is the one that houses the Elsi program has everyone heard of the Elsi program some so that is and I'm gonna cheat a little bit from the time on genetics and just tell you about it because it's pretty cool that's the program that is money set aside from our budget to look at the ethical legal and social implications that's what the ELS is of genetics and genomics and it's been in our budget for 20 years part of it was a response to when the genome project was just getting started someone said wow you're gonna do this genomics and genetic stuff it's pretty scary aren't you worried about the ethical legal and social implications and in fact Jim Watson who was heading the program at the time said we were concerned about this in fact we're gonna fund research into this into the area of these implications of the genome project and have been doing so for the last 20 years so some of them has been bioethics some of them been legal work is anyone not heard of Gina the genetic non-discrimination Act so that's the act that says you can't be discriminated based on your genetics alone that part came out of this this program as well helping to do to set up the legal framework for it so that's what I do with the other hat today what we're gonna do though is just talk about genetics and general genetics I am going to focus this lecture and this is a lecture that I also give to a summer Institute for not sure what the formal title is but the nursing Institute has a Summer Institute on genetics and I've been lecturing in that course for the last decade or so and the students in that course tend to be more interested in complex disease the Mendelian disease but we'll cover both but most of the lecture will be on complex disease because I'm gonna guess that most of you are more interested in complex disease than strongly inherited type issues and I warned you it was interactive meaning there'll be questions and answers this is an informal small room there's not that many of you so you can feel free to ask questions there will be some quizzes during the top so how many points a lot of points so be prepared no good you have to keep taking it again till you get it right this is an education not not so let's just talk a little bit about complex disease I think that in I will preface this by this is not a lecture about stuff that you don't know in fact this is a lecture about things that you will find you know at all really and I'm not making this up you know it all in the lecture is just to kind of put it in buckets and bins so that you can figure out the relationship between things all the concepts that we're going to talk about in fact most of the details we're going to talk about all of you already know and but you may not have thought them about them in context so that's what I'm really here to bring that's why the quizzes should be pretty easy because you already know it and there's not there's no detail minor details of this thing that you have to take home it's just the relationship between the different genetic concepts is really the take-home message for the next hour in matters of scale and that kind of thing right so I think everyone knows what a complex disease is it's a little bit of genetics it's a little bit of environment and the to work together in some way we don't totally understand and the patient gets sick or the patient gets tall as we'll talk about where the patient is short right not that short as a disease from my perspective anyway and so we used to have to say our genes involved in this condition and anyone who is gonna look into the genetics of a specific condition used to have to bend over backwards to show that genes were involved I think the field has gone so far to the other extreme is that you can look into the genetics of almost anything and everyone will believe you that there's a genetic basis probably because there is and what really we want to figure out from today is how to decide whether there's a big genetic component or a small genetic component okay so we don't have to sell genetics anymore when I first started this it was crazy to look into the genetics of breast cancer literally I mean marry cracking one of the pioneers in the field told she was crazy to look into the genetics of breast cancer and ever think everyone knows how that story turned out there are genes involved in breast cancer right so that was a success the other thing that we used to do a lot more was try to find genes now we don't define the genes anymore because somewhere in this course we're probably going to talk about the the genome being sequenced and the way to look at them information so we never have to find genes anymore we just to figure out which ones are important so we'll talk a little bit about trying to figure out which ones are important a little bit about how you do this and I don't know whether this group is going to go back and wants to write grants or wants to do investigations or just wants to be more informed about your patients so we'll talk a little bit about how you do it that's because the how you do it tends to change really really fast and I said I'm not going to load the talk up with with technical details as opposed to conceptual things okay and then the why should we care we'll get into a little bit but I think the fact that you're here and have decided to come to a place that is normally much more uncomfortable in the summer than it is today says you probably care because you're you think genetics is important I hope by the end of the lecture if you think maybe they right now think they're important by the end the lecture help you thank you they will be right so complex disease how many of people do some super highly specialized clinical or have done I don't know exactly where you guys are but in your locations or careers or but how many people do really highly specialized that only takes care of pay patients that have strongly inherited disease anyone do medical genetics no so that means that you're gonna be looking at the at complex at traits or diseases that are complex right it also means that in some cases the risk allele so the risk allele is just the flavor of the different genes that are out there so every gene comes in multiple flavors there is no breast cancer gene there just gene involved in breast cancer that comes in a one flavor that gives you a lot of risk in another flavor that gives you not so much risk it probably will true be true that a lot of these risk alleles are probably common in the population for common disease and I'll show you and this is one of the examples we're gonna tie scale and I'll show you in a few minutes how that works this is just a list of some of the diseases that essentially would be considered complex I didn't put the few things that we say don't have a genetic component because he always things like trauma and car accidents you say well that doesn't have a genetic component it probably obviously does if it's related to alcohol intoxication which is a metabolic process that probably has a genetic component it's related to risk and thrill-seeking that has a genetic component so really you could say that the genetic component is present and everything again we want to figure out which ones have a lot which ones have a little bit okay and so what we're really looking at is genetic variation right and so we're not look what we're not talking about today are changes in your genome that make you have a tumor right sorry make changes in your genome that lead to it becoming a tumor cell those are somatic changes we're going to talk about is inherited variation so we're talking about the Constitution of the genetics that you and hurted from your mom and your dad and I just used this slide to illustrate variety in part because it was in a magazine called variety and if you look at these two guys in these two ladies there's a lot of variety there right so you've got ethnic variety you've got the environmental side of things right so that and that's the other theme is measuring the environment and the genetics the fact that these guys have short hair is environmental right the fact that these two ladies have blonde hair maybe but environmental but no one's saying but we can clearly change a lot of things based in the environment right and for those who can't see I I always forget that's maybe saying that Sharon Stone and Goldie Hawn and that's the Dalai Lama who was actually gave a talk in this building last year and I don't know who the other guy is the part of genetics that you probably are most familiar with or pops into mind is this right everyone thinks that's genetics so Who am I who my channelling here Mendel right and if it's not that so here's Mendel here's this piece and this is part why I got into genetics because as a biologist we have very few rules and we have very few times when we can really predict the future Mendel could predict the future he could cross a plant and he could say half of these peas are gonna be yellow on half of these they're gonna be green and he'd be right almost all the time and some many of you know that the people who work in scarred and kind of thought they knew what he wanted so they started cheating a little bit because when you go back and reanalyze his data it's too good but we'll just say that Mendel was not involved in being that good and so Mendel's laws tell us that we can predict what the outcome of a cross is going to be in human genetics there are some Mendelian traits but most of them are disease traits so for example and this is the first quiz you ready that's it sit up straight how many Mendelian traits can you name that are not diseases in human beings yeah I color is actually a complex trait because it's the browner or bluish kind of are the closed system in doing so you can either be in some huge spectrum of brown or use spectrum of Bluegreen so that's that one I'll give you I'll show you it's slightly height isn't definitely not Mendelian and I'll talk about height in a few minutes so what was it telling you I never get a straight answer when I try to figure this out in that some people contend that you can learn how to do it my kids can do it I cannot and I can teach myself maybe I'll have enough patience so tongue rolling the jury's out on anything else hair color is complex trait we now actually just relatively recently know that there's some genes that are responsible for blonde hair in europeans and some other genes that are responsible for blonde hair and Polynesians it's not the same gene but children skin color definitely not right skin color is is a gradient so when and we'll get to this in a second so the quiz the answer to the quiz is we've got 22,000 genes most of them don't behave like the piece and that's your first kind of take-home point to really think about the genetics that we've been talking about in the past and we even maybe get most the public thinks with these peas is the really highly predictive genetics and that's not the case for almost all human traits there are thousands of human diseases I don't remember the total number but it's up to like three or four or five thousand that are in the catalog the Mendelian inheritance and man catalog that are mostly Mendelian but those are specific diseases most of them rare what type is a good one if you do a B oh yeah and obviously they're minor antigens as well so but that's not a trait you can see so I'll give it to you there's a point but it's if you think about what you can see because men look at see the piece right and the other one that people talk about is the free versus that detached earlobes ten probably is one there's some dimpling things and a few others that are mendelian but by far most of what you see around you in variation in skin color and height and hair color and even eye color is not Mendelian so when you're thinking genetics I think what kind of genetics this is the other thing that you think of when you think genetics right this is the fruit fly experiments and these got these became a great tool to do genetics in part because peas you can only do once if you're in Austria probably wants a season fruit flies you can do every couple weeks and they really were the workhorse at the turn of the century and started because there were flies with different color eyes that actually the offspring could produce white fly eyed flies and red eyed flies very much like the piece and so that gave the first organism most human traits yeah are not right and Mendelian for those in I'm going to stay way mostly from jargon but Mendelian in this case means the mode of inheritance is pretty clear its dominant its recessive or excellent and you'll hear more about those in other parts of it but most traits don't look like that this is the other things that we also know right so we have I'm just telling you genetics is maybe not as powerful as we think in a lot of cases but this is a pretty powerful example of genetics isn't it right these two girls are identical twins we've not we Diane Arbus dress them or they dressed as identical and you know that identical twins share all of their DNA the same I mean you know there's profuse differences but not many and they are remarkable concordance in their phenotypes is anyone known identical twins are you you're an identical twin no nope you are were you so identical that people couldn't tell you apart when you're younger and then how about later in life why is that because your genome didn't change but environment yeah I don't need to get personal about what but right so even identical twins you can start to see this diverges I know this Ken Kenworth yeah yeah yeah there's actually study of twins as a whole field of study there's there's a journal on twin research there's a group and it's based in Australia that coordinates the entire world's twin research okay what about these guys right not twins right I'm gonna guess that about half of you or more know who these guys are right right I can tell you that when I show it to college students so these guys clearly show you the other range of variation right so there are phenotypes their traits are very very different and yet you know that if we were to cross these guys like Mendel's peas so just to forget the biology and just for a second we would not get offspring that were tall short tall short tall short right or black white black white black white right suit this is what I mean you know this stuff already you know that those things the skin color and the height that we're talking about is a complex trait because it does not segregate in a nice easy fashion we also know that environment has some influence but not over everything I mean Wilt Chamberlain went to high school with my dad so they had the same environment do you think my dad was this tall he played baseball actually look not not to this extreme and you don't think so because you're looking at me and you're saying yeah not at all guy student younger students don't know they're if we finish early I'm gonna do that too so here's height right so here's how you think about complex traits and everyone knows what this distribution is right looks like a normal distribution a bell curve height is mostly genetic and so height is your height is determined mostly by your genes yet in the population we don't see short tall short tall we don't see we don't even see middle short and tall right we see a nice smooth distribution this is only a I don't know how many kids are on here but these were military academy students looks like about 50 or 60 of them there may be more than that maybe 100 some how many genes do you think control height in humans hundred probably a hundred strong ones hundreds a hundred strongest let's say not a hundred strong ones because we don't and we didn't know that until recently until we started genome-wide Association studies if I take the strongest one and I say I could magically switch say I have the weakest of the of this the ones that have the influence and I take the one has the strongest influence on height and I have the weak one now and I gave myself two copies of the strong one how much do you think I would shoot up Oh No millimeter yeah I mean if I was born with it yeah millimeter so kid did I am i moving a millimeter I can't quite tell if a movie little tiny effect right from all these years but together they all determined because everyone has their own Constitution determines their right the other again I'm gonna hit these themes again and again look at the average here it's about five six five seven and these are all guys right I'm five six I'm not average anymore I'm short now right in my cohort I'm short and in the next cohort I'll maybe still insurance and so why is it shifted to the right now right environmental influence interest see I don't need to be here because you guys do know this right so environment has shifted the entire curve to the right so when you're thinking diseases you want to think especially if you're thinking from the patrons center point of view you want to be thinking what is it about the genetics and what about us in the environment and it pushed this patient into this state that we see them at today this is the eye color just to show you that there are a lot there are multiple genes and maybe their genes that determine whether you're Brown and the brown because flavor or the non brown flavor but they're multiple genes and we we know most of them now this is not realized this is taken from a company that will let you design a doll that looks like you which which I find a little creepy I don't know if it's a know maybe it's American Girl cookie yeah I think it may have been that one I just I look for I color in the web at something and so that and you I mean I don't know about in this room because it's dark but we probably have almost this whole range even just in this small sample within this room okay so we talked about what that sorry I should have made this not step through this just encapsulate s– what we're talking about in that you end up with the disease you have a germline predisposition you have environmental influence there are times especially in cancer and you're probably gonna hear more about it where somatic changes changes in the cells that make up the diseased tissue are quite important and I always underline this because we do a miserable job at accounting for and doing research on behavior which is if you think of the top five causes of death there are a lot of them are driven by behavior things we talked a little bit about this already non-mendelian can be modified by environment height is an example of things where you get effects it's not totally a truly epistasis and I won't don't worry about that term if you haven't if you don't have it already but height is where there's combinations of genes and sometimes you need to have a gene over here and a gene over here in order to get the trait if you want a good take-home project or do most some of you teach it sounds like though some of your teacher ready look up Labrador Retrievers if you want to use an example for epistasis it's a great example for students to work through because you know they come in three flavors one of which is really a flavor and the genetics of them are the genetics of those three flavors is actually more complicated because there's something called epistasis going on it's a great teaching module so instead of genotype equalling phenotype we already talked about genotype approximates phenotype to a certain extent the equation is actually more complex the phenotype is the genes plus the environment it's actually more complex than that and again and so all these can they all the slides are going to be left here and you can have them all I did pull a bunch of images off the web that are used with fair use but not for reproduction you can use them I've but don't tell them you got them from me so really the phenotype is the genes plus your environment but genes can interact with genes all right so that's the gene gene interaction and then the genes can enact with environment in a multiplicative way and so if we were really good and we wanted to be as good as Mendel predicting peas for any phenotype let's say height we would know all of these things and know how to put them in and then we would make be able to make reasonably good predictions we are nowhere close to doing that for most complex disease in part because one of the things if I if I look at my DNA now and say what's the chance I'm going to get type 2 diabetes I I would know some of these things but I wouldn't know the ones in the future right and by the time I had my blood sugar being through the roof then you'd probably be pretty good at predicting it but you wouldn't have needed the rest of the stuff anyway so we're not there yet and that's a pretty important take-home message that we're just not able to make super strong predictions about complex disease can we use them can we use genetics and complex disease here's a trait think of it as let's see let's make the right to be bad so let's think about blood pressure we now know a lot of the genes that contribute to blood pressure has a strong environmental component has a stress component but it's distributed like this in the population what the geneticist learned told us at the turn of the century was a little bit later in the turret century is that a distribution that looks like this really could be made up of something that looks like this and if you were to sum those three distributions they would add up to that one distribution right so this was the the work of a geneticist called Pearson ever heard of him Pearson correlation coefficient that's the Pearson he was a geneticist and he was using he invented the Pearson correlation coefficient to help describe his quantitative genetic studies so now let's imagine and I'm oversimplifying it because I can't draw it if it's that complex let's imagine this is one genotype this is one genotype and this is another genotype seems to make logic a little sense that you'd have people who have a genotype that pulled the trait in one direction you have people who have have a certain flavor that pull the trait in the other direction and yet there's lots of overlap in between the two so the genetics itself doesn't project if it was a Mendelian trait we'd have three Peaks separated by nothing right again so can we use genetics take a look at pretend this is where a disease level is so whatever the trait is you get up here you have disease now look at the proportion of the different genotypes in the disease pot right so that whatever this and I guess it is two colors didn't seem to bleed through the right way but this distribution of this genotype there's more people in there with the disease than the other genotypes so if you were designing a public health intervention that could be benefit by stratification by something other than age which is how we do most of our public health interventions you might say well the people who have the yellow genotype maybe they don't have to scream let's say it's screening for something screening as often or start as early whereas the people in the green genotype or whatever this is maybe they should start a little bit early or do it more often that's the hope that we can have enough prediction not to tell an individual what's going to happen to them but that we could shift the populations and shift practice a little bit and this is could be the power of complex genetics because we can now add up all of those things and I didn't bring this slide but we're getting close to having enough data to start modeling this for breast cancer for those of you that know mammography is very controversial because of whether or not it has political components and there's people say it doesn't really save any lives there there is undoubtedly and we know in the population breast cancer risk is got some different distributions the question is are they separated enough like this to actually revamp screen no they do that they do that for the entire population they don't think about yeah right and this is where epidemiology for some of you that study of it and genetics is going to merge in a good way so the epidemiologist has to believe that everyone in the population is the same the geneticist believes that everyone's different and the environment doesn't matter and they're both wrong right everyone the population is not the same we know that geneticists know that like crazy right everyone in fact everyone in this room is different except for you not different musicians but what we also tend not to be good in the environment so if those two things merge then the US Preventive task force twenty years from now might be tailoring the recommendations toward genotype yeaji okay thank you I'll repeat the questions so this is the one of the other big take homes is this is what we think risk looks like this happens to be four I actually drew it in for breast cancer but this is the one of the ones that you should reproduce and put in your book to think about okay so here is how common it is right so the more common is to the right here's how how strong a risk is associated with a particular flavor of a gene and once you start getting up to ten twenty thirty fold risk that starts to be Mendelian like which means you don't find it very often in the population and you find it quite often within the same family again and again right but you know those are rare right so that this is 10 percent sub 10 percent of the population so those kind of genetic effects are quite rare this is really as a continuum down here are the thing that you find by genome-wide Association studies so for example the 30 percent allele frequency means that most of us in the room would carry something actually most of us carry lots of things that predispose us to specific diseases by just a little bit one would be no risk at it right so they're in the 1 to 1.2 1.5 risk range and that's not that's a little tiny amount of risk and so there are there will be thousands and thousands of genes and and flavors of genes that you hear about that fall down in here heights up to 100 diabetes is up to 100 breast cancers up to 100 prostate cancer I'm not sure where they're at but any condition that we really push will have a hundred things or more that do a little bit of risk and that's hard to figure out what to do in the individual may be okay in the population and then here's like things where brca1 would stand so in breast cancer if if a person carries a brca1 mutation their risk of breast cancer goes up by about 8 fold that's a lot given the occurrence the population rate is is so high but very few a few percent of the population actually carries those and if you're not used to looking at relative risk if you were to put lung cancer and smoking on this the prevalence would be down around actually would be up here and yep there may be about 10 fold just about 15 percent I think it's down to it's going down but it's still 30 million 30 million Americans smoke there are things that are very very low risk and very infrequent but we can't study them because that you require probably samples of a million people to find them so this boundary here is an artificial boundary because it's not tractable there probably are not genetic things that are very very common high frequency here and very very strong because we would know about them already from family studies and this is really the landscape that you want to be thinking about if you're want to translate genetics to what to the conditions or traits that you're interested this is a little bit of the wise in case you haven't heard this or internalized this yet we really do think that there probably can be some predictive and preventative type benefit from some of these understanding some of these genes we still have a long way to go to do that and the medical community has a long way to go to embracing prevention because right now especially once you get into the hospital situation if you're eating the hospital it's too late to do prevention right and so most of the money is going into acute disease and chronic disease where prevention is too late that's where the preventative task force can actually help disease classification you probably have and will have heard about using genetics to help understand better the disease and then the other and I'm sure there's a lecture in this course on pharmacogenetics and pharmacogenomics about understanding drug response so these are a lot of the whys let me do a little bit on how you study it we could study complex diseases in families if families look like this so if this was a Mendelian disease and the green box is someone who has the disease so this was a Mendelian disease and let's say it was dominant how many of these kids would have the disease right about half right so the fact that it's only three out of a gang tells you it's not Mendelian but there's probably something going on in this family anyone come from a family that looks like this I had one time someone did have 15 siblings on when I want to use this slide so we can't do this we can't use family studies to study complex disease we can use family studies to study Mendelian disease so what we do is we do twin studies as we already talked about and we look for familial aggregation and those allow us to estimate heritability heritability is just a fancy term for how much of the phenotype is involved in a person's genome compared to a person's environmental exposures and other stuff don't I can tell you that we've been doing heritability studies for a long time they probably overestimate the genetic component and geneticists haven't been as good about saying that because we like to have a lot of stuff in our column but as the twins I showed earlier they share a lot of environment too and so the ideal way to do this is identical twins reared apart and that's a hard thing to do reared apart at birth and so that that happens and you hear remarkable concordance things that happen but you don't we don't have tens of thousands of those to study this is again back to the twins monozygotic twins share a hundred percent of everything their alleles dizygotic 50% the environment you could decide whether it's similar in both cases or not I think we need to get better at that if you take a look at various diseases and look at the concordance in monozygotic twins so take multiple sclerosis 18% of cases where you have one two identical tuned with multiple sclerosis the second twin hazard if you look at dizygotic that concordance is 2% so the Delta here the difference between this number and this number hints at the genetic component right and multiple sclerosis is one of those things that even ten years ago 10-15 years ago if you said you're gonna look into the genetics of it outside of HLA the immuno immune system people say that's crazy this these data tells you that there is a genetic component and so here's type 1 diabetes pretty strong genetic component this is we know what actually the one of the big players in this is the HLA there's specific haplotypes in the HLA that strongly pre pre deposed predisposed to type 1 schizophrenia arthritis this got shifted rheumatoid arthritis osteoarthritis cleft lip and palate so we here's a range of conditions where twin studies have said this number is a lot higher than this number there's a genetic component the other way to do it is epidemiologic studies you can use families like this and do fancy segregation but it requires getting everyone in the family and sometimes in multiple generations and if you're looking at something that's very late onset it's quite hard to get the two previous generations to do that so often what we do is epidemiologic studies and those are are great because they're simple well something up into this one too you just give you some examples of how we can before you can watch in how you can look at it so here's a condition that is present in one individual and then present in another family member right but this not that present in the population and so you can look at the formatting all got thrown off on this one you can look at the frequency in the population and the frequency in siblings and see what the ratio is and these this one that some parts have fallen out of the slide so I'm gonna skip this because the date on the slide is not right right now so this is kind of what I was talking about linkage analysis and Families SIB pairs in individuals and then these things where we're counting and so we can think about genetics moving into the counting realm which I don't slide yet where you can take thousands of individuals with a disease and a thousand in the thousands of individuals and it really does take thousands without a disease and you can look at their genome and figure out what is more present in one group than the other and it's other than lots of multiplication and lots of statistics it's no more complicated than that and that's what we're doing a lot for complex diseases I'll just use an example this is everyone know what this is it's mammography and your one read mammography this will help that's not good right so that's speculated calcium-rich tumor if you wanted to study the genetics of breast cancer in a population this shows you the the data on the rates per hundred thousand for the different ethnic groups and what you'll see is that very few women have cancer down here most the cases are up here if you were to study breast cancer and you wanted to get to the genetics you'd be better off enriching for these younger onset cases because that's getting them earlier before the environmental exposure has also contributed to it and that's obviously works for breast cancer because we have breast cancer genes this is what breast cancer might look like in a family note what about this guy can someone tell me what's going on with that person yes so that's incomplete penetrance and in this case it's what's known as sex limited incomplete penetrance because he's he right and so he presumably from this information you can tell that he inherited whatever predisposition was in his sister and his mom and passed it on to his daughter but did not manifest the disease because he was a guy now he could because one percent of breast cancer actually occurs in men but but he didn't and the person who is it these women have breast cancer I can tell you now and I'm not gonna I don't not going to talk about it but the identification of these genes has now led to treatments based on understanding brca1 and 2 biology to treat tumors in people who are brca1 and 2 positive that and drugs that have already gotten to there in Phase two trials right now and they directly came out of understanding the genes what we also can do is it was this woman wants to know what her risk is and so dude who thinks her risk is the same as the population risk which is about 10 percent lifetime you already and get another thing that you already know intuitively her risk must be higher empirically we know that if you don't have any other information other than an effective mom her risk is doubled right the risk goes up for having more relatives if I if I told you that this was not breast cancer and ovarian cancers anyone work in this area does that make the risk go up or down that she her risk of breast cancer go up or down oh right because ovarian cancer is a feature of having a brca1 mutation and it makes it more likely that something is going on in the event in this family so this is where the brca1 and p53 which is li-fraumeni syndrome kind of fall in this risk spectrum there's a bunch of things that are starting to fill out the middle in breast cancer and this there's already 30 to 40 of these in here it's the p53 it's the formal name of the p53 gene which is the gene when you inherit a mutation in it you have li-fraumeni syndrome which is a an early susceptibility to lots of different types of cancers it's a very rare syndrome it also p53 happens to be the gene that is mutated and lots of tumor cells in fact about half of tumors have a mutation in it so it's a very very very highly studied gene and you can have germline and somatic changes in it this alphabet soup will expand going forward and already has genetic variation can kind of produce protein variants you can ignore this because we don't do this anymore a lot of us spent way too much time on RFLPs this is where a lot of the action is and DNA sequencing is how you find variants this is just what a snip is if you haven't had it already I look at my chromosome I might have an A there and everyone else in the room might have jeez you might have a T there and everyone else might have C's that's all it is it's just minor changes in this room we have 18 people we've got easily 30 million differences between all of us most these differences don't really mean anything oh sorry to them okay why do we have that DNA is amazing in that it can copy itself so if I were to ask a stripe the best scribe in the world to copy a document word for word the best they can do is making one mistake per document so if it's got a thousand elements the best they can do is one in a thousand and this is actually information theory because you have to copy one thing to the other DNA actually almost is as perfect when it replicates the reason that I say luckily for us it has made mistakes because if you didn't make mistakes in copying DNA where would we be we'd still be in the primordial soup because we couldn't have evolved so there would still be nothing without these errors most of these errors that are in DNA and all this variation really just doesn't mean anything it's great for a geneticist because we can follow it around in populations in the genome but they're really not about consequences so finding a genetic difference does not mean it causes anything that's another thing to keep in mind it also gets this is the frequency of genetic variation they get injected into the population at some rate and they drift out of the population at some rate so there's always new genetic variation most and and all of us in this room have new variants because when the two cells that came together that made us each of those harrods had some new variants but most of them will go to the grave with us because they won't be selected for they won't be in our future generations occasionally you get things that either is selected for or just drifts up to being a high frequency and these are things that can be selected for if you look into any population you see that these are variants at all different frequencies and so if I were to look at everyone in the in the world I'd find all kinds of frequencies of variation what I won't find is too many variants that are present in one death Nick group compared to another okay so you might think that there are variants present in that define an ethnic group and don't define another in fact because most these variants were in the human population when the human population lived in Africa and then diverged out there all shared across what you'll find is different frequencies in some populations to others so some groups will have high very high counts of a certain variant compared to others but they almost all those don't have any biological function at all we used to worry about how you could find Jenner if you were going to go back into a study how could you find genetic variation you just have to roll up your sleeves in the lab and find it in the people you wanted to study and now you don't have to do it because it's all online thanks thanks in part to our Institute there are whole genome sequences online there's catalogs that have millions and millions of snips online and so if you want to look for genetic variation to do studies it's all been found for you or almost all found for you the other trend in genetics which you can hear more about and I think everyone has to show this slide is that DNA sequencing has gotten incredibly cheap compared to what we're used to not as cheap as I think I would like and to give you an idea of what this means so it's really come down a hundred thousand fold in in a decade and a little bit more than a decade ago I bought a Honda Civic and if I were to buy it again at this time and the price of my car had come down in that rate how cheap do you think my car would be just to tie it home a dime yeah that would be a good deal everyone thinks they got a great deal on their car a dime would be a really good darkroom technology is constantly evolving this is why we're not gonna spend much time on it but they're there DNA chips that you can do and there's DNA sequencing machines that can sequence an entire genome in a few days now there are maps of genome-wide Association studies so this is an online map actually I haven't updated it in a long time but it gets too crowded now and so this is the different chromosomes and every dot shows you where there's a trait that's been tied to a genome-wide Association study result so if we were just doing height you could imagine there'd be a hundred dots just for height and so what you don't want to do is say I'm gonna go look for the new gene I'm gonna find the new genes that are there reasons that my patients have kidney disease and I need to take their blood the first thing you need to do is look on the existing maps and see whether or not someone else has already found the genes that predispose to kidney disease and some of them are harder to find in the literature compared to these online resources it's easier to use these online resources this is just an example of what sequencing machines look I don't know there's going to go to Niska okay I'll make you not feel bad about missing the tour you'll see a room with some machines in it look like this and you used to need all these machines and now you need just smaller smaller machines so it is actually a good tour but it nothing blows up with bubbles or anything like that it's just small things so so this is a lab that would have been a DNA sequencing production center using the sequencing technology of five years ago and there's this and there's a backside today if you were to go up there this would take care of all that so it's gone from that which are automated but still need someone to do some care and feeding to this and so our sequencing center has not hired new people in fact we've shed some people because we don't need as many people because these machines one of these will do this entire row in a day this entire row would probably take a week to do what one of these machines doing today one of these new looking machines so if you were going to disk for the tour you'd see some boxes that are great let's talk a little bit of and kind of wind down with you know what you can do with this we talked a little bit before about personalized medicine really having some impact in Diagnostics pharmacogenetics risk assessment hopefully if you can do risk assessment you can do risk modification as well as understanding the new biology and new drugs so the example I gave there was the brca1 you know understanding what PRC wanted to did opened up a whole new avenue of biology and the understanding of DNA repair and that allowed some smart people to say well if these people have faulty DNA repair in their tumors maybe I can get a drug that will just hit their tumor and it really does compare to it hits the tumor there's some nausea involved but compared to a conventional chemotherapy which is toxic to all cells it's really quite a breakthrough the problem with these I'll tell you in advance and when we we target toward the tumor often the tumor figures out how to outsmart it and it comes back we're not there with the breast cancer ones yet but the lung cancer experience is such that you you can give someone more months of life but you can't cure them yet but it's really helped to actually open up new avenues because otherwise what we're doing you most of you have heard what oncologists do is you know slash poison or burn and having a tool that's a little more fancy than that would be great so these are the realms where we think genetics and clinical practice really can have a the impact I wanted to leave at least five minutes for questions we have seven so I'm ahead of schedule and I wanted to end with that kind of again it was a broad brush of things that mostly you know but now especially that one that one diagram of the landscape is some things you really kind of think about so when you hear gene for type 2 diabetes to say is that a common gene is it a common allele and is it high-risk or is it a commonly on low risk think about the parameters of frequency and potency for lack of a better term when you're talking about genes or conditions right you had a question yeah so the the question was about wheels coming and going in the population and don't they stay in hardy-weinberg whereas the next generation almost has the same frequency as the previous generation and you're absolutely right the thing that I did not put on this slide was the time scale and so the average time for something to go from here to here is its it's a statistical model is four times the effective population size times the number of generations and so in the founding human population they think it was about 10,000 individuals four times 10,000 it's 40,000 times twenty would be that number of years to take to have the shift so you're absolutely right then that these things take tremendous amount of time to drift one example and this is why you cannot make the population better by doing the kind of breeding that people tried to do in the eugenics movement it just doesn't work so anyone take care of cystic fibrosis patients so up until recently no one with cystic fibrosis has ever reproduced because the males are infertile and the women had often died before reproduction has the the frequency of cystic fibrosis in the European population changed at all in the last hundred two hundred five hundred years probably not and that's with having everyone who has two bad alleles never reproduce so that shows you how stable the hardy-weinberg kind of thing is because there's a lot of heterozygotes so if people tell you we're gonna use genetics to evolve the population totally crazy we just can't do it because of this big pool yes sure so the question is these new compounds that have been are being in there now in Phase two trials for treating tumors in individuals who are brca1 or 2 positive they take advantage of the fact and shame I have a picture of it and it's easier in a picture but I'll just tell you is that DNA has two strands right and think of it these two strands being really long in a chromosome if you have a double-stranded break in those two strands then the chromosomes can fall apart right because they're no longer attached to each other so if you have a big chromosome so double-stranded breaks are really bad if you have enough of them the cell dies if you have a few of them the cell might become cancerous a single strand of break on the other hand if I have one strand up here and I break here and once in the other strand everything stays together and it's easier to fix that so there is there are two different components to fixing DNA there's a whole bunch of proteins it's actually a lot of proteins it's almost twenty or thirty of them that specialize in sensing and fixing double-stranded breaks there's another set of proteins to fix single-stranded breaks you know brca1 cell the cell that's deficient of brca1 it has some extra double strand breaks but it apparently can survive because it doesn't have that many if I take a chromosome now that has a single strand of break and I'm ready to copy it so the strands come apart I now have one I can copy and then I have another one that falls apart because it's already cut and so what the folks in in UK said is what if I inhibit the single strand of break machinery that would flood a cell with double-stranded breaks if it tried to copy itself and a cell that a normal cell might be able to handle those double-stranded breaks but a BRCA deficient cell not and it would kit commit cellular suicide apoptosis and in fact they did that in a dish they did it in a mouse they did it phase one trials and had some change in disease free progression in phase one trials and in phase true trials there's significant disease free progression and they're doing it's mostly in ovarian cancer patients who have failed all therapy the study that came out actually just a couple weeks ago in Lancet Oncology showed five or six months shift in disease-free progression it didn't show a decrease in mortality in the patients that were studied they're still at the midpoint so that's that particular mechanism derived from two things understanding this complexity of DNA repair and understanding where BR say plays a role in it happy to answer any questions about yeah so I so the question is where do you see the role of nurses in dealing with this personalization of Medicine and I will tell you that it's been shaped by a student that I had my lab who was a nurse who did a PhD with me and by gene – I think that we're totally underutilizing nurses in general there really should be a specialty there's I don't know what you there's some technical term for it but a a thing that you could certify in so you could do risk assessment and you could do behavior modification if you did and you could be the local expert in genetics because this we know the medical community is not ready to handle this there's not enough genetic counselors now to handle this and there are a lot of nurses and a lot of them are very anxious – that's why you're here right you want to learn more and so Gina's written about this it's a ready-made force work force to help deal with with all aspects of this and act as a facilitator a translator and a knowledge expert you just need to do these courses and convince whoever it is in the hospitals in the medical community that this is a good role but know the amount of people that are available or is tremendous and the amount of yearning for new new and different experiences is also tremendous as well so it's it's the biggest untapped resources we talked you know we don't need to don't need to train a zillion internists about this we need to train people who are available in the medical system to do it so I think you could have a role in both but I think there needs to be some official buy-in from the entire system and as you know that's always complicated in this specialist so that the comment was there's a certification for genetics in nursing I'm gonna get is bet that it's mostly involved in medical genetics as traditionally which is the Mendelian disorders and now genetics is strip is drifting into everything and that's really where you need it right so the cardiology practice should have someone who is a nurse who's part of the practice who is up on what the latest low-risk penetrants were right because you that practice is really going to see a familial hypercholesterolemia patient which is what the Mendelian people would see they're gonna see people who are drift on to one side and certainly the oncologist need this as well because they're not only is the I think that the advance treatment based on what the tumor genome is like that's gonna happen quite quickly but the susceptibility is is not being covered very well or or or even understood very well we still hear cases of oncologists who have told woman took a family history so that's a plus they actually took a family history and then found that all the breast cancer was on their father's side and said don't worry about it cuz it's all on your father's side so that's not that shouldn't be happening today and it still does

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Reimo Priidik

Great introduction into the subject of complex diseases

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