Ancestral ghosts in your genome | Michael Skinner | TEDxRainier

well today I'm going to talk about the ancestral ghosts in your genome essentially what your grandmother was exposed to when she was pregnant in terms of environmental factors may actually influence the disease you get later in life and you're going to pass this on to your grandkids essentially this is what you would call a non genetic form of inheritance directly impacted by the environment and it's called epigenetic transgenerational inheritance so I'll describe that and this turns out to be a very significant role and where disease comes from and in general just regulating most of biology so for the past hundred years in science in general particularly the biological sciences there's been a concept or theory paradigm a Dogma that's pretty much predominant way we think about how things work and this is called genetic determinism the concept is that the DNA sequence the genome is the most the building block for biology and it basically regulates directly what genes are on and off and that then turns around and influences the functions of different organ systems this then gives you the biology of the organism when the DNA sequence has an abnormality in a mutation then the genes are not turned on and off correctly so a physiology of the organ systems is abnormal and you have a susceptibility to develop disease but this Prem this affects all of a biology in evolutionary biology the current concept is is random DNA sequence mutations drive evolution pretty much if you want to think about anything in science we think that the DNA sequence is the driver so what I'll talk about is turns out the environment has a major impact on biology and for the past 50 or 60 years a large number of observations have been made so she suggests the genetics really can't explain many of the things we're seeing the first is there's regional disease frequencies go anywhere in the world this frequencies of different diseases is different if you take someone early in life before they age about 5 moved into a new region allowed them to grow up they will develop the disease frequency where they grew up so this can't really be a genetic phenomena it has to be more of an environmental phenomena we've looked at the large number of the major diseases we have and we've looked for genetic mutations that correlate to those diseases and in many cases we have found genetic mutations but pretty much across the board it's in less than 1% of the population with the disease less than 1% so it's good that we found some genetic mutations but what about the other 99% if you look at pretty much any of the major diseases the increase over the past 20 or 30 years is so dramatic and many of them it's a tenfold increase for autism it was 15 years tenfold increase I'm sorry there's no genetic mechanism known that could explain that phenomena it has to be induced by the environment if you have identical twins that have essentially the same genetics allow them to grow up in different regions guess what they develop different diseases if it was all genetics they should have the same diseases there's hundreds and hundreds of environmental factors that are known to promote or be associated with disease the vast majority of environmental factors cannot change DNA sequence they're not mutagens so how is it an early life exposure promotes a later life event in terms of evolution there's these rapid evolutionary events that basically we can't really explain easily with with classic genetics so there appears to be an additional factor there regulates how the DNA functions it's not the DNA sequence and the genetics isn't absolutely critical it is but it appears that there's something else it's regulating how it works it basically it goes forward so what I'm going to talk about is epigenetics this is what the phenomena is I'll describe in a minute epigenetics provides solutions for a number of the failures for genetic determinism again I'm not suggesting that genetics isn't absolutely critical it's just a small piece of a much bigger story okay so epigenetics is a small are these small molecular factors around the DNA that regulates how the DNA functions what genes are on and off but it does this completely independent of DNA sequence and so it sees molecular factors around DNA that regulate how it works what genes are on and off but it's independent of DNA sequence and when a cell divides into two daughter cells not only does it replicate its DNA but it also replicates its epigenetics so that it keeps that Mane maintains that cell identity so this is what epigenetics is there's four main epigenetic factors that we know about the first one identified was DNA methylation a small chemical group called the methyl group gets chemically attached to the DNA when that happens it has the ability to turn genes on and off the next idea the next thing identified was these groups of proteins called histones turns out DNA is wrapped around these histones like a beads on a string and when the histones are chemically modified they can influence what genes are on and off independent of DNA sequence another one is chromatin structure basically the whether there's a loop a coil or twist in the DNA can also turn genes on and off independent of DNA sequence and the last one of these non-coding RNA is these small RNAs it get expressed and they come back and react on the DNA to regulate how it functions independent of DNA sequence these are the four known epigenetic processes I'm going to focus on DNA methylation because it probably has the most important role in programming events in terms of developmental biology in terms of DNA methylation there's two times during the lifespan of an organism where there's a major reprogramming of the epigenetics the first one is during fetal development at the time of sex determination when the fetus determines whether it's going to be a male or a female the cell that's going to the precursor cell for your germline whether you're going to get a sperm or an egg that cell is D methylated methyl groups are removed at sex determination there re methylated in a male or female specific matter so you end up with a sperm lineage or an egg lineage so this is the first time the second time is at fertilization so as you become an adult reproduce at fertilization the sperm and egg come together and immediately within a cell division the DNA starts to be d methylated this is what creates eventually the embryonic stem cell that can turn in to any cell in the body then as the embryo develops a little bit further it will remelt in a cell's specific manner so this is a reprogramming of that epigenetics there's a set of genes though that are protected from that demethylation they don't get D methylated they're called imprinted sites and they basically maintain their DNA methylation and they're protected from it so they've thus they can get passed from generation to generation that's a non genetic form of inheritance so we did an experiment we exposed at just stating female what we call it f0 generation to the gestating female rat basically they we expose is the first generation we expose it during that time of sex determination just transiently a remove the exposure been so a number of different environmental toxicants we then bred the animals those offspring that were born and grew up when they grew up they turns out they started developing large amounts of disease tumors prostate disease kidney disease testes disease and very high frequencies so then we bred the animals again so we had the grand offspring we have equally level high levels of disease in all the same diseases bred it again to the great grand offspring this is the F three generations three generations removed from any exposure the only exposure was in that for F zero generation female also had high levels of disease took it even further to the fourth generation same levels of high levels of disease so we induced this and it gets passed from generation to generation even though the exposures way back here and the level of disease is extremely high what we see in the males is predominantly test the disease infertility we have prostate disease those are specific to the male and the female we see ovarian disease pubertal defects and also pregnancy defects in terms of both male and female we see kidney disease increased mammary tumors behavioural effects in terms of anxiety and stress in a large amount of obesity as well ninety percent of the met animals have multiple diseases this is one of the highest frequency induced diseases ever found in any animal model we've now repeated this with eight different environmental factors agricultural fungicides agricultural pesticides industrial contaminants like dioxin plastics like bisphenol A the insect repellent deep that all of us use terms keeping insects away the historic pesticide DDT and also hydrocarbons like jet fuel or oil each one of them independently promoted these transgenerational inheritance of disease now other laboratories have also shown that nutritional defects both high-fat diets or caloric restriction will do the same thing in plants temperature and drought did the same thing smoking alcohol is another factor that's been shown and more recently just in the past year a number of different forms of stress particularly maternal stress will actually promote this as well so this is a large number of different types of environmental sort of actions this has now been shown in plants flies worms fish rodents pigs and humans therefore it is very highly conserved this is not a unique one-off just for studying rats it really has been shown in most species investigated so this is a complicated graph I'll explain it here so it turns out that the only cell that's going to pass any information to the next generation is a sperm or an egg it has to be a germ cell no other cells in your body passes anything to the next generation on a molecular level okay so to show that this phenomena was doose through genetics which we talked about earlier we took the f3 generation sperm essentially f3 generation sperm and look for epigenetic changes so this is a complicated graph that basically shows all the chromosomes 1 through 20 and the size of those chromosomes so this is a snapshot of the whole genome ok all your DNA and every single red arrow essentially is a differential methylation site it's what we call an epi mutation that's been induced there's an abnormal differential methylation so that's an epi mutation this was in was this particular signature here was induced by the so fungicide germ zapping mutations there was over 200 of them this turned out to be an exposure specific signature in terms of where all these things are or you can also consider it a fingerprint of your ancestors exposure that's being passed through the germline for generations to come all right so we did the same analysis on all those other factors we actually analyzed plastics DDT jet fuel pesticides been close aligned so you don't need to worry about this complicated graph the only thing to pay attention to zero overlap what this means is each exposure had a specific signature or fingerprint that was not overlapping with all the other ones so theoretically we have a diagnostic now to say what's your great-grandmother was exposed to during pregnancy or what you're exposed to and you're going to pass it on to your grandkids this could be a major role advance for us in the field of environmental sciences we also know then which diseases these directly associated with so essentially what I just described is an environmental factor affected the developing fetus during that time of development of the germ line the sperm or the egg and the epigenetics got reprogrammed as that individual became an adult reproduced in its germline it's passing this altered epigenetics such that the next generation then the embryo now has an altered epigenome every so that's generated from that embryonic stem cell now has an altered epigenetics and an altered set of genes going up and down those tissues sensitive to that will develop disease those that aren't won't and so then basically as this one reproduces and goes to the next generation it's the same phenomena and this keeps going generationally it's a non genetic form of inherit let's just we'll show you one example so what we did so we exposed did the exposure with DDT and when the exposure was just this transient period of pregnancy for the f0 generation mother then we bred it for three generations both male and female lineage and what we found was there was a whole series of diseases in the f3 generation but the most predominant disease turned out to be obesity in the first generation we did not see any obesity but by the third generation half the population both males and females had a susceptibility to develop obesity this is called a susceptibility this phenomena doesn't promote the disease it promotes your susceptibility to develop disease so for example if we had two individuals one susceptible one not on exactly the same diet exactly the same exercise exactly the same living conditions the one that's not susceptible wouldn't develop obesity but the one that is will so this is truly a disease that there's a susceptibility for diet and exercise is absolutely critical for the onset of the disease but your susceptibility to develop potentially came from your ancestors this is a completely different way to think about where disease comes from it also means what works goes to today is going to affect our progeny for generations to come so this is a very different way to think about and a different mechanism for how disease develops so what I just told you is the environment has the ability to dramatically affect the epigenetics this then influences how the DNA functions under what genes are on and off and you go and these epimutations these epigenetic Epping mutations they get put in place become a permanent constituent of the date of the DNA this then causes this change in what genes are on and off and with the organ systems if it's a normal biology then you're going to have normal biology going forward if there's an abnormal expression and there's abnormal biology you'll have a susceptibility to develop disease so in terms of another consideration is this doesn't only affect disease etiology you also have an increase in phenotypic variation the characteristics that the individual have within a population are different this has direct impacts on natural selection and evolution therefore environmental epigenetics may play a significant role in evolution which we hadn't considered before so it doesn't just affect disease affects really all of biology okay so essentially as I started out these are those ancestral ghosts in your genome these epping mutations that were put there through an environmental stressor now what I just talked about is a pretty doom and gloom situation what your ancestors were exposed to is going to affect your disease and what we're exposed to likely a different set of contaminants we're going to pass on to our grandkids as well okay however so I'm going to give you the upside so essentially knowing this phenomena exists knowing that there's epimutations in your genome that may be exposure specific and directly correlated with disease we can now use these as Diagnostics for those past exposures and potentially what disease you're going to get later in life so in early in life reader 20s we could potentially analyze your epigenome determine what your ancestors are you were exposed to early in life because of that what diseases you have a high susceptibility to get later in life this allows us then to put into the whole thing called preventative medicine we can do preventive therapeutics preventative lifestyle changes and so forth to actually prevent the disease from ever developing the reason we haven't done that yet is we never had early stage Diagnostics genetics has not provided that to us today epigenetics gives us that capability so we may not be able to fix it but we definitely can treat it and this would have a significant impact on future medicine health of the population that doesn't mean at all that we shouldn't clean up our environment get rid of these toxicants you get rid of these environmental factors but during the interim we have actually a way to maybe treat the condition and help the health industry and our healthcare so without all finishing thanks for attention

Channel: TEDx Talks

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Keywords: ted x, United States, Biology, ted, tedx talk, TEDxTalks, tedx talks, Agriculture, Genetics, ted talks, Science (hard), English, ted talk, Health, tedx

Id: f1Pf5S8Nbfk

Length: 20min 19sec (1219 seconds)

Published: Mon Jan 05 2015