"Mitochondrial DNA variation in Human Origins and Disease"

Case Western Reserve University's Institute for the science of origins proudly presents the origin science Scholars Program the Institute advances the scientific understanding and application of origins and evolution of human and natural systems the origin science scholars lectures are presented with the assistance of Case Western Reserve University's Segal lifelong learning program College of Arts and Sciences and media vision it's my pleasure today to welcome Doug Wallace director of the Center for mitochondrial and epigenetic medicine at Children's Hospital of Philadelphia and professor of pathology and Laboratory Medicine at the University of Pennsylvania professor Wallace is one of the founders of mitochondrial medicine and so it's a particular pleasure to have him here to tell us about mitochondria and their effects on humans well I really want to thank you all for the invitation and for you all for taking some time in the evening to visit with me so we're going to talk about the human cell and an aspect of the human cell which you heard something of from your lecture last week the energy generating structure of the mitochondria so the human cell of course shown here as a circular spherical cell in the center there is the nucleus which contains the vast majority of the DNA but outside that are the structures which are in fact the mitochondria and the mitochondria are symbiotic bacteria that live inside your cell and they generate the vast majority of the energy that you use in your daily life so sitting in your chair right now is a hundred trillion separate individuals and those separate individuals are cells those cells are interacting with each other and in it by interacting with each other they've created the illusion of a unity and that is what you consider yourself so that illusion of eyeness is in fact really a Wii it's not an AI but a Wii but interesting inside each of the Wii is of a and inside that they there are literally hundreds to thousands of them in the Veii inside the we that is you I think I got that right but anyway the point is that you are the product of two totally separate independent lines of evolution and those two lines came together as you heard from Joe last week in a fusion of these two life-forms together to form this symbiosis which then is what we call the eukaryotic cell which you're seeing up there so the eukaryotic cell has a nucleus and its cytoplasm well that was one organism that was an RKO that the time and the other organism these mitochondria they are an oxidative bacteria called an alpha Proteobacteria but they were both bacteria co-equal bacteria with the same size genomes but over the period after the symbiosis when they came together they began to exchange genetic information and so now many of the genes that were in the original oxidative bacteria have been transferred into the genome of the archaea bacteria to create this very complicated nucleus but still these are two independent life forms so you are in fact a unique experiment in evolution it is thought that this symbiosis only occurred one time so all plants and animals all complex things fungi yeasts they're all related to you through this one unique event if that event had never occurred there would only be very simple bacteria on this planet and that one event transformed life as we know it so this is a very important issue why would it then be obviously important or why should it be obviously important because Newton said half a millennium ago that mass is inanimate unless it's acted on by energy and yet you're the most animated thing in my environment and I believe in yours too so that means said you are a mass but you are animated than the thing that's animating you is energy and without energy you would be an animate which is what we call dead so wouldn't it be interesting from a medical point of view to understand the difference between being alive and dead and that clearly must be energy so therefore the subject of today's discussion is the most important thing about biology know biology exists without energy flow and energy flow is why you are here and the reason you can be complicated why you can be a hundred trillion cells a colony is because there's enough energy generated by these symbiotic bacteria to make that possible the single-cell bacteria cannot make enough energy to be complicated but by creating this situation where you have one cell to harbor much of the DNA but you can draw on hundreds of bacteria to make energy than the sum of all that energy is enough energy to create arms legs eyes heads bodies intestines okay so this event the creation of these energy factories transformed life on this planet and that is the evolution and the origin we want to talk about tonight sooo we're going to talk about evolution and evolution has been associated in the last 115 years actually in the last 60 years by the understanding of a molecule called DNA deoxyribonucleic acid DNA but before that fellow named Charles Darwin he had the idea that maybe in fact life evolved that is simpler forms gave rise to more complicated forms and that idea of evolution was of course actively debated even to today amazingly but one of the things Darwin didn't understand is how the information occurred to create this evolutionary process now this evolutionary process we now know is encoded by information molecules called DNA so at the turn of the century of the previous the beginning of the 20th century it was known from studies on fruit flies that in fact certain aspects of inheritance followed a inheritance pattern where it seemed like there were two copies of each inheritance factor and then when the sex cells were made one copy was put into each of the sex cells and then at conception the two copies came together to make a new individual that idea fit very nicely with some observations a man named Mendel made in the 1800s and it followed exactly with what the inheritance pattern of things of anatomical significance and fruit flies also followed that is if they had a bent wing the bent wing was inherited in that way or if they had too many bristles on their bodies or they had too few legs they all followed this inheritance pattern and that led then in the beginning of the 20th century to the idea that in fact genes were inherited courting the laws of Mendel and then in the 1950s DNA was discovered by Watson and Crick and it was found that that followed that same inheritance pattern and those DNA molecules were in the nucleus and the nucleus had chromosomes where the DNA molecules were and the chromosomal dance exactly followed the laws of Mendel fine so that led everybody to say wow everything solved we now understand how inheritance occurs therefore how variation would exist and how by selection different variants would be forming creating new forms that's fine that is called neo-darwinism and that is the fusion of classical Mendelian genetics and Darwinian evolutionary theory but there are all kinds of problems with that theory and I'm going to argue today that in fact there is a big disconnect between the idea of genetic variation in the nucleus and the ability for a group of organisms to adapt to a new environment and ultimately give rise to a species and the question is what allows that transition that key transition of speciation to occur and the answer to that question is going to come from very interesting discussion about what it means to feel badly and so our interest in our clinic is three things who are we where do we come from and why do we feel bad and so we're going to try and figure that out in this discussion and lo and behold it's going to give us a new insight on how we all arose and the Origin of Species okay so as I said the cell is two life forms and one life form now makes up the nucleus cytosol and that life form became specialized in making anatomy so all the genes for anatomy are now in the so called nucleus that is the derivative of the original archaea bacterial genome but the mitochondria have become specialized in energy the vital force so it's just like any other city you have in fact specialization with different components doing different jobs now this symbiosis as you heard from Joel a sweet year last week occurred about two billion years ago and as a result now inside your cell there are literally thousands of these bacteria drudes of thousands and so there you are a colony each cell as a colony of bacteria okay okay so how do these bacteria generate energy well they generate energy by burning hydrogen in your food with the oxygen that you're breathing so when you eat food food is made of either carbohydrates or fats and carbohydrates and fats have a lot of carbon and hydrogen that's how those molecules are made so inside your body your body strips the hydrogen's from the hydrocarbon and reacts the hydrogen with oxygen so how does this all work well first we start with sunlight sunlight is impinging on green plants and green plants also have a symbiotic bacteria and that symbiotic bacterium is called a chloroplast in fact the reason plants are green is that they have this symbiotic bacterium it's called a cyano bacterium that cyanobacterium can take the photon of light and use that to split the hydrogen's off of water so you then get the hydrogen and the oxygen the oxygen is released into the atmosphere and that's why there's 21% oxygen in the atmosphere right now so the hydrogen then is put on carbon which comes from carbon dioxide in the atmosphere to make sugar so in fact a plant is a polymer of sugar all linked together so cellulose is a big long string of sugars so we then animals collect the energy from the sunlight by eating the sugar in the plants called starch okay so the sugar and plants then goes into our mouth into our guts into our bloodstream into our cells and they're the sugar is split into hydrogen and carbon and the hydrogen then goes to another symbiotic bacteria the mitochondria where it reacts with the oxygen to give energy so all energy flow is not about the nuclear cytosol it's all about symbiotic bacteria both in plants and in animals and all those symbiotic organisms both the chloroplast and the mitochondria came from that original origin of that symbiosis so all energy flow and complex organisms plants and animals all goes back to this original single event that made life complex like possible ok so if you don't think that this reaction process is important then I recommend you to stop breathing for the rest of the lecture ok ok so when you burn hydrogen with oxygen you then convert it into heat or ATP and the ATP is a chemical structure that allows you to get energy to do work and heat of course maintains your body at 37 degrees centigrade so how does this all work out from the point of view of DNA so we really have two life forms this is the nucleus and it's cytoplasm that's the archaea bacteria and this is the oxidative bacteria the mitochondria now the way enter information flows in biology is information is stored in DNA which in the nucleus is on chromosomes the information is converted into a working copy called messenger RNA which still has the same DNA basis base DNA has a code of T C and G in different combinations and the RNA simply makes a copy of that so it's just like a stenographer that's taking dictation so the messenger RNA then takes one of the genes information out into the cytoplasm and there it's going to be converted into function because RNA is just a linear molecule like a tape so how do you convert the tape into a three-dimensional structure like you you then use the information one unit at a time which is three bases and that three units relates to something called an amino acid so there are 20 amino acids and each of them is coded by three bases in DNA or RNA so this process of transforming the linear information in RNA into protein which is three-dimensional occurs during protein synthesis on what are called ribosomes so there are 20,000 genes in your nucleus each one of them is converted into a protein and that protein then goes from a linear structure into a three-dimensional structure that then can do a reaction or create hair or be a structure okay so that's how information flows DNA RNA protein the same system occurs in the mitochondria because it's also a life form it has DNA which is circular not on chromosomes it makes RNA and the RNA again is read on ribosomes in protein synthesis to make proteins so what's the difference between the DNA to RNA to protein of the nuclear cytosol versus the DNA to RNA to protein of the mitochondria the mitochondrial DNA codes for the key enzymes to make energy and so the mitochondrial DNA is like the wiring diagram of a power plant power plant if you want to build a power plant you have in the city manager's office big boot print about where the parking lot is and how many bricks are going to be on and what the roof is going to look like but the wiring diagram the power plant has to be in the power plant because if anything's going to go wrong quickly it's going to be in the electrical flow and so have to be close to the energy source to solve that problem and nature solve that problem in exactly the same way by putting the energy genes within the energy generating power plant okay so this is then the wiring diagram of the power plant and then all the genes to build the power plant are there in the nucleus okay so if we want to understand energy flow then we have to understand this gene they didn't have this in high school when I was in high school so I'm probably didn't have me in high school either all right I understand sort of how with the within the nuclear DNA how the base pairs could be separated and replicated but where they're intertwined and then form a circle how the heck can that happen so the DNA strands are complementary they're anti parallel like so right okay so this is one strand the other strand and their base pair in the middle okay so for a linear DNA you just pull them apart and make a copy the circular DNA you have a topological problem so what happens is in fact you pull the strands apart and then you make one strand in fragments okay and then you can read around the other strand as a continuous piece and then you glue the fragments back together to make the circle how do we know that this event of fusing two bacteria occurred only once because we know we can determine the DNA sequence of all the organisms that were willing to sequence and then we can deduce what changes would occur so let's say we have two two humans you two right there and we sequence your DNA how many differences are they between you well the number of differences between you is the time since you had a common ancestor right so if we do that for everybody in the whole world we can go all the way back to their common ancestor and if we did that for every species in the world we can go back to their common ancestor and if we go that every mitochondria and every chloroplast we can go back to this common ancestor there's only one chloroplasts and mitochondria have a common origin yes the original eukaryotic so the answer to that is no the the plant cell and the animal cell had a common origin the chloroplast is one kind of bacterium the mitochondria is another kind of bacterium but the first symbiosis was with the cell with the mitochondria and then later the chloroplast was added so a plant has both mitochondria and chloroplasts but the common origin was with the mitochondria now it turns out that there were multiple different chloroplast origins and that's why we have brown algae gold algae red algae those are all different cyanobacterial symbiosis but all green plants had a common a common alum common cyanobacterial origin right is that clear sorry I maybe was unclear on that I just read an article about scientists making the tree of life bigger and they added like a third branch and I'm wondering if the first tuber if one of those branches was the mitochondria thing and if you're going down to the bottom of the Tree of Life what the heck's there haha so the there is a very famous in biology scientists named Carlos wo e se and Karl was studied a particular kind of gene that's found in every living organism called ribosomal gene it's one of the one of the one of the RNAs that make up that structure and he was then able to create a just this kind of phylogenetic tree by comparing the sequences and putting most similar ones closer and the most distant ones farther apart so when he did that he found that there was a common origin but there were three branches what were the three branches branch one was what he already knew were the regular bacteria we call those you bacterial branch 2 was in fact what we now know is the genes and the nucleus here but branch three was this other branch and that became the archaea bacteria so in fact the archaea bacteria and the you bacteria formed the symbiosis and the you bacterias might made the mitochondria in the chloroplast they're still you bacteria they're just now in a different environment okay and it turned out that the archaea bacteria gave rise to the animal and plant cell nuclei okay so those are the three forms of life thank you for joining us you've been watching dr. Douglas Wallace discussing how genes are found not just inside the nuclei of our cells but also inside our mitochondria for more information on the origin science Scholars Program please visit the Institute's website at origins dot case dot edu and the next part of the talk dr. Wallace will discuss the variation of mitochondrial DNA across human populations now back to the talk what are we going to do today why are we talking about origin we're talking about origin because of a simple experiment that we did a number of years ago first of all we did an experiment where we looked at mother and father and children and we looked at the DNA inside the mitochondria and we looked at variation and what are we fine we found that contrary to what we were taught in school where mother and father each gave one gene to their offspring and since a mother and father each had two each offspring could have different combinations what we found is every child had exactly the same mitochondrial DNA as the mother and never the father okay so that we showed that the mitochondrial DNA was transmitted from mother to all of her children and her daughters from their children but male mitochondria into the egg are seen as foreign and are selectively destroyed so men have been thrown out for two billion years it's really appalling but as soon as we realize that that we realized that if I sequence the mitochondria have everybody in this room the number of nucleotide differences between any two of you would be proportional to the time you had a common mother and therefore if we sequenced everybody in the room we could literally reconstruct the maternal lineage that brought you all together okay or even broader if we looked at Aboriginal populations from around the world we could find out what the common mother was and knowing where all those populations were and knowing their genetic relationship we could in fact reconstruct the origin and migration of women now those of you that have a y chromosome will be reassured that we also did the Y chromosome study and we found that we went more or less together which I suppose is not so surprising given the divorce rate but anyway so this tree which we'll come back to is actually a diagram of how our ancestors started in Africa and migrated out to colonize all the rest of the world and we'll come back to that but what that's really from my point of view old news that's work we did in the 1980s what surprised us and everybody else is that these mitochondrial DNA types which we'll get back into our highly geographically oriented and that is totally different from your nuclear genetic variation because every population around the world shares many of the same nuclear variants but in fact the mitochondrial DNA variants are highly geographically and constrained by in digital population so the surprising thing is the question why okay so why is it that there was a single origin for human mitochondrial DNA doesn't mean that there was only one woman even though that would be a biblical idea no there were probably at least five to ten thousand women but only one type of mitochondrial DNA started the whole process why did that happen or moreover why did only two mitochondrial DNA of all the thousands that lived in the Africa only two mitochondrial DNA is left Africa and colonized the rest of world sixty-five thousand years ago or why of all the mitochondrial DNA is in Eurasia only three mitochondria days became concentrated in Eurasia I mean in Chukotka and crossed to colonize the Americas why were these huge bottlenecks in mitochondrial variation and that has been the question I think has been preoccupying me for the last 25 years okay so we're going to talk about that so we're going to first ask why maternal inheritance why would it be important to have one mitochondrial DNA so here what we have is we've taken a mouse and we've generated its embryos and those embryos have the ability to make a whole Mouse because those are embryonic stem cells so we can take these embryonic stem cells with the mitochondrial DNA from that Mouse we can then take another cell with a different mitochondria day this is one two nine mighty Konya it's just a number nzb we can take this cell remove its nucleus take this cytoplasm with this spider chondral DNA and fuse it to this cell so we've now mix the two mighty cuddle DNA's we can put that ploy potent stem cell into a blastocyst put it into a foster mother she's kind of embarrassed she's gotten any way and then breed the female to see if we can get a chimera which will be some of these cells plus these cells and so these are brown this is black and then we can take this female and if the brown cells made her eggs then we will transmit the two mitochondrial DNA into the mouse okay so what we can do that is we can then artificially mix these two mighty kind of the days which would never happen in evolution I mean a normal life right because of maternal inheritance so what happens here's an example this is the founder mother this is the one mighty kind of day and this is the other so you can see that she has the two different by teakettle today's her daughter this is females this is a male these are a mating her daughter has the two mighty count on today's and when this daughter is mated with this male all of her offspring have the two mitochondrial DNA s and all the daughters have the two mighty Khan DNA's but the males with the two my teakettle today's mated with females with only one they only get the one showing maternal inheritance okay there's absolute eternal inheritance but we're transmitting this mixture so called heteroplasmy through the maternal lineage never happens in normal life so what happens so here is an animal with a uniform nucleus we then have the mixed heteroplasmy and we then segregate out to an animal that has one type an animal that has the other type and we're going to compare the three to see if there's any difference remember the nucleus is absolutely the same okay so if we then look at the activity of a mouse so the mouse is active at night then this is the one to nine pure one to nine might come today active in daytime low high active at night this is the nzb active at night low at nee active at night but look at the hetero plasmic animal with the two mighty head of the days it's hypoactive it's depressed if we now put that animal in a stressful environment it's completely uncontrollable it actually goes crazy so it's manic depressive it has a manic depressive phenotype if we then ask that animal to learn a task so we're not going to put the mouse in the middle of this field we have red green blue and yellow so it can orient and behind this little hole there are holes all the way around the circle is a little black box and a mouse wants to hide so we put the mouse in there and it wanders around until it finds the hole and jumps in and then we can time it okay so if we look at the one to nine animal it this is the first day it got tested the second the third the fourth it learns where the hole is because of the colors and goes in quickly and the nzb does to the hetero plasmic animal learned slower okay that's fine but now we just let the animals rest for 24 hours just don't show them this experiment again now we put the 1 to 9 animal back in the case back on the plate and it runs and jumps in the hole we put the nzb animal on plate runs and jumps of the hole but we put the hetero plasmic animal in and it has absolutely no recollection that had ever saw this before so by simply mixing two perfectly normal mitochondrial DNA s we have a severe manic-depressive phenotype and a massive lack of long-term memory and that's why there's uniparental inheritance you cannot mix two wiring diagrams for the same power plant or the whole thing shorts out simple physics okay alright so this is the wiring diagram it codes for 13 proteins that are necessary to make energy and the RNAs for the ribosomes to convert the message into protein and there are many mutations in this circle that give you genetic diseases but there are also variants that are very ancient this variant in the circle of mitochondrial DNA is found in three quarters of sub-saharan Africans this variant is found in about half of the Europeans variant a B C and D arose in Central Asia and they cross the Bering Land Bridge to colonize the Americas I'm going to argue that these variants allowed our ancestors to adapt to the different environments they found as they moved around the world and it's that adaptation that makes those mitochondria stick to where they are because that's where they're good at being right okay so again mitochondrial DNA is maternally inherited there are thousands of mitochondria in each cell and they're constantly replicating inside your cells so they're growing and then they're being eaten up by a process called my Tata G so it's an active colony in fact if you don't really believe that this is true lie awake tonight when it's really dark put on your mask and if your maid is not storing that's really distracting they're not storing you lie there very quietly and think about it you'll feel them wiggling in there anyway the point is that as they're replicating they accumulate damage and so over time the number of mutant mitochondrial DNA accumulates and that's aging because as the mutant mitochondrion ace increases the energy output of the system declines and when I asked my mother what it meant to be old she said I just don't have the energy I used to I didn't believe her until now I'm 70 and now I can hardly get up the stairs so this is in fact the process of Aging decline in energy so as the amount of damaged mitochondria increases it ultimately falls below the minim for that organ to function and the most energy demanding organ is your brain it's 2% of your body way to use 20% of the energy therefore a 5% reduction in your mitochondria is more than enough to give you a massive headache and so as you'll see that is in fact the cause of all the common diseases variation and energetics okay so here's an example this is a family that's a father that's a mother these are their children and these then are their marriages and this woman had a mutation in her mitochondrial DNA in a gene called nd6 and it just changed this protein amino acid prolene at Nuuk amino acid 25 to Lucy this woman was 50% hetero plasmic 50% of my colonies had the mutant 50% did not and she had problems with her eyes and her balance her sister only had 5% mutant mighty kind of day because it's randomly distributed through the maternal lineage but she had three different consorts and every one of her children had 100% mutant and they all died in childhood so this extra nuclear DNA is not inherited by the rules of Mendel it's inherited randomly by a stochastic process along the maternal lineage and the more mutant the worse off you are okay so we can make a mouse we have exactly the same change in the six protein 25 - leucine we put this mutant mitochondria into the mouse female gerbil so what do we get this is the optic nerve of the normal of a normal Mouse this is the mutant Mouse and you can see that the axons are swollen they've lost the myelin and we get a selective loss of the high-energy neurons and these animals go on to get a neurodegenerative disease this is another animal that we created here we have an animal that has two different mitochondrial mutations one in the nd6 gene but this is a very severe one it kills that gene I'm sorry I should have mentioned this mutation oops this mutation is only causes a 30% reduction in energy oops but this mutation if it were pure mutant there would be no energy but that's not the case here this is a mixture of this mutation that's very severe and this mild mutation we're going to put that into a mouse okay so what do we get well here is then the tissues of the derived Mouse and the blue is the mild mutation and the red is the severe mutation it is hetero plasmic in different organs okay so then we take that animal and we has about 50% of the severe mutation and we cross her with a normal male and what we found is all of the all of the pups all of the offspring have in fact instead of 50% they have 16% of the mutant and then we cross her again the next litter is only 6% and then the fourth fifth and sixth pregnancies are no mutant so there's a directional elimination of the most severe mutation through the female germline okay why is that important so mitochondrial DNA is a very high mutation rate and most mutations are bad so if in fact all the mutations were put into the population with a very high mutation rate it would kill off the species so what happened mother nature built into the female germline a way of testing each egg and if the egg had a really bad mitochondria it killed it off and didn't allow that to contribute so what does this mean this means that all of us mammals all half of all of us mammals sorry all of you female mammals have a very high mutation rate for your mitochondrial DNA but you're only allowing the best variants to go out into the population the bad ones you're throwing out and that allows a lot of variation to exist in the population okay so almost everybody in this room has a slightly different mighty kernel today and a slightly different energy metabolism okay because of this high mutation rate let's see if I can phrase this in a way that makes sense but so when these mutants appear when they're inherited is there is there anything that determines which is dominant or is it just the fact that they're there and there they screw up the wiring yes and yes so what happens is on first of all the egg the the female egg has about 500 to a million mitochondrial DNA s okay so inside that egg you might get one mutant mitochondrial DNA all of us would be normal right but then when that a gets fertilized with a sperm it starts dividing into making cells to make the blastocyst and then you go on to give the animal well up for the first large number of cell divisions it doesn't replicate its mitochondrial DNA molecule so what it does is it replicates the nucleus but not the mitochondrial DNA so literally you take that five hundred thousand molecules and then randomly divide them up on all the cell's okay so just a small amount number it turns out about a hundred then only a few cells actually give rise to the female germ line so what you've done is you've made a sampling of a very large number of mixed population and that by sampling a small number you will create a large statistical variance that is you either get a bad one and then you have high mutant or you only get good ones and then you have normal and so by this sampling error inside the germ line you create very bad my techs and I mean very good yeah eggs and very bad eggs the bad eggs then when they start to grow they have an energy deficiency and as they start to ovulate they die and the good eggs are ovulated and can get fertilized so you have a system of sampling error statistical sampling error giving you large distribution followed by selection to get rid of the bad ones and that preserves the genotype but if the mutation is mild or beneficial then that will rapidly become an egg that then gives rise to a new adaptive lineage of the genome and that's the key idea here we hope you've been enjoying the origin science Scholars Program with dr. Douglas Wallace dr. Wallace's director of the Center for mitochondrial and epigenomic medicine at Children's Hospital of Philadelphia the second part of our talk we learned how variations in human mitochondrial DNA emerged and were carried around the world in our final segment dr. Wallace will discuss the mitochondrial basis of disease now back to our talk so this just shows that the milder mitochondria mutation we'll give you and in this particular mouse we've now lost the severe one because it's segregated but we now have the mild one and this mild one gives you a muscle problem a heart problem and diabetes so a nucleus is normal but a single point mutation the mitochondria day has already given you all the complex diseases okay so this is a human family these people have all gone blind they're all related through the maternal lineage but note there's four times more males that are affected than females and all of them get this exact same nd for mutation so why is that interesting because this sex bias is seen in Parkinson's disease it's seen as an autism it's seen in many different genetic diseases and we feel this is characteristic of milder mitochondrial disease but there's also another factor and that is even so not everybody not all the males are affected so why is that okay so this is a disease where you're fine in normal life and then suddenly in midlife you lose vision in one eye and then in the other and are legally blind called Labor's hereditary optic neuropathy it's a maternally inherited mitochondrial predisposition there are multiple different mutations in the mitochondrial DNA that will give that blindness this is a severe mutation this is an intermediate one and this is a mild one that's the biochemical defect so if they have different biochemical defects why do they give the same problem if it was really a quantitative thing you think a milder one would be less affected right well the reason is because this isn't the only factor it depends on what the mitochondrial DNA that the mutation occurred was like so this is a lineage we're going to call Jay it's found in 10% of Europeans this severe mutation it will give you blindness whether you're a J or not this is just random sampling but this milder mutation will give you blindness if you're also Jay that is you have a higher probability and this very mild one will almost have to be Jay to give you blindness there are other mutations like this 339 for variant so it's not just a single nucleotide change but also the maternal lineage on which the change occurred okay so that's back to this so remember what we did here is we we went all over the world found Aboriginal populations that had lived there for ten thousand years sampled them did a very careful anthropological study and then sequence their mitochondrial DNA s and then we could build together this whole phylogenetic tree so these are quite some people of the Kalahari these are two different African pink pygmy lineages you think pygmies look the same but this one has existed for ninety thousand years and this is only thirty thousand years okay still the same adaptation this variant sub-saharan African gave rise then to all the people up here in Ethiopia to mitochondrial DNA zeros m and n sixty-five thousand years ago of all the hundreds to thousands of different mighty kind of the days only two maternal lineages left Africa and colonize the rest of the world one lineage M state of the tropics all the way down to Australia and much later moved into the temperate zone to give lineage as we called C D and G these are just letters as we discovered them but n move directly into the temperate zone and gave these European lineages HJ t uu k v iwx these of course have been most studied because there's the most money to study them okay then much later one of the lineages from this n lineage called a and two of the lineages later from the Emily C and D became enriched in Checotah and they crossed the Bering Land Bridge to colonize the Americas okay so this is a huge geographic separation of these types so why would that be because here in Africa if you're a woman and you want to reproduce you need to be able to run away from lions being raid run away from lions you need to have very efficient mitochondria you have to take all the calories that you eat and convert them into ATP because that's how you run right you heard that from Joe and you it's hot so you don't want to make a lot of heat well a calorie is a unit of heat every calorie you burn you get heat in your body okay so you want to minimize the number of calories maximize them or heat to run away from lions okay that's fine but up here the Lions froze to death that wasn't a problem for you problem is you froze to death okay so how did the women survive up there they changed their efficiency of our mitochondria so now they were less efficient they had to eat more calories for the same amount of ATP but burning more calories generated more heat what was going to kill them was the cold so it's better to be inefficient to make more heat okay so changing the energetic efficiency will allow our ancestors to adapt to different environments now that meant that these people had to eat a high fat diet because fat has a lot of calories so they had to kill marine animals and we all look down on them I'm sorry that's too bad that's her niche so this in fact then was how our ancestors actually came to live in those different places and therefore why is there only one mitochondrial DNA in Africa because a small population of protohumans happen to become isolated in a particular part of Africa with a particular mitochondrial DNA that was good for that area and that then gave rise to all the rest the variation of our species okay it wasn't that there was Adam and Eve it was that selection limited the amount of variation in that environment okay is that clear because that's a key idea yes sir you had a question I'll repeat it he says did this happen to just two humans no I believe this is the missing evolutionary principle that makes Darwinian neo-darwinian work okay and that's what I'm going to come back to but our studies on human medicine gave us the insight because we looked enough within a species to figure out what variation really meant it's not about whether we have an extra arm or not it's whether we are cold in the winter are hot in the winter whether I'm fighting with my wife because she Scandinavian and she's always hot and I'm not the Scandinavian I'm always cold and we can never agree on what the thermostat should be okay that is mitochondria in action that is divorce okay anyway this is an example coming from Jess Europe ten to fifteen thousand years ago this transfer RNA had a single change at a to a G that a to a G is very minor change it didn't affect the reproductive capacity of human women but what happens if people live long enough it certainly affects the quality of their brains so this variant is only about 4% in people that are young but in people with Alzheimer's and Parkinson's disease it's 7% so this is a mutation that has no selective disadvantage because evolution only carries cares about reproduction but because we wish to live to a hundred this then becomes deleterious it's called antagonistic player trophy very classic idea in evolutionary biology and we see this over and over and over this is another mutation that is much more severe and it will give you outsiders of Parkinson's disease if you just get it you don't have to keep that thousands of years to get that mutation okay so here is another variant this variant is this is the lineage of em out of Africa this is the N lineage out of Africa and these are mitochondrial DNA zwi sequence from Tibetans in a high altitude and you can see on the M lineage we have this 3 3 9 4 C mutation occurring three times and if we look at the frequency of 3 3 9 4 C versus altitude of the village we studied it's clear that there is strong selection for this mutation so this mutation changes energy metabolism to deal with low oxygen tension ok now what's amazing about this 3 3 9 4 C this is good at high altitude but this is one of the same mutations that at sea level increases the pensions of Labor's here is another case of antagonistic player trophy but now the difference is altitude high or low as opposed to young versus old okay so in fact there is a whole bunch of associations between the different mighty cattle lineages and disease and we've correlated them with Alzheimer's Parkinson's macular degeneration migraine psychiatric sorter stroke diabetes gravis disease metabolic syndrome sepsis IgE asthma aids aids therapy osteoarthritis altitude adaptation aging cancer and athletic performance now this is my most important observation because when I was a boy my father he was a big advocate that all boys should be good baseball players okay so I was his son he dragged me out he coached Little League he was such a noble father and I was an unmitigated disaster so I'd put it foot out the outfield that ball would come and I run around it hit me in the head and he would go Oh God so he put me as a catcher I'd be down and it would hit me a face and I finally he was completely fed up and I felt bad about this you know I've always felt bad that I disappointed my dad well I thought you know it was just some kind of incompetence but then I began to learn about mitochondrial DNA lineages and one of the things dad said was well if you can't play baseball why don't you run long distance so why would I run long distance nobody will ever see you out there ok ok I tried to do that it was humiliating because I was always the last I could figure out I trained and I ran and was always the last so he said well don't do that anymore anyway so so you know I did dumb things like I hope to do a Boston Marathon I'm going to show him couldn't finish who finishes the Boston Marathon these Ethiopians I mean duh they're Kenyans Tanith the Kenyans always win the Boston Marathon in fact they win all the long-distance races this is so humiliating why would they win the longest at races and then I learned that in fact if we look at my Takano lineages these are the European lineages these are the African lineages and lineage l0 is the most efficient mitochondrial DNA and all Kenyan long distance runners are l0 ok and I'm T Holy Smoke I suddenly feel much better I now know why I could never on long distance I feel better about my father but now I hate my mother ok so there are a huge number of phenotypes that are related to by diccon or variation and they're exactly the ones you care about you don't care about whether you're going to have an extra arm or not that's something about deep evolution what you care about is whether you're depressed or whether you're going to get back into degeneration or whether going to get neurodegenerative disease and people have looked and looked and looked in the nucleus and if you follow the field we can only account for 10 or 15% of the variants with all the variation around the world for these diseases and they say where's the missing variance you know what they never ever once looked at the mighty Connell DNA because it was irrelevant because they believed in Mendel ok but if we look at mice with these different mitochondrial DNA variation and we just look at something simple like a neuropsychiatric response ok so we're going to do something equivalent to my being told by being told I have to write a grant that's not the same as actually spending the month sweating blood and tears I'm writing a guy I'm just being told so we're going to take the mouse and we're going to put it in a little confined environment like a hole for 30 minutes and then let out misson nothing right nothing what happens to this mouse so here we're looking at it here's the mitochondria these are the enzymes one three four and five this is a gene that exchanges the ATP and this is an antioxidant Jean s serve for the mitochondria so we have all of these mice and we're going to expose them to 30 minutes stress and we're going to ask what happens to their stress response so when you get stressed you make quarter Coster own it's a kind of stress hormone okay so we should see then what happens for corticosteroid would we stress these mice so this is the mutation in the nd6 gene this is a mutation the co one gene and you can note that the ND 16 the corticosteroid for the 30 minutes of stress goes up and it stays high relative to the co one and the wild-type if we look at glucose metabolism which should be downstream of glucocorticoids we see the nd6 goes up and then down where it's much less for the wild-type but now let's look at the nuclear genes this is the AMT that exchanges the ATP and ADP look at the huge effect it has on glucocorticoid and then down yet its ability to change glucose metabolism is null on the other hand the antioxidant mutation of the mitochondrial DNA has no effect on gluco co2 corticosteroid but a huge effect on glucose what am I saying here these are the things your psychiatrist would look at if you're stressed and he would say well GU GU koko de Coster own is very important we'll measure that but I'm showing you the same stressor has totally different effects by very subtle mitochondrial changes okay so if we then just compare the nd6 and the a and T and we look at the change in glucose change in GU coke quarter Coster own for a 30-minute stressor we can see that they're on totally different sides of the stress response so that's why people here are going to differentially respond to stress because you all have a different mitochondrial genotype from the mitochondrial DNA and as soon as you're put into a stressor environment you're going to have these kinds of differential responses okay so let's look at something you might have heard of these are so-called catecholamines dopamine or epinephrine a nephron there this stress flight fight flight fight hormones so here what we're going to do is put the mouse normal Mouse and put it in the little 30 minute constraint and this is one genotype one genotype one genotype odisha so dopamine they all show an increase in dopamine but now look at norepinephrine these are up these are up but this one is already so stressed out it doesn't even respond okay and now look at this epinephrine these are still responding this is less but this one is completely wiped out again these mice look perfectly normal just as normal as you do but a subtle change in energy metabolism has completely changed the psychiatry of that Mouse okay and this just shows that there's something called inflammatory stress this nd6 mouse shows inflammation the NNT shows inflammation but the other three have less information well that's asthma and inflammatory responses to all kinds of things okay and if we just look at gene expression the mitochondrial DNA mutations are totally different from the nuclear mutations the point I'm trying to say is there's a huge amount of variation in mitochondrial DNA just among this population it didn't affect the fact that you could walk here or that you walk home or you eat dinner or any of those things but it erratically affects how you think about yourself whether you're predisposed to disease and to all of the other clinical things that are important about being human okay just one more point so the idea is that we have two genetic systems the mitochondrial genetic system that's important in energy and the nuclear cytosolic system that's important in anatomy but in medicine we're not worried about Anatomy because if you're alive you have a normal Anatomy so therefore we must be worried about energy and yet ninety-eight percent of all the federal budget has gone into the nuclear cytosol and almost nothing and study the mitochondria all the Association studies on common diseases have studied only the nuclear DNA and never the mitochondrial DNA so if we don't ask the right question how can we get the right answer okay so the last idea is that the mitochondria then is your sensor to the environment there are all kinds of environmental challenges your mitochondria perceives those by changing energy it sends a whole series of signals to the nucleus and the nucleus then responds by changing the gene expression to reconstitute normal function of the mitochondria and as long as we can maintain that we have energetic homeostasis and health but if there's a defect in energetics or the environment then in fact we get energetic decline and disease and death so if we now put energetics at the center of medicine instead of Anatomy then all of the genetic diseases have the same origin we can have genetic changes in the nucleus that will affect energy mitochondrial changes that affect energy but also calories and how you use them will affect energy if energy is defective you will damage your mitochondrial DNA that Gaye's you age-related decline at energetics and that's aging and a minor change in energetics will affect the most energetic tissues the brain heart muscle and renal those are all the common disease organs and if you foul up the power plant then you won't burn the fuel that's glucose and fatty acids and that's why diabetes has high levels of glucose and finally inflammation is all about Anna Jetix and the mitochondria are bacteria so if the bacteria release to the bloodstream you're going to get inflammation and that's how why inflammation is present and all the common diseases and finally cancer is all about cells having enough energy to grow so if we just stop thinking about energy at madami and start thinking about energy then we have a single cause for all common complex diseases and that means we could treat them because all we have to do is treat energy why don't we do that far before most suitable industries are not interested because they believe one gene one polypeptide one disease and those genes are nuclear so I just like to finish by thanking all the great people that have done this work Dimitra Shockley was very important in the population studies Meagan Martin and and Ryan Mauro were very important in the mouse studies and then we have Studies on Tibet with Fujian Yi and my colleagues or two more and others in Chongqing and in Tibet studies on neurology with my colleagues at chop cardiological studies with jargon Rula and a whole series of Optima logical studies and of course some support from NIH thank you very much the origin science scholars lectures are presented by Case Western Reserve University's Institute for the science of origins with the assistance of the Segal lifelong learning program the College of Arts and Sciences and media vision for more information on the origin science Scholars program including a full video archive please visit the Institute's website at origins dot case dot edu

Channel: Case Western Reserve University

Views: 21,781

Rating: 4.8720002 out of 5

Keywords: Case Western Reserve University (College/University), cwru, case, origins, science, wallace

Id: zOU6ptM8Y94

Length: 57min 52sec (3472 seconds)

Published: Wed Jul 20 2016

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