Svante Pääbo at Nobel Conference 44

ladies and gentlemen could I ask you to take your seats please I have just a couple of announcements I have an announcement for mr. Douglas George please go to the registration desk in the lobby area for an important message this is mr. Douglas George and also you probably noticed that it's raining out today and you'll those of you who've been with us before know that we usually have coffee and goodies and the area outside here in view of the weather we will have coffee and punch in the Lund forum which is the building just to the north of us here so at the conclusion of this session we'll move into Leung forum for coffee you can also get coffee in the Jackson Center in the marketplace lounge and also the bookstore will be open at that time to now now it is my pleasure to introduce to you my colleague in the biology department dr. Joel Carlin who will come up and introduce our next speaker dr. sponte pay well welcome back everyone a a Nobel prize-winning biochemist once said that research is to see what everybody else has seen and to think what nobody else has thought as a doctoral student in molecular immunology at Uppsala University a young sponte Pavo applied the technology of viral genetics to something that everybody else had see Egyptian mummies fearing that his PhD advisor would not like any distraction from his dissertation he worked nights and weekends until he had successfully extracted and decoded DNA sequences from an infant boy who lived 2,400 years ago this is no mean feat chromosomes are long protein colored polymers that's after death suffer from the breakage of chemical bonds and the formation of new chemical bonds with sugars and amino acids the result can be a fragmented cross-linked collection of broken chromosomes that are difficult to extract without further breakage at the time the traditional method of obtaining a readable genetic sequence would require the use of bacteria to accept and replicate the DNA instead he used the polymerase chain reaction a method of rapidly and reliably making large numbers of DNA copies from very few original molecules suddenly the chromosomes of the dead could be read and understood and his publication became the feature article in the journal science all before finishing his doctoral degree since then he has investigated the genetic secrets of extinct giant birds extinct bears and other animals his laboratory developed a method to break cross links between DNA and other molecules allowing them to amplify and sequence DNA from of all things fossilized sloth feces that had been laid down by a now extinct mammal 10,000 years ago in Nevada not only did they recover extinct sloth genes but also genes from six species of plants that the sloth had eaten what once was a fossil curiosity now tells us about ancient climate and vegetation patterns other techniques were developed to recover gene sequences from wild grass seeds domesticated by humans in Central America such information allows us now to ask important questions facing modern agriculture what proportion of our modern corn plants contain the same variations for kernel size or starch manufacturer that were found in these original maize and as we plant more and more corn with less and less genetic variation what traits of survival may have been lost along the way the societal impact of his work helps us understand not only ancient organisms but that which makes us so very human he discovered that a single point mutation in the fox p2 gene can cause severe grammatical and linguistic impairment fox p2 is present in many vertebrates but humans have two copies that have been the subject of significant natural selection thus changes in select genes and perhaps more importantly when these genes are expressed are tightly associated with our cultural separation from the rest of the animal kingdom today he is discussing his investigations of Neanderthal genomics the human genome project has greatly increased our understanding of humanity or at least of modern humans where Neanderthals fit into our idea of humanity has been a question of long debate were they competitors mates victims of or just a disinterested witnesses to the rise of modern Homo sapiens these questions I will let our speaker address he is the author of 216 scientific publications which have been cited in the past decade alone by 9000 research articles that's more than me if you want to look that up since he first worked nights with mummies he has emerged as both founder and leading force in paleo genetics this field blurs the lines distinguishing genetics linguistics zoology and archeology he has been counted as one of the 100 most influential people in world by Time magazine and has been honored by the national scientific academies of Sweden Germany Belgium the United States and China ladies and gentlemen it is my very special privilege to welcome to the stage dr. sponte well dear friends you will let me start out then by thanking you all for the invitation to come here to Gustavus and to the Nobel conference coming here is not only intellectually stimulating to me due to the talks we get to listen to it also strangely feels a little bit like coming home although I've never been here before since I'm a native of Sweden that have lived abroad for many years when I come here I see all these swedish flags and all the swedish paraphernalia in the guest house it feels a little bit like i finally arrived back home again so what I wanted to do is to just start out by reminding you all a little bit about what you are all very well aware of and that's the fact that since about five years now we know the DNA sequence three billion base pairs or so that make up the entire genetic material the genome of humans and that genetic information are stored on the chromosomes which exists in the cell nuclei of almost all the cells in our bodies and as you also are very well aware the genetic information is stored in a form on a very famous double helix and it's stored in essence twice such as let me try this out then that when you have this is too complex when you're on one strand have a see you always have a G on the other whenever you have an A on one strand you have a T on the other and so on and this is important and since whenever a cell divides and especially when that happens in the germline where a new generation is formed there are enzymes in ourselves that unwind the DNA make the strands come apart and other enzymes that then synthesize new strands using the old ones as a template in a process that is almost perfect always putting in complementary bases as we say goe to see and a opposite T however nothing is across perfect especially not in biology so now on the game an error is made and if enzymes don't correct that rapidly that may then be incorporated as a difference in the DNA sequence in the next generation and we can pick that up if we study the DNA sequences of different people for example in this room so if we sequence a piece of DNA from one chromosome in one individual and compare it to another chromosome in another individual every thousand or 1500 bases or so we discover a difference between these two individuals if we take the same segments of DNA from a chimpanzee we'll find more differences about one every hundred bases or so and so what molecular evolutionists do is them to use this information to reconstruct the history of this piece of DNA as well as we can using the best models we have for how these mutations accumulate in our DNA and we generally depict the result of such a reconstruction in the form of a phylogenetic tree in this case it's very similar is simple the two humans trace their history back for this part of their genome the common ancestor quite recently and quite a bit further back is recommen ancestor shared also with the chimpanzees so you can then start using this approach to reconstruct history you can ask questions such as who was our closest relative from a genetic perspective is it the vulnerable pygmy chimps or the common teams or the gorillas or during attacks in Asia so then do that by taking for example a piece of our genome stained apart ten thousand base pairs in one case here on their X chromosome and sequences in one team one vulnerable one one human and so on and estimate such a phylogenetic tree and you will then find that on average for most parts of our genome humans trace their ancestry back to common ancestor shared with the two forms of chimps a bit further back is there a common ancestor shared with a gorilla and quite a bit further back also with the orangutan and since these mutations rain down on our genome approximate as a function of time we can translate these differences we observe in DNA sequences to approximate times to common ancestors for this DNA sequences and in the case of humans and chimps it's in the order of five to seven million years ago to the karela a bit more and orangutan quite a further back in time now but as you notice when we go through this this is a quite an indirect way to study our revolution it is using extant species looking in their DNA trying to reconstruct what has happened in the past using models and inferences what we would like to do in a dream world where we could have everything we would have what would have cost me to go back in time to actually look at the ene sequences from our ancestors or from close relatives which are extinct so what I want to describe to you or our first baby steps to try to do that to actually do what paleontology is do to go back and try to retrieve old DNA sequences and as Curtis Souter pointed out this goes back now over 20 years when we started looking in the into preservation of DNA in ancient Egyptian mummies which then go back to three four thousand years and often look very well preserved when you look at them microscopically however if you then look in the tissues in such a well-preserved mummy it's often quite too depressing undertaking so this is a contemporary human muscle that have been a draw to in some way imminent mummification and then rehydrated and processed for microscopy you nicely see the muscle fibers with the contractile proteins making striations in then you see the cell nuclei where the DNA would be if you look in a well-preserved mummy like the one we looked at on the last slide it looks very different apparently see there are muscle fibers here you see no intra cellular structure whatsoever it looks very degraded and there's no DNA preserved here however fortunate is not always the case things are this depressing so this is the first Namie which was where we did see evidence of DNA a sample from the leg here 2,400 years old as we heard and if you look by microscopy in the upper layers of the skin you in the basal level of the epidermis here you see things that look like cell nuclei and indeed you can stain them with dyes that bind to DNA and you can then go on to extract the DNA from such tissues just like a boot from any contemporary sample and the first thing you will then notice is that the DNA degrade it is so short little pieces this is an analysis where you left your DNA mine rate in an electric field the smaller the pieces are the further down we're living in this picture a contemporary DNA would be tens of thousands of bases up here and you will see that this DNA is extracted from archaeological and paleontological remains are really small one hundred two hundred bases and they're also arranged here from left to right go from younger to older so you will see that irrespective of all they are they all are degraded approximately to the same extent to start out by a four year old piece of a sausage that happened to have in the lab it goes on to 120 year old zoological specimen Egyptian and Peruvian mummies a few thousand years old and a twelve thousand year old brownstones so this degradation probably happens rapidly after death actually as AM Sam's leak out in ourselves as we die and shop up the DNA in small pieces but there are also other forms of damage in this DNA chemical damage if you by mass spectrometry look at the DNA you will find modified forms of bases many of them the result of either hydrolytic processes assistance spontaneous processes that happen on water is present or oxidative damage from oxygen radicals from the atmosphere so your issue then is that if you want to study modern DNA our nice long nice pieces here for the ancient DNA is degraded to short pieces and have these chemical modifications which may cause errors in your sequences so if you want to look at a lot longer segments of DNA you have to retrieve short overlapping pieces and reconstruct the longer part here and still deal with these chemical modifications so because of this degradation and all these problems most Chris work in this field had concentrated on one tiny part of our genome that actually not in the cell nucleus but outside in the mitochondria and exists in hundreds of thousands of copies per cell and this little genome has advantage that there are many copies of it so you can easily then retrieve it from archaeological remains and the problems you have to deal with is a prosthetic rotation damaged and quite important less we'll discuss in a minute contamination of your experiments with modern DNA so all these problems have led to criteria that we another subtract to promote you should adhere to that all have to do with reproducibility of your results that you yourself should be able to repeat them and others should be able to repeat them and chemical analysis to make it reasonable that things have survived in a specimen what can you then do with this how far back in time can you go well what is now very routine as to use so logical collections that have collected been collected the past 200 years exist by the thousands and thousands in museums recently extinct animals such as here the marsupial wolf from Australia that became extinct around a hundred years ago or so the ground sloth that we've heard about disappeared around 10,000 years ago mammoths and mastodons that go back 40 50 thousand years some of the samples and so one question and often comes how far back can we mad and we could go in the future what I think could be mad and to do dinosaurs for example what I think that will always remain impossible because if we look on the sort of extrapolation about what we know about the chemical stability of DNA when there are even traces of water present you can see that if we start with 10 to the 12 DNA molecules which may be how many mitochondrial molecule services in a gram of tissue and sea of rapidly they become degraded when water is present and the last molecule of those 10 to the 12 who disappear before a million years ago so I think that for example inclusions in amber that are beautifully preserved and go back many millions of years unfortunately it's not possible to retrieve DNA and even if you found a dinosaur in amber it will not be possible but so within the last few hundred thousand years then there's still quite a lot of interesting things you can do this is just going to 2,000 the number of extinct species for which believable DNA sequences have been retrieved many many more now but our special interest them in our lab and here today are the Neanderthals that we already heard merited mention my Kurtis before lunch so as we also heard Neanderthals they evolved in Europe and Western Asia depending on how you define a Neanderthal they may the first traits may go back as much as 400,000 years and they then become more and more typical and then modern humans appear as we heard between a hundred two hundred thousand years ago first in Africa then spread out of the world and exist until the present day Neanderthals disappear from the fossil record something like thirty thousand years ago and as we also heard nicely laid out before lunch there are two competing today there's really just one model of origin Hamada Yunus at a widely Heil that we come out of Africa to discuss but what is still discussed is when modern humans came out of Africa is it so that it was admixture so that Neanderthals in Europe contributed some genetic variants to Europeans today and the same went on in Asia although is there a complete replacement for people coming out of Africa didn't mix it all in the under-told and folks in Asia so this is a very extreme view but the good thing is that if you study any particular part of our genome any particular little piece of DNA either the right model or the left model must be right either the was admixture for that part of our genome and then if you looked at the Neanderthal it would be closer at least to some Europeans and to people in Africa or people in Asia if there was no admixture and the Neanderthal would be equally distant from people no matter where they live in Africa in Europe or in Asia so we got the chance to look at this for the first time then in 1997 when we got a chance to extract DNA from this fossil and this is not just any fossil it's done the under-told from Neanderthal that was found in 1856 and gave its name to this group of hominids and I should be careful since there are distinguished paleontologist here but I think we were very lucky in that the first DNA we could extract was actually from the type specimen that defines what a Neanderthal is so to say because almost every Neanderthal we've since learned on Utley someone has come and told us it's not quite a typically under college it's a little grass island it's a little lat but if this is not Andrew the undertones don't exist so to say so with an extracted a sample from the left upper humerus here extracted under sterile conditions to avoid contamination focus on a very valuable part of this mitochondrial genome reconstruct cumbersome with many many small pieces of DNA repeated many times and believe the things that are consistently there in all experiments and then we can begin comparing this piece of DNA to that in present-day humans and this is an analysis we've had a few thousand contemporary humans and just look at pairwise differences human to human that exists today and have a distribution of differences like this with a mean and a mold around six seven differences this is comparing these humans to this one Neanderthal the distribution of differences looked like this something's twenty six twenty seven differences for comparisons humans to chimps here so clearly the Neanderthal seemed to fall outside the variation of modern humans and it's also the situation that if you look on the range of differences we don't find some few Europeans that would be more close to now because and others in minimum distance to the Neanderthal is the same wherever we lived in the world so we reconstruct the phylogenetic tree for this we find then that for the mitochondrial DNA humans go back to common ancestor one hundred two hundred thousand years ago and something like bit over half a million years ago back it's a real common ancestor with an e on the top but this was now only a single Neanderthals of course the relevant question is what about other Neanderthals could they fall in here could there have been and mixed you for this part of genome so there are now being several Athenee under toss retreat first was one in the Caucasus from Croatia here they all more than twenty Neanderthals fall together here outside the variation humans so it's very clear that for the magnet chondral DNA there is no evidence that now that has contributed anything genetically to us but we should not forget that if we look in our nuclear genome our variation is much much deeper if you just look in people in this room for example many variants we have go back eight hundred thousand million years so much further than our separation to Neanderthals sounds like for five hundred thousand years ago so even if there was no mixed evenly under thought whatsoever it's still true that if we for some part of our nutrakey no trace around set straight back some people in this room will be closer to now at all than other people in this room ago that further here so in other words then we are even if there was no admixture are we not that different from the Neanderthals and this is an attempt to to illustrate that so that means them that what would be very interesting would actually be to study the whole genome the nuclear genome of Neanderthals because Neanderthals are our closest relatives all categories we separate you from them three four or maybe five hundred thousand years ago so we would then be able to say what genetic change has happen in our genome after that split from renowned because in the last little bit of human evolution that would be a rather comparatively short list of the changes and sudden long them maybe some interesting ones that actually is crucial but when it makes fully modern human different from other forms but to do then that we need to leave the comfort of the mitochondrial genome and go to the nuclear genome the vast majority of our genetic material and in the last two years it has been possible to start doing this and the revolution is driven by technology as so often in biology and it comes from you see DNA sequencing techniques that make it possible to see once millions and millions of DNA sequences in just a few hours using new technologies so what you would then do is make an extract from the fossil did you do run on your sequencing machine that generates in the order of say 50 million DNA sequences you get on little database here that you can start comparing to the human genome that we know to the chimpanzee genome that we know to bacterial genomes finally knows and so on and the first place where this worked was a cave site in Croatia Vindhya came and actually from this piece of bone from this little piece here a 38 thousand year old bone of a Neanderthal the fragments of DNA with and find all really very distribution like this on average 70 base pair long pieces so when this first worked two and a half years ago we got together with actually the founder of the company that put the first of these technologies on the market Jonathan Rosenberg and set house the goal of sequencing three billion base pairs so the equivalent of an entire Neanderthal genome by the end of this year 2008 and it's often a a bit regretted actually setting a timeline for this but it seems that we are almost going to make it I think we are here now just about the time to ramp out the secrecy so if this conference was a few months later I would be able to tell you much more about the Neanderthal you know than I can now and actually what we will discuss is the data freeze from name of around 70 million base pairs that we will talk about but although we then just have a fraction of the total human we can look at some part of the genome where we have a lot of data to address some technical issues before we look into the biology and it's again the mitochondrial genome that exists in many copies to have actually by now sequenced the mitochondria in um of this individual 35 times and the issues are briefly want to touch upon SM chemical damage to the DNA and contamination damage first what we can then do is look in all our sequencing reads say it for this position here everyone says a here almost everyone seen successes see but our two ones that say T here so we can look at these errors in individual sequences from our consensus of our sequence and see what they are and the pattern is very clear it all goes back to modifications of one base C to uracil and uracil is an R and s T so we have C 2 T changes and that's result of a spontaneous hydrolytic process that happens in the fossil as in lies in in the sediments so our model of these DNA sequences look is that our double stranded but their inner ends here they have single-stranded pieces but have lots in this damage C 2 T it's a flex 70% of the seeds or T's here and the ends of the molecule inside is around 1% the other issue which is in a way much more serious is contamination than modern human DNA because as I indicated we are so close to the Neanderthal so just from looking at anyone's DNA sequence it's impossible to tell that's from an Amber talk or from a modern human that may have handled a fossil or from us in the laboratory so we try to come limit contamination by working on those cleanroom conditions and we do ask this in the fossil extracts that we start working with and we can then use these differences that we now know between thousands of humans that have been studied for the mitochondrial DNA and 20 Neanderthals so we can then look in the mitochondrial molecules that we can amplify in an extract and often it's again very depressed often the vast majorities contamination and are rare Neandertal molecules in there sometimes it's like 5050 but they're also fossils were actually the vast majority of the human-like DNA comes from the Neanderthal so with them select those few extracts and these are quite human today looked at around 200 extracts from 70 fossils six sites and found three bones that are actually almost free of contamination we then do a few other tricks we line it onto the ends of the molecule a little Neanderthal specific key in our cleaner so that we know when this goes out to become sequence that this molecule was actually in our clean room and it's not mixed up with something after that and what is now good when we get lots of data is that we can look in our in our output in the sequences we actually produce for evidence of contamination and now many positions around the mitochondrial genome within the undercount differ from all humans that have been started today looking many many sequences and stop saying whoops here is one that looks like a modern human contaminant so best estimate of contamination at the moment in our day that's 0.5 percent 9 contaminants among this 1900 sequences we can also go back to early work two years ago we've actually took our things out of the cleanroom without this tag we lived on what we published in nature at the time got 10 informative sequences non look like a contaminant but as an elite in illustration that you have to be very careful and reevaluate your work in when you do science is that if you actually look at the data from that time we and others pointed out that if were evidence in the day that we produced that it could have been contamination if you looked at the diverter from the human genome and some other features here because in another data that we produced if you compare them this one looks like it's closer to us so indeed if we go on sequence more in these old extracts gradually find among seventy five sequences eight contaminants you have a contamination rate of something like ten eleven percent there so this is absolutely crucial I think to do all this work on the cleanroom conditions and have this key here what we will need though is also an asset for contamination from the nuclear genome I'm glad to leave the mitochondrial genome and I think will actually be quite sexist in this project we will focus on mainly on the Tal remains because with males will carry only a single X chromosome as you know so what we can then look at we know that any male innovator should have only one signals from their X car so if you find differences there it has to come from contamination so we'll actually focus on mainly on dirt on individual for this product so having them dealt with this technical issues we can then turn to what we see in the data actually so what we have done as is that is go around and look for good Neanderthal fossils and we used the opportunity to actually go outside the classical range of Neanderthals in Europe and Western Asia the eastern most Neanderthal you'll find in a textbook that almost everyone agrees is a Neanderthal is in your spec used on you also got samples child here we also got samples from southern Siberia that are so fragmentary so you cannot say what they really are morphologically when we looked at their mitochondrial DNA with this assay I destroyed for contamination we find that they aren t and they fall within the variation of other Neanderthals so this is the one from a sexist on this is the one from Russia so one insight that has come almost as a side product of this project it says the Neanderthals were actually further east than what William bule is think they were in southern Siberia on the border to Mongolia and China so that's why I think an interesting research direction in the next few years is actually go to China and Mongolia and see what were the people there around thirty forty thousand years ago maybe we'll actually find an Marco Polo Neanderthal one day in China so what we're also interested in is finding avignon the tall's useful for this project the first one was from Croatia here as we discussed the other one we use is from Germany from the Neanderthal site this specimen still where a sample had been removed for dating and DNA work earlier and we were allowed to take another sample a year ago and a third site is actually very ideal for this type of work it's a site in northern Spain here in this mountain here at cave it's a fascinating site that deep cave or when you go in and a side gallery you find the remains of nine Neanderthals classical Neanderthals around 43,000 years ago let has clearly been eaten by other Neanderthals actually you have lots of captain marks or muscles attached to the bones long bones I mean crash forget the bone marrow and so on but the good thing is that they excavate there now so when that ever they start finding a bone they can dress that their sterile clothing that we give them remove the bone with so little contamination as you can imagine put them in sterile bags and freeze them inside the cave so that they can't frozen to our clean room and then look like this after you so whether these three sites all around 3040 thousand years ago and this is how much begin a sequence with them determined from them in May last year this is four billion base pairs here looks is very impressive but you should then not forget that the vast majority of the DNA is bacterial and fungal I didn't say that but only round a percent or up to maybe four or five percent in the best cases of the DNA in such a bowl actually came from the Neanderthal the rest comes from bacteria and fungi that have lived in a bone after the Neanderthal died so what we then do is take the nickel sequences compare it to the human genome to the chimp genome find the best places make sure these are the places that really correspond to each other in the human and the underdog you know EGM genome and start asking questions and the first question you might want to ask is well this divergence from us to common ancestor to the Neanderthal how far far back on this village to the common ancestor with the chimp is that so how far back is this in percent of this lineage and the answer to that is twelve point four percent so if we say six point five million years for this point this means that this is then in the water of eight hundred thousand years ago or so for the divergence of DNA sequences to the Neanderthal the population split of course is more recent because if we trace two DNA sequences back they don't go back to the time pond where the population split but into the variation of that population and a bit further back so get perspective on this with all the sequence with the same technology a typical European person which we take to mean a French person and that divergence is then eight percent backs up like five hundred a Chinese individual similar and some of the deepest divergences that mainly in Africa which is at like 10% so the Neanderthal is something like 50% deeper as typical non Africans and then like 20 30 % deeper than the deepest divergences we know of inside Africa there are some other parts of the genome that may be interesting to look at one is the Y chromosome the mitochondrial DNA we know a lot about and it's inherited on the maternal side from mother to offspring I mean only on the cuff didn't contribute that the Y chromosome is a cross inherited from father's to sons just a male side of history if you like and it doesn't recombine most of it so people particular Peter Underhill and collaborators have estimated a phylogeny for all Y chromosomes around the world and we find a typical pattern or where the deepest please go to Africans and then we find Africans and others here so what we can now do in among our Neanderthal reads it started looking for when we hit these positions that define these deep splits in the white chromosomal phylogeny and for each such position say well is that Neanderthal ancestral outside the variation of Y chromosomes in human males today or inside here and the answer is that for all such physicians have found the Neanderthal is ancestral so unless they carry some very rare variant here is clear that Neanderthal white chromosome falls outside the variation of modern humors how deep the split this we need more data to be able to say so there are a few other genes that may be of particular interest that we started hitting and one I want to spend a couple of minutes on is a gene called Fox p2 this gene is interesting because it was found a number of years ago by Tony Monaco in Oxford in a family that has a severe language and speech problem so when one copy of this gene is knocked out in an individual your big problems with producing speech so difficult for you so that naive listeners at least will not understand but family members will learn to understand what is the evolution is being altered looks interesting because in a tiny segment of it here with two amino acid changes in the encoded protein that's unique to use and differ from chimps and apes and other primates so of interest was of course to start asking while are these amino acid changes here that may be of interest specific to humans relative to Neanderthals are shared with them so a while ago we're now in our shotgun reads for the first time hitless so this is one of the positions the change in amino acids it's a CG in the him an alien modern humans and then the articles actually to our surprise turned out to have an a just like us so we went it after this more systematically by targeting this piece of DNA in the two Spanish Neanderthals from that cave I described doing lots of controls to make sure the mitochondrial DNA and the Y chromosome and so on is ancestral and really Neanderthal like here and it turns out that both these positions in both this other Neanderthals are really derived just like in modern use so it means then that from the point of view of the only gene we know has to do with language there's no reason to assume that they were different from us but there are cost many many genes we don't yet know that also have to do with language that we just haven't found yet that could mean that they were different from us but from what we little we know about the genetics of language when the undertones may not have been different from us so this one means that these changes in fox p2 were older than the separation from any other calls they're also actually evidence that something more recent happen in this scene so the native still be something human specifically but what I want to focus about on a few minutes is them well this amino acid changes but it's then mean that they are really not very interesting for origins of humans since they are not different from the Neanderthals and how can we ask that question and it's a general question in this field I think whenever we now find something in our genome that we think is of the interest of being a fully modern human how do we ever point make our point or that'll prove our point since we cannot do experiments in humans and for definition we cannot easily look at animals because we look at human specific things well my idea about this is that we have to try to use animal models in sound form after all and in this case is actually rather easy because these two human specific changes are localized to one little part of a gene ear and apart from that this gene fox p2 is very conserved so if you compare a human to Mouse there's only one other difference here a conservative difference in the protein that's encoded so if we just in the mouse exchange this part of the gene for the human here we essentially create a human gene for fox p2 in the mouse and you can do that of course by targeting this gene from all of this recombination in Mouse stem cells you can get rid on the selective markers you need here in the vicinity so you then have a mouse that from its own fox p2 gene makes essentially the human protein so then you have the next problem that we've found ourselves in front of two years ago then you have this Mouse you look at it and how do you test for its linguistic ability so you try to speak to the mouse within that for six months and nothing much came out of it so what we then said is well obviously it could have to do with almost anything since this is a very conservative it must be involved in many functions in all mammals actually so we started a collaboration with something called a mouse clinic in outside Munich in southern Germany where they do various oral health checks on that mice much better than what you get when you go to the doctor just to give you a feeling for this test here in bone density the pathology muscle strains startle response hematology I find from lack function blood pressure EKG and so on all in all they analyzed the mice for three hundred and twenty three different genotypes not all of them independent of each other many very correlated but it's still a much better health effects than what you get at the doctor always comparing his humanized mice to lift their manes that have been borne by the same mother together with them but where wild-type didn't have this human form of the gene and around it two features in which this mice differ from their litter mates at our wild-type the first one I have not easy time to think about maybe their ideas from the audience and that is that there are slightly more cautious in a new environment so you measure that by having them in a social group the mice get to go in and explore an open area might seem more comfortable along the walls here and you see that the humanized mice the humanized mice here only ever in the initial phase go into the center where's wild-type mice or Boulder but so this is just a transient thing for the first few minutes in a new environment the humanized mice are more cautious as I said I have no idea what this is about the other feature were the different really not me with my heat almost and that is that they have altered vocalization the measure vocalization in the tops that are removed from their mother you have a microphone here and a key to get the mother to come back to bring them to the nest and you record that and we work with people that are an expert in analyzing sonograms of these organizations and are a number of features you can look at the peak frequency starting frequency and so on and there are a number of features such as the slow appear with a humanized mice differ from the wild-type mice and actually the heterozygotes that one copper the humanize was or in between there's other things you hear that are the same and others here so this is very encouraging to me it sort of supports idea that this D that use changes in the scene that happened on the human lineage actually something to do probably with massive coordination or cell of the whole forest the millisecond control we need between our vocal cords the tongues lips to produce articulate speech and we now have a mouse model where we can begin asking about the neurological background for those changes over the next few years so what happened with this year is this change he has shared with renowned atolls and as I said there is also something more recent that have happened that we don't know what it is that didn't change the protein directly made this expression or something like that that you're also actively looking for at the moment there yes before we end the last few minutes to Morgan's I want to mention or to mold parts of the genome one is the huge region here on chromosome 17 which is an example of several rock parts of the genome where people have suggested that this might have been contributed by Neanderthals into modern humans when they came into Europe of Africa than forty thousand thirty thousand years ago and this region is special in that there are two versions of this game that exists in modern humans today there's a deep divergence between these two forms that go back almost three million years here two very very deep divergence what is also very interesting is that whereas one of these versions in humans today are a lot of variation another one has very little variation although it's quite high frequency in Europe particularly so since it's as little variation it suggests it's a recent change that spread quickly it looks like it had been on a positive selection and in fact there is a study in Iceland that shows that women that Karen this version of this part of the chromosome as higher fertility than others there seems indeed to be positive selection or Nami and since this occurs particularly in Europe and Western Asia it is a question suggested that this comes from Neanderthals into modern humans and is positively selected so we now got the chance and to look at this in this firstly under calling sequence so this is the number of positions in this huge segment nine hundred base pairs and we see the frequency difference from the percent frequency difference in the yellow ones here between the one version and this is a positively selected one specific for Europe and if you look at the basis in each of these positions you will see that in each position here it actually carries the common variant that we find all over the world not the one we find in Europe so the two chromosomes in this first Neanderthal from Croatia resequenced clearly does not carry this variant that is suggested to come from the underdog because we will have to look at in more Neanderthals a time goes but I'd like to point out that we also find this in Africa at very low frequencies that come back to that in a second so another game where the stories were is similar is microcephaly not chromosome eight this gene is quite interesting because it's a bit like fox p2 when it's mutated in humans you have a very small brain a chimpanzee like brain but of normal structure and just a mild mental retardation if you look at the variation is this gene in humans today it also quite old go back 1.7 million years himself and again there is one version with little variation but that is quite frequent and exists particularly outside Africa here so this again been suggested by Bruce alone but this is contributed by archaic forms of humans such as Neanderthals so we have now been lucky enough to hit the diagnostic position in this where where the derived version the one that exists outside Africa has a sea others have a gene so this is the positions where humans and most humans have a G and the Neanderthal turns out to also have it to not have this version that exists particularly in Europe and Asia again this variant exists also in Africa it's not absent in Africa so I think at the end of the day for most of these things that have been suggested to come from Neanderthals into non-africans that exists today when they came out of Africa I think instead what has been going on in most cases it's actually that when modern humans originated somewhere in Africa probably as we've heard in southern Africa a spread first across Africa in incorporate some deep old variants here that they took women when they left Africa and yes from drift in small populations some of these came to high frequency in non-africans today we can also now start asking much more directly what happened when modern humans came out and met named in Europe and Western Asia did they mix or not in a more statistical way all over the genome and to do that we make use of what has started out by talking about that if there was no admixture across the genome that in the end it all would be equally distant from people in Africa today as from people in Europe if the voice admixture then the under toss would an average feel a bit closer to Europeans than it would be to Africans so to ask that question we need to look compare the Neanderthal to variation we find today in humans and we need to look at that variation in a very objective way because there is a problem that most work not only has we heard before lunch in paleontology have been done in Europe but most genetic work has also been done in this country and in Europe in people of European descent so if you like just look at what we know about genetic variation it looked like Europeans are most valuable but that's just because we've studied them more overall as I said we know Africans are more valuable so in order to look objectively at differences we decided to just compare one single African to one single European of European descent and just look at positions where these two individuals happen to differ from each other and then we have these two individuals here with a difference and we take the Neanderthal and we say on average across many such positions how often is in the under-told as the European how often is it as Africa if it on average is closer to Europeans that would argue for the inflow if it's equally distant from them it would argue at Ninian because it's an earlier divergence all over the genome so just to show that this really works it would take another European today and sequence with the same technology as we use for the Neanderthal we find that in 63% indeed European looked like the other European rather than the Africans 63% of such cases when we now take our Neanderthal date and do the same analysis it looks like this almost dead 50.2% so this 0.2% there is compatible with an admixture or contamination in our in our date of 1.5% but it's also compatible with zero as you see here it's as we now go on until the whole genome will have much more power to detect even a small contribution but it's very clear from what we see today that if the most contribution from the Neanderthal it is very very small indeed so to wrap up then the big picture all over our genome is clearly one of a replacement could have been some little contribution but if it was it was quite small so to end them I think that is quite good news for this Neanderthal genome project actually because if we think for a minute about why are we doing this why are we putting so much effort into getting a Neanderthal genome there are really three reasons for it that I want to mention one is quite obvious and we already discussed it that is that there's quite this is quite long lineage from the separation to the same here five hours to seven million years so so having the genome of a Neanderthal would be able to divide up all the genetic changes on the image in those that are very recent and unique to us very source that are older and we already know that this is around 12.4% for the differences here we will have human genome we already have the chimp you know we're 35 million positions where they differ we'll have one Neanderthal and find the 12 percent of positions whether Neanderthal extinct lines the second big old we have is a little more subtle and it makes use of this thing we mentioned that variation among humans that live today is so big so it goes back to before the separation from the undertows goes back before three four hundred thousand years so that of course that means that in an average part of the genome if you look at positions will be varied today we will know which is the old variant because we have that in the chimp so in this case the T is a new mutated Miriam so to say in quite a few such positions will be very than the undertone will actually have the new derived mutated line that's not in the chair in average part of the genome but in positions with something interesting happened recently where there was a positive selective sweep in humans since we separated from the Neanderthal in such positions of course it means that in that part of the chromosome something happened some variant has spread to all humans today because it had an advantage there of course the variation today is per definition more recent than the separation to the Neanderthal so in summary in the Neanderthal we always look simpler so what we will do is use two or four million positions who will know about resume is very today we know that ancestral old condition from the chin will have a single Neanderthal and we look in the window and in any average window some positions Eunice the Neanderthal women had new nutritive variants in other machine one was slide that across the genome and look for regions like this verse and a little Neanderthal looks all Jim people because there something interesting seems to happen something positively selected since we separated from the Neanderthal so goals this is cataloger changes that are recent shared among all humans today but different from the Neanderthal evidence of positive selection and eventually of course also looking for Neanderthal specific features although that will really have to await a much better Neanderthal genome over the next two or three next years so with that I should end and I'll say that what I presented the produce production of the sequences is an intimate collaboration before five for life sciences in Branford Connecticut my key role in particular that worked with us in Leipzig on this should say that this is a close collaboration also with the paleontologists that excavate the fossils particularly with the team in Spain that excavator Seadrill and also people in Croatia some of the analysis I showed of the snip analysis have been done by David Rives and the molecule at the Broad Institute in Boston and they've energy or I and I should also end up by saying that we will as you notice produce a lot of data over the next few years so we are looking for people to help us with analyzing all of this if you are interested in buying informatics or Genome Sciences please talk to us thank you very much could I ask the other members of the panel please to come up and join us table here and we'll begin the Q&A session and perhaps five minutes here ladies and gentlemen yeah ladies and gentlemen could you take your seats please we'll be in the Q&A session here in just a moment okay whoops okay - unclear hear me the problem is when you okay all right ladies gentle let's take our seats here and we'll begin we'll ask other members of the panels if they have questions or comments Dr Weber was talk dr. Dunbar I'll just go back to the Fox PG stuff really very interesting waveless when it first came out for this kind of trumpet is the gene for grammar what you're clearly showing with the math stuff is that actually something to do with the capacity for vocalization which kind of M makes it very interesting in the context whether Nanda tars had language as we know and love it or whether they had some other form of vocal communication and this is raised one of the possibilities that Preet the precursor to language before full-blown modern human languages came in the grammatical structure was a kind of vocal chorusing sort of singing the end of John would have any comment not really any comment I mean I think that yes when this gene was first described it was actually talked about as a grammar gene or the language gene and as I understand the consensus now among the people who studied as really based on rather bad clinical work there that the problem was in the families one of articulation is a sort of basic problem of muscle coordination in the world Forex and it seems them at least human specific substitution also had something to do that it may be that Fox b2 does other things also that has to do with communication it's actually fascinating that if you look in birds in songbirds if you knock down this gene interrupt it you disturb vocal learning in when they learn their song and I just learned the other day that vagine has now been found even in octopus and it's actually expressed in the neurons where octopus make counter signals to mate or aggressive signals so it seems to be incredibly conserved and have to do with communication I've been hosting just to add to that I wondered about this you know Steven my friends book that maybe thirteen now doesn't even make sense then to to speculate about proto-language and for those who are interested in the evolution of language what might have been the case in terms of Neanderthal in terms either music or proto-language or do you are you cynical about that other than say that it might in the sense that you just said indicate some form of communication in the way of nah I try to really stay away from speculation and I say that from the little window there is from the point of view these amino acid substitutions there's no reason to say they were different from us as I said there is genetic evidence that something else that hit the scene there's some evidence of a recent selective suite that's actually different from the amino acid changes we didn't know that when we first published it but it's now obvious from the data so remain it still be something there but we have to find it first and define it and before that I wouldn't it seems obvious to me that the Neanderthals at the time must have had communication that was very similar to modern humans that live in social groups they took care of into people etc etc how about if I ask one more quick question I was interested in your conclusion about the el sidrón cave it seems like a very strong conclusion to go from scratches on the bones to cannibalism did I understand you correctly the others was eating our details yes yes it seems I understand from the paleontologist that it's more and more common now when you look for the traces of defleshing and it's of course but this also discussion is some ritual that has to do with burial or so or is it actually consuming your fellow Neanderthals digging in that cave although I'm not an expert I do think it looks rather more like eating your neighbors is it's a group that seems to have been washed into the cave at once time that's to infants to adolescents and adults the the hands are in one part of the cave rested somewhere else it looks pretty green to me I was gonna find out that it's not unique to Neanderthals there's a site on the coast of South Africa called claw sees river mouth that has a series of hominid remains these are Homo sapiens that date around anywhere between 70,000 and 90,000 and there's a very high frequency of stone tool cut marks on the human remains as well and then in fact the the frequency of cutting is higher than it is with the antelope loans that are in that collection but it's always difficult to go from that pattern to an interpretation of what it means is a cannibalism for the purpose of food or is it some more ritualized bodily defleshing activity and at least with the South African material we don't have a big enough sample to say one way or the other but but the the pattern of stone tool modification of human remains cut marks and hammerstone percussion marks is fairly common in the Paleolithic another question I am the toss at that time at least as far as we know there were not yet modern humans at that time in IVM Peninsula dr. Feldman do you think it's fair to use mutations like fox p2 and microcephaly which have huge developmental impacts on the human carriers to ask questions about evolution at the structural level we're all interested in so I think that finally these genes are found because mutations in them yes give disease phenotypes in humans very very serious depends on how serious I mean a articulation problem how serious on those two but this is one way of finding genes that are involved in these pathways of course we can now go and look for the target of fox p2 what I didn't say is Fox p2 is a gene whose function is to turn on and turn off other genes so I can of course look for the target so that gene and the gossip or special evidence in in those but it's perhaps of limitation also of where we are in human genetics today if we are interested in genes in language for example we're really two big extent limited to studying pathologies of language define these things they often turn out to be pathologies of other things too and that's some of the problems they're not just pathologies of language they developmental abnormalities as well this is an Internet question here that came how do you think that these genetic modifications that resulted in say the microcephaly gene have been able to persist so lon they're so far-reaching considering that the phenotype results in a smaller brain what's so so that the mutation that causes little the smaller brain size it's very rare in the Qura just in rare families in in Pakistan and in seen sign a the gene itself is necessary for the development of the brain it's in conserved in all of us since this notation and that's very very rare what do you think the potential is for finding ancient DNA from that dates to the time period of the early modern in Africa so I think from the top point of view how old it is it should be possible what makes me skeptical is the warm climate that it's very clear that the warmer it is the worse it is for DNA preservation so we have tried some the undertones in the Middle East none of them have worked we tried some animals from blombo's came actually and didn't get anything so maybe one finds very deep inside with cold temperatures but are there any other conditions for example maybe in bogs so another important factor is pH acidic conditions are very bad the most bogs in Europe are a city in Yucatan Peninsula for example in a Florida particular or alkaline box that are quite good for DNA preservation but these are the rare cases extract DNA they will help unravel the issues of the people of the Americas yes I think partner Frost's are excellent conditions and there are magnets for example they're up to 70% of all the DNA in this specimen is actually from the mammoths now here we have a question from the audience is when you look at the chimpanzees and the modern human and talk about positively selected genes why did the ancestors of the chimps not also have why weren't they selected for that positive trait as well is it the assumption that the chimp has not changed in the last seven hundred thousand years no so actually there was lots of positive selection in the shims to only that was chimp positive selection so if you look for just evidence of positive selection on the chimpanzee lineage and a human lineage there's even some evidence although is probably not so safe confusion that there have been more positive selection in the chimpanzees than a headband in humans there's another question what what specific characteristics actually determined or distinguished Homo sapiens from their predecessors I was at all the genomes and DNA or the other distinguishing characteristics probably more a question almost for a paleontologist of course what our million-dollar question in our field would be to find the few genetic changes has actually made a difference then we can of course discuss culturally and behaviorally what are these major things that distinguish us from archaic forms of humans from Neanderthals or the common ancestor humans and Neanderthals it's one thing that tends to strike me for example when we look at the presentation this morning is that these earlier forms of humans as you said left Africa 2 million years ago the first men never came to the Americas never to straight yeah exactly actually no evidence they ever cross water where you don't see land on the other sides they were quite sane then comes early modern humans Out of Africa for two thousand years ago and in those forty thousand years ago we go to the Americas Australia down to every little speck of Island right we go to Easter Island and now we go to Mars there's no trace in us there mr. glass their question about your fox p2 mouse we saw the mouse that had the human fox 2p gene variant is there a fox p2 mouse knockout gene that doesn't have that gene and what does this look like yes that's a very good question if you know count again and we and others have done that in the homozygous form where you have both copies destroyed you actually don't survive at all you died shortly after birth and if you have one copy knocked out like this family in Britain or in the mouse you have a number of in the mouse you have a number of muscle coordination problems and problems with lying and many physiological issues that happen you're actually quite sick sick as a mouse and as a human question to the Basques in the mountains near Spain are claimed to have a unique genetic history do you have any information on how they may be related to yes you should be careful we've just saved but I'd busks that bones some things and they're actually just as modern humans as all of us are there's no special relationship there whatsoever slanty there is some suggestion that they the remnants is the kind of original modern human occupancy replaced by the indo-europeans nearly over I mean is that still people worked on that maybe more yeah two lines of evidence one is that their language doesn't fit on any language tree of non languages languages in somewhere close to Siberia like the Everson the other thing is that they're the only population on the planet that has a higher rh-negative frequency than rh+ so there is something strange about their evolutionary history but maybe due to simply due to their isolation in the Pyrenees but nobody knows beyond that okay well here's one final question the practical significance for is how useful and valid are the DNA swabs presented by various websites I think that of course it can be interesting to relate for example your mitochondrial DNA to that tree of all the mitochondrial DNA there I think you should not forget if you do that for example that that's a tiny tiny little fraction of your genetic inheritance there are shaft groups at these sites where everyone in the same related mitochondrial DNA gets in and talked to each other and it seems to be ridiculous to him it seems to be just like astrology is related to astronomy this form of genetics is related to what we do there are three companies that are competing at the moment for that market that I regarded as legitimate and they each has two components to it one I call recreational genetics which is where you ask what places on the plan your ancestors might have come from the other one is not so recreational and that is the company has huge databases and they look at your DNA not just the mitochondrion not just the white chromosome but lots of the rest of the old genome and has a list of the variants that may predispose you to certain traits and there are about 12 disease traits which are currently accepted by the genetics community as having a single change in the DNA which is a good risk marker the risk may only be an added two or three percent but that's something that you might want to know about so those are the two things that the companies do and the good companies on their website say exactly what they do and they're very clear about what you can expect from the information and how to use it well at this point I think we should break for a little coffee remember this will can be found in the forum which is the building just to the north of us here we'll assemble here once again at 3 o'clock

Channel: Gustavus Adolphus College

Views: 13,271

Rating: 4.8709679 out of 5

Keywords: gustavus, adolphus, college, Svante Pääbo (Academic), Nobel Conference

Id: YSQ_BeSH094

Length: 82min 14sec (4934 seconds)

Published: Thu Aug 20 2015