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this ucsd-tv program is presented by university of california television like what you learn visit our website or follow us on Facebook and Twitter to keep up with the latest programs we are the paradoxical ape bipedal naked large-brained long the master of fire tools and language but still trying to understand ourselves aware that death is inevitable yet filled with optimism we grow up slowly we hand down knowledge we empathize and deceive we shape the future from our shared understanding of the past Carta brings together experts from diverse disciplines to exchange insights on who we are and how we got here an exploration made possible by the generosity of humans like you you well thank you very much for the introduction Ann and to the organizers for inviting me to participate in the symposium today and also to all of you for coming back after the break so it’s nice to see everyone again so I’m really happy to have the opportunity to tell you about some of our recent work on mapping archaic common and DNA in the genomes of modern humans and actually my talk you’ll see is going to be pretty similar to our first speaker Shriram and in fact when he was talking I was thinking to myself how nice it was actually that some of the things he was saying overlapped with what I was going to talk about because we were working on these projects completely independently we developed very different statistical methods to answer the same questions and yet by and large we came to many of the same conclusion so I think it engenders confidence and the things that we’re presenting today and my graduate student Benjamin Brno and I first became interested in this question of archaic admixture a few years ago and I think this is actually one of the most fascinating topics in all of genetics and genomics these days is all of the things that we’ve learned from ancient DNA sequencing and one of the more contentious questions I think in human evolution has been whether or not modern humans made it or hybridized with archaic humans like Neanderthals and Denisovans and for many decades this was just sort of an acrimonious debate and that was largely because the data didn’t exist to answer the question but with technologies developed by Svante Paabo and some of the other speakers we’ve heard from this morning matthias and kai in the not too many years ago we were able to get high-quality genome sequences from the Neanderthal and d7 genomes and this provided sort of unambiguous evidence that modern humans and these archaic humans did in fact hybridize and exchange genes and as matthias talked about this morning though studying ancient D a from fossil still remains really challenging because you have to find an appropriate specimen first of all and we have to hope that the DNA has been preserved over hundreds of thousands of years so my student and I thought well if there was gene flow between modern humans and archaic humans maybe we could excavate ancient DNA not directly from fossils but indirectly from the genomes of modern humans and to give you a sort of a little bit of an intuition of how this works I’d like to argue that a little bit of archaic introgression goes a long way and so in this schematic I’m

showing you a picture of ten or so individuals these aren’t random individuals these are my colleagues and the department of genome sciences and this is what happens when you put your picture on the Internet so so each line here let’s imagine represents a stretch of each person’s genome and from previous work we knew that all non-africans had about 2% of their DNA inherited from Neanderthal ancestors and that’s what’s represented by these yellow chunks of sequence and so what we wanted to do was develop a method where we could walk along an individual’s genome and pull out the parts that were inherited from the and earth all ancestors and the key here is that the 2% of my genome that was inherited from Neanderthals might be a little bit different than your 2% so that when we aggregate the data across many individuals we can actually recover a substantial amount of the Neanderthal genome and actually what I find most compelling about this approach is that as opposed to sequencing ancient DNA from a single fossil by recovering these all surviving archaic lineages were potentially getting data that was getting sequences that were inherited from multiple archaic ancestors so we’re getting population level data and that will allow us to make inferences that are difficult or impossible to do if you just have genetic data from a single individual so I’m not going to talk a lot about the details of how we scan along an individual’s genome and look for our K X sequence but I did want to give you a little bit of intuition so what are the characteristics of interest archaic sequence that we look at well what I’m showing you here is a simple schematic showing that Europeans diverged from Africans about 80 thousand years ago or so and what we want to find or if we look at lineages superimposed on this tree we can see that what we’re actually interested in finding are cases like this so sequences that are found in non Africans that were inherited from a Neanderthal ancestor so what are the features that we expect for these types of sequences well the first is that in contrast to to modern human sequences that have a much more recent common ancestor mutation will have had a long time to act and accumulate we want to find these sequences so mutation will have had a longer time to act and accumulate on this lineage compared to to modern human lineages but the other key feature is that admixture happened relatively recently so in the last sixty to eighty thousand years or so and therefore the Neanderthal haplotypes will still persist over sizable genomic regions so it’s this combination of highly divergent sequences that stretch over large genomic distances that allow us to accurately and robustly predict what our archaic sequences versus what our modern human sequences and actually the approach we’re using is a modification of a statistic called s star that was developed by Geoff wall and one of the nice things about this approach is it doesn’t explicitly use the Neanderthal or the niece of n genome when making the initial inference and the really powerful thing about that is we can potentially discover archaic lineages from groups that we don’t even know about yet and actually that’s a major part of what we’re looking at now but that will have to be a story for a different day so what I’m going to tell you about though is applying this method to 1500 geographically diverse individuals so whole genome sequences from about 1,500 people all throughout the world these are largely sequences from the thousand genomes project so this is a publicly available data set but to supplement this we also sequenced in collaboration with Svante Paabo group 35 individuals from Melanesia and the idea here was that we knew from previous work that these individuals should have substantial amounts of both Neanderthal and d7 sequence and if we look at the amount of archaic ancestry that we find per individual that’s what I’m showing on this slide so this shows the distribution of the amount of archaic sequence per individual in Melanesians East Asians South Asians and Europeans and you can see that Melanesians have on average much more archaic sequence per individual compared to some of the other non African groups and the reason is as I just mentioned they have substantial amounts of both Neanderthal and Denis event sequence and so each row here is

an individual and the bar plots correspond to how much Neanderthal versus the niece of in sequence each individual has and if you look closely there’s a small amount of sequence that we label as ambiguous this is sequence that we are confident is archaic in origin but we can’t distinguish robustly at least whether or not it’s Neanderthal or Denis ofin okay so on average Europeans have about 50 to 55 mega bases of archaic sequence per individual and this is largely Neanderthal in origin South Asians have a little bit more East Asians have a little bit more in Melanesians have about on average a hundred mega bases of archaic sequence per individual so that’s a hundred million base pairs so that’s great we can identify archaic sequence but I think the really interesting thing is the things that we can potentially learn from it so what are the types of question is that surviving archaic lineages allow us to ask so I’m going to tell you about three things that we’ve been interested in so the first is was hybridization between archaic humans and modern humans deleterious that is where they’re bad consequences conversely was hybridization beneficial or were there some good consequences of hybridization and finally what demographic model is consistent with patterns of interests archaic sequences so let’s start with the first question were there deleterious consequences to hybridization and one of the most striking things that we found when first looking at patterns of Neanderthal sequence across the genome is that it’s very heterogeneous lis distributed so I’m showing you sequence sequences from chromosome seven eight and nine so the blue pics represent places where we find Neanderthal sequence in European individuals the red line indicate places where we find the and earth all sequence in East Asian individuals and the grayed lines represent parts of the genome that are too repetitive for us to study and be confident in the predictions from and so if you squint long enough that this figure you can see that there it doesn’t appear and Shriram mentioned this earlier that patterns of surviving sequence are sort of randomly distributed across the chromosomes but you find these regions that have been called deserts or depletions of archaic ancestry that extend over really large genomic regions and this is consistent with their being deleterious consequences to having the nderful sequence in these regions and in fact when we do extensive simulations and try to model this process we see that there’s an excess in the observed data of these depletions or archaic deserts compared to simulated data under neutral models of evolution so what does that mean it just means basically that under neutral evolution so where there’s no fitness consequences to the Neanderthal sequence we really wouldn’t expect to see deserts this large in the real date so I think this is pretty compelling evidence that there was deleterious fitness consequences to hybridization and what’s really kind of fascinating to me is that if you also superimpose Denice event sequences on top of this data you find that there’s a significant overlap between Neanderthal deserts and Denice event deserts so the same places in the human genome that are depleted of Neanderthal sequences are also depleted of Denice event sequences and again this is very consistent with the idea that these regions may be are harboring genetic changes that are very important to modern human phenotypes so for example the largest region or the largest depletion is on chromosome 7 it’s about a 15 mega base desert so there’s lots of genes one of the challenges in interpreting these regions is that in a 15 mega base sequence there’s about a hundred genes or so so you don’t actually know which one is driving the signal that you’re interested in but one thing that caught our eye and a Shriram mention this morning is right in the middle of this largest desert is a gene called fox p2 and fox p2 has previously been associated with being important in speech and language and in fact work from spawn T’s group has shown that there’s human specific mutations in regulatory regions of box p2 so again I want to be careful here and we haven’t proven that fox p2 is driving this depletion of Neanderthal sequence in this region but it’s really interesting and and I think these deserts of archaic

ancestry can help us pinpoint places in the human genome that might be important in modern human evolution so the search space is much narrower now compared to when we first did these studies another question that we were interested in asking is well so it seems like there were some deleterious consequences the hybridization was there also evidence that maybe some of the sequences we picked up from the end of or Denisovans was that beneficial and probably the simplest way to look at this question is to look at the frequency of Neanderthal or Denis event sequences in modern populations and that’s what I’m showing you here so each dot represents a frequency of either a Neanderthal or a Denisovan haplotype in East Asians Europeans Melanesians and South Asians and you can see that for the most part the vast majority of archaic sequence that persists in modern human populations is pretty rare so usually less than ten percent frequency but there’s a number of regions that have risen to high frequency those 60 percent in some cases in some cases even a little bit higher and we’ve done extensive modeling again to try to determine how likely it is to see these high frequency haplotypes in the absence of selection and it turns out that above you know 50 percent or so it’s actually really unusual for a haplotype to randomly drift up to such high frequencies so there’s about a hundred or so I think really high confident targets of adaptive introgression and you might wonder so what what phenotypes were influenced by adaptive inter aggression and so we knew previously that a version of a gene called epas one in certain Tibetan populations was inherited from Denisovans and it’s this gene that allows them to live at high altitude so there was already some pretty good a priori evidence that admixture with archaic humans was beneficial for some genes and when we look carefully at these hundred high-frequency archaic Apple types we see that they are largely comprised of genes that can be categorized in the two classes one the immune system so many genes that influence immune phenotypes and in particular innate immunity so the part of our immune system that deals with viruses bacteria so that seems to be a very enriched target or substrate of adaptive introgression and I think you could have predicted this a priori so it’s known that the immune system is often a target of selection but the other category of genes that actually I would have never predicted a priori it turns out to be a number of genes that have important functions in skin biology so for example one of these genes as as sure you are mentioned is B and C – – gene called basal nuclei and – that has recently been shown to influence skin pigmentation levels in europeans and so it’s a very high frequency each row here again is a individual and columns are variant sites and these individuals carry the Neanderthal haplotype and you can see that it’s a very high frequency haplotype in Europeans not found in East Asians and finally and real quickly I’m just going to give you a brief synopsis on the things we can learn about demographic models and whenever I think of demographic models this image from National Geographic comes to mind I think it’s sort of a fascinating picture actually my kids really like this too because they say I look like him but that’s a different story and so one of the things that we can try to learn well we want to know things like when when did hybridization happen how many times did it happen the different populations have the same or different admixture histories now the postdoc Joshua Schreiber who developed a really clever method of trying to infer whether two populations had the same admixture history or different admixture histories and so when we apply this method them two pairs of populations that we analyzed the details here are important but we can infer sort of this general picture of so this is Europeans East Asians Melanesians Africans Neanderthals and Denisovans and the main point I want to impress upon you is that maybe even compared to as certainly as a few years ago it seems like the admixture history between modern and archaic humans is much more

complex and in fact the data is consistent with multiple pulses of admixture between Neanderthals and modern humans and at least one pulse of admixture with the nice ovens so in conclusion I’ve shown you that substantial amounts of the Neanderthal and Anissa van genome remain scattered in the DNA of modern humans but there were Fitness consequences to hybridization both good and bad and that the history of contact was much more complex than previously thought and I would like to thank people in my lab so this guy right here in the middle is Benjamin verno he was a graduate student who was now a postdoc with Svante Paabo but he by enlarge did most of the work that I talked about today so with that I will thank you and I guess answer questions after everyone’s done so I would like to start with acknowledgment so the work I’m going to present is actually the work of many many people who are involved in sequencing these two genomes I’m going to talk about and helped analyzing them I will give some more credit during the talk so let me start by just introducing the samples that were used to generate these sequences so both of these samples were found in DD so our cave and our Altai Mountains in Russia and one was actually a small finger bone that you see here on top yeah and another one was a small toe bone that you see on the bottom and the reason that we are actually having two genomes from the same place has to do with the fact that the Denisova cave actually preserves the DNA in these bones particularly well it’s one of those exceptional places where most of the DNA that we get out of these very old bones really comes from the individual that died and are not from bacterial or microbial contamination and so what this allows us also to do is to not just sequence these these genomes to a low coverage meaning just a couple of sequences from the nuclear genome but we can actually sequence them many times over and how this looks like then is that you have small sequences stacking up like this that are distributed randomly over the entire genome and you’re you always have several of those for each position and so taking together you have 30 fold coverage meaning at any position in it or on an average position in the genome you would have 30 different fragments for the pinger bone and for the door bone you have 50 fragments and so using these genomes then to actually understand how they are related you see that one of those two genomes that we produced from this cave folds together with other neon the task that we have sequence before to lower coverage and we call this the Alton yeah Notah and the second individual the nuclear genome is from a sister group of of Neanderthals that we call the denisa one because they are fall outside of the variation that you observe of Neanderthals so they are more closely related to Neanderthals but they are not not looking close enough related to deserve to be just called in Indiana Thailand via rather call them a Denise one and so one of the questions that you might ask yourself is why are we actually bothering with sequencing these genomes so deeply why do we sequence them 30 or even 50 times over and the reason for this is the fact that we are diploid organism so we are actually having each chromosome twice one complete set are inherited from them is inherited from the mother and another complete set of chromosomes is inherited from the father and so one of the things that you can do it when you have so many fragments in so many sequences is you can call confidently the differences between these two copies that you have from the mother and the father and this is really the reason why your sequence it’s so deeply so that we can call the differences between these chromosomes and one of the most easy analysis that you can actually do once you have sequence so deeply and call these differences between the chromosomes is to just ask how different are they on average and so this is called hetero zygosity and you can actually put this into perspective by also showing as in this plot the level of heterozygosity so the level of differences between the chromosomes in modern humans in present-day modern humans and we have some individuals from Africa here and some individuals from outside of Africa and what you can see is that Africans have about one in a thousand differences between the chromosomes that they inherited from the mother and the father by non Africans

have between six and eight and ten thousand and the archaic Tsar much reduced compared to both of these present-day human populations or present-day human regions and they are at a level of two to three in 10,000 and as even a quite significant difference between the two our cakes and that the Denisova is higher than the Neanderthal so in the ana tile is further reduced and so one can actually look into this in more detail by looking over the chromosomes so just going in a small window over the chromosomes and just counting the differences that you observe and we have done this here for French individual detainee so far and the altai neanderthal and what you can see is that the level of heterozygosity is with the differences between the chromosomes varies over the genome um but there’s one thing that is very special and that is that the altai neanderthal has this as this very long stretch here for instance on chromosome 21 there are other stretches like this on the other chromosomes where there’s hardly any difference between the two parental copies and so now what one can do this one can actually take the size of these stretches and how much of the genome is actually residing in those stretches to calculate back how closely related the parents would have to be to generate stretches like this and this is an analysis that flora faith won in Monte Slatkin slab and Berkeley was carrying out for for the analysis of the altai neanderthal genome and what you found is that there are several different relationships between the parents possible that would actually generate exactly the patterns that we see and so I guess one easy way to say this is that the parents of this individual would have to be at least related on the level of whole siblings to generate these these patterns so they were closely related and then you can take a step further and you just take your prediction of how much you would actually expect in terms of long stretches that are looking like this almost identical and you just ask if I would subtract now based on what I what I understood the family relationship of the parents would be if I subtract this away today actually anything left and this isn’t in fact the case so for the Alton Jana time you still see an excess over dere these stretches that you see in the Denisova and in modern humans and this actually means that this is not just a singular event that just once happened that just by chance the parents were closely related but all of also further back in the past they were probably closely related ancestors and so another topic that I would like to talk about is our cake admixture and so we already heard about a cake admixture from Neanderthals and Denisovans into modern humans what I would like to talk about this really archaic admission between both our cakes but before I get to this I would actually like to go a little bit deeper into how we actually know what signal you have to look for to understand that there’s vd8 mixture and so as a very simple way of depicting this just imagine that you have a certain individual and of course as I already explained every chromosome has two copies so this individual has these two copies of of a certain chromosome an arbitrary one so when you’re of course you can go back to is to his parents and one of those copies will come from the father and the other one will come from your mother so I can paint them now blue and read em but I can also go a step further and actually paint them according to a whether they come from the grandparents or from which grandparent and what you see in this picture now is that there is actually a process called recombination that is actually mixing up these different chromosomes in the parents of the individual so now you have kind of these random stretches from both from all the grandparents that are painting these chromosomes and you of course you can take another step another step another step and so essentially what this means is that you’re breaking up the ancestry when when you go through the ancestors you kind of jump between different ancestries when you go over the chromosome so you change which ancestors genome you look at and so when you repeat this process for a very long time and let’s say or you have ancestry from one population for most of the genome but you have a couple of ancestors from a different human group hiding among your ancestors then what the most common outcome will be is that you will have these short stretches where one of the chromosomes actually shows to say this ancestry of this this other human group by the other chromosome is actually looking like the chromosome of the majority of the groups because these stretches will be randomly placed on your on your two chromosomes and now we can actually use the altai neanderthal and the Denisova to find out whether there is any Neanderthal

ancestry in indeed a nice oval or valid as any the niece of an ancestry in the Neanderthal individual that we sequenced and so in one direction just showing so if Neanderthals would contribute to the Denis Sivan what we would expect is that there are some stretches where the Denis Irwin looks very much like a Neanderthal but on the other chromosome we would expect that it actually looks looks like a normal – nice one that that means that the two chromosomes are actually very different and so the prediction that this makes is that if you go to two regions where is shown here on the left hand side so the X scale is giving you how closely related you can make this make and make any a particular window that you look through our closely related you can actually make that to the other other archaic so when you have Windows where the altai neanderthal is very closely related to the Denisovan shown here in blue you actually see no effect but if you look in the same for the Denisovans when the Denis of our has s can be made very close to village oak it looks actually very closely related to the altai neanderthal you see that the two chromosomes are very different and this is shown here in red at this position and so this is a hallmark sign today’s actually among the ancestors of the Denisova and some Neanderthal ancestry the last signal I want to talk about is actually the one of unknown archaic material that we found in the Denisovan and so the first signal that we saw for that is really just when you look for divergence to Africa so that’s nothing else than just looking for how many differences we observe we actually see when we take larger windows and we just compare to a to an African that it Anissa was always a little bit more different than the altai neanderthal so these two distributions that you see here they are did the one for the Denise over and blue which is slightly shifted to the right and you can look even deeper into this by actually looking at different allele frequencies and divide up your comparison in by how many Africans actually carry a certain derived variant meaning a new variant at that accured sometime after the split from chimpanzee and when all Africans are the same you actually see that the signal is strongest so you see the most differences and in an analysis that also Monty slatkin slab carried out in Berkeley with Fernando ASIMO M what they did was essentially taking the signals that did I just described and they tried three different models to actually compare how these otters could come about and so the first model assumes the dam was gene flow from Neanderthals into the common ancestor of all modern humans da second model is assuming that all modern humans actually gave some material – to the Neanderthals and so these first two models are essentially to explain how you could make the Neanderthals and modern humans more closely related and the last model is is is one where you have some lineage that we haven’t observed so we don’t know what it is that contributed to the Denisovans and that would make the DNI’s one more distantly related to the year two modern humans and so in most comparisons the model 3 was actually the best explanation that we could find for the data and so we believe that there is this super archaic admixture of some very deeply divergent lineage into the tinny salon and so what I would like to say in the end is or what I would like to show on the end is we did just a general overview of the different gene flows that we have now observed and this picture is not quite complete yet so what you can see is that we have the ancestry of this dis deeply diverged a deeply divergent ancestor that contribute to Denisovans we have the Neandertal admixture into the modern humans we have contributions from the ease of our to modern humans and the Indiana tar admixture in to the Denisovans that I just talked about and they are it seems that they are said by now there are also other publications that say that there are contributions to Africans and so on and so on and so I think what this all means when you sum it up is that these different types of admixtures are actually something that is quite common so it actually happens quite a lot in the past and that is something that is really a transition in our thinking because originally I think we were all very skeptical that there was actually any admixture between these archaic groups and with this I would like to end and say thank you for your attention thank you very much so I couldn’t have asked for a better introduction for I’m going to talk to you about here today we heard from several the previous speakers about the genetic legacy of interbreeding with Neanderthals but I’m

very interested in understanding what if anything is the phenotypic legacy in modern human populations is this Neanderthal the DNA that remains in us is it functional and if so what function does it have and so as we’ve seen thanks to the pioneering work of many of these previous speakers we know that Neanderthal DNA remains in certain modern human populations and if we look at a schematic of a human chromosome here you can think of this as a long string of A’s T CS and G’s I’ve colored in blue all the locations where we’ve ever observed someone living today to have Neanderthal DNA in their genome and if you sort of look across many many thousands of European and Asian individuals you’ll see that on average around 2% of their genomes are derived from Neanderthal interbreeding as we’ve surd different people will have a different 2% my 2% is different than Ed’s 2% of and Anne’s 2% and I want you to remember that because this is a really important feature that we’re going to use later to try to understand the function of these different bits of Neanderthal DNA that remain in our genomes and as some parts of our genome are more likely to retain the and or tall DNA than others so in one extreme we see these Neanderthal deserts like the position here on the the right hand side where we’ve never observed anyone to have in the and earth all DNA and then on the left hand side we have the other extreme where we have up to 60 percent of European individuals if you went out and sequenced a bunch of European people would have a Neanderthal DNA at that location and so ultimately this suggests that Neanderthal DNA had an influence on our ancestors after the interbreeding in some cases perhaps positive in other cases perhaps negative and so for me this this raised a very big question that I really wanted to answer is okay so then what is the phenotypic legacy of this Neanderthal interbreeding in the DNA that remains from it in modern humans and so I I hope if you if you remember nothing else from my talk really just two main points the first is that indeed interbreeding with Neanderthals has left a phenotypic legacy in modern humans and the way I’m going to go about trying to show with that legacy has been is using up sort of a new type of resource that’s just becoming available and that’s of large clinical bio banks with electronic medical records from patients from hospitals linked to genetic information and this is a really really powerful resource for studying the genetics of disease but I also think it’s a really really powerful resource for studying genetics of our recent evolution and so if you want to you can go to sleep now and just remember those two things and I want I won’t blame you so basically we got the idea for this project because I collaborate with a big national consortium called the electronic medical records in Jeannette and genomics network and what this is is a collaboration of about ten academic hospitals from across the nation that have electronic medical record systems implemented in their in their hospitals and also genetic information from those patients linked to their electronic medical records and so this looks a little something like this where on the left hand side we have you know john doe’s patient record he’s been coming to the hospital and seeing doctors let’s say for the last ten years and we’ve got records of all those events and all the treatments he’s received in that electronic form and then someday john comes in to have blood drawn and he says yeah actually it’d be okay if you use any leftover material from from this blood draw for basic medical research and if he’s consented to do that then all that information is sent through a de-identifying process where all the identifying information is removed from from that electronic medical record but the basics of the treatment history are maintained and then the blood sample is also passed through and bio banked and given an ID that links it up to that anonymized version of the electronic medical record and now this is really powerful because it enables us to do genetic Association testing on a very large scale so what is genetic Association testing well we can tell it let’s imagine we’ve got a number of patients here for which we have these these bio banked blood samples and let’s say we’re interested in studying something about their genetics well we can look at these blood samples and see at one given position in their genome whether or not they have an ATC or G and so in this example patient one has an A a patient two has an A and then patient n has a G and let’s say we’re also interested in heart disease and whether or not this particular location in those patients genome has any effect on their risk for

heart disease what we can do is then go look in their electronic medical record and say all right well as this person ever been treated for heart disease and let’s say in this case we find that yes patients one and two have and then patient n has not and once we have that information we can perform statistical tests for association between these individuals DNA at that given position in their genome and whether or not they’ve ever been treated for heart disease and so in this you know simplistic example we might say that yes having an A at this location in your genome increases your risk for heart disease now of course we don’t normally do this on three people we do this on tens of thousands of people to try to find significant associations between regions of our genome and disease and so now that this is all well and good but let’s say we’re interested in another disease let’s say we’re interested in arthritis in the genetic basis for arthritis well if we didn’t have this electronic medical record system we’d have to go out and collect a whole another cohort of people that had arthritis and then some matched control people that didn’t have arthritis and then genotype them and then test whether or not the genetic Llosa I had any effect on the risk but because we have the electronic medical record system we can instead just go look in the record and say alright let’s find a new set of cases and controls or arthritis and perform genetic Association tests again on the genetic information we already have so that that’s all well and good but we’re here because we care about human origins and human evolution so let’s let’s get back to that how can we use this kind of data to answer this question about the effects of the Neanderthal DNA that remains in modern human populations and so what we did was to start with data from this large emerge electronic medical records and genomics Network from across the country we got data for about 28,000 patients from from across the country and we first looked at their genotypes we first found genetic information from about 600 thousand positions across their genomes and so you can think of this as a stream again of about 600,000 days T CS and G’s that we’ve associated with each one of these patients and then what we realized we could do was use these great high quality maps of Neanderthal DNA that remain in remains in in modern human populations that you’ve heard about from Shriram and Josh and so we could look at those maps and then intersect them with our own patients and apply those techniques to our patients genomes and identify regions where each patient had Neanderthal DNA and so we could do this for about 1500 of these positions in these patients genomes we can see where some may have Neanderthal DNA and others may not and then finally the last piece as I indicated before comes from using these electronic medical record data to define a set of phenotypes or traits for each of these patients we can ask for hundreds of different phenotypes covering the whole spectrum of things you might be treated for by a doctor whether or not each of these people either had that had that disease they were a case or they were a control or we couldn’t really figure it out we should leave them out of the analysis and so then using this this matrix of data of genetic data annotated with Neanderthal ancestry and then many many different phenotypes we were able to start testing for the effects of Neanderthal DNA on a much broader scale than then really had been had been possible before and so before I get into what we we actually find I’ll try to be a good scientist and think about what we would expect to find before actually running the spearmint and so what did we expect now as the as modern humans migrated out of out of Africa where were they first appeared they encountered a number of different environments so they encountered different climates you know different levels of of sun exposure different temperatures different different sort of seasonal patterns they also in kind of different animals and plants that led to different diets and very importantly they also encountered different pathogens and so it’s been proposed that perhaps by interbreeding with Neanderthals and Denisovans and perhaps other archaic human forms that have been living in these environments for hundreds of thousands of years in many cases before anatomically modern human groups ever arrived there perhaps there really was some adaptive benefit you could get from you know spending a night with a Neanderthal maybe that was not such a bad a bad bad trade-off but but so but you know but this is really a hypothesis this hasn’t hasn’t been shown at all so under under this hypothesis we might expect that the Neanderthal DNA that

could have been adaptive in in our modern human populations would have been influencing human traits that are involved in interactions with the environment so things like our immune system of course be one of the most important but our skin perhaps and you know perhaps also or metabolism or other traits related to our diet and so we also expected that well we might see some effects on our our bone or skeletal structure because we also know about many important differences are many many very easily technical differences between the bones of anatomically modern humans and Neanderthals so those are some of the things we were expecting as we went into this analysis so what did we find and now in doing this analysis we we decided to split up our data our 28,000 dividuals into two different sets a discovery cohort of about 13,500 individuals which we run initial analysis and then a replication cohort in which we would try to replicate anything that we we found in that first cohort so in the discovery I’m going to show you just some of the top associations we found between Neanderthal DNA and potential phenotypes in a European and European ancestry anatomically modern human populations and so when I saw this I I almost couldn’t believe it because so what we see at the top we see osteoporosis a bone trait then we see hypercoagulable state so so what is that that’s just blood clotting your Bloods too thick at clots too much what’s going to lead to all sorts of problems then we see protein calorie malnutrition a metabolic trait and so this is really surprisingly matching sort of what we we expected but before I go too far into interpreting these let’s talk about that that replication analysis I mentioned so what we did here is we looked at the other 14,500 individuals we left out of the initial analysis and tested to see whether we saw consistent effects in that group and so luckily for four for four of these top associations I’m telling about we did see something consistent we did see a consistent effect unfortunately the osteoporosis one did not replicate there and I should say just as an aside I don’t think that necessarily means it’s not true but but it’s it’s sort of notoriously difficult sometimes to replicate these genetic associations and we’re following that up and some other cohorts but so let’s focus on on these four that did replicate so first we have this hypercoagulable state association that i talked a little bit about so this means that your blood coagulates very quickly and this is actually a very important part of the early immune response the coagulation factors are like really some of the first proteins that pathogens interact with when they come into your body and so this really fits in with this idea of the potential immune benefits and we’ve looked into the molecular basis for this association we’ve actually been able to show that the Neanderthal DNA nearby sorry this Neanderthal DNA is associated with increased kogai coagulation increases the level of several nearby coagulation factors in your blood so we have a very with molecular mechanism for how that might be might be happening and now I’m sure by now you’ve read the rest of this list and seeing one that’s sort of a little bit more difficult to interpret right and that’s tobacco use disorder and so that really just means addiction to nicotine and so I think you know it should we should we be thinking about this are we’re Neanderthals sitting around outside of caves smoking and I want to say unequivocally no no we cannot we cannot say this you should not say this you should not think this this this extreme example highlights a really important point that the effects of genetic variation in modern environments may not actually reflect its effects fifty thousand years ago against a very different genetic background in Neanderthals or in early human Neanderthal hybrids and on top of that of course tobacco is a new world plant they didn’t really have nicotine existing in their environment so but what this does tell us is that Neanderthal DNA in modern humans is influencing a system in our body that is now in modern environments relevant to this trait and in particular this bit of Neanderthal DNA is very nearby a transmitter transporter for a neurotransmitter called gaba it’s involved in all sorts of important processes in the brain and you know even may have a role in circadian processes so well we don’t really know what might have been behind this this association so now just to move on I want to tell you about one more analysis that we did so in that first set of tests we were testing for the effect of one bit of Neanderthal DNA with one trait in a human population but we wondered well what if we looked at all the Neanderthal DNA that a person might or might not have an aggregate and ask whether or not

that could predict better predict someone’s risk for a disease and so we did an analysis of that and again we found several very interesting associations that replicated and now I think this this top one is really really fascinating it’s Neanderthal DNA if I know your Neanderthal DNA compliment I can better predict your risk for actinic keratosis and this is a in case you don’t know this is a a skin disease it’s not is not terribly serious it’s it’s often seen in fair-skinned to people after long-term sun exposure and it’s caused by malfunctioning of a gene of a type of cell in your skin called keratinocytes and i find this so fascinating for really several reasons because keratinocytes one of their main functions is protecting our skin from UV radiation so again a very important environmental difference between in Africa and other non African environments but they’re also really intimately involved in early stages of the innate immune response and signaling for for the activation of other immune factors when we look at patterns of where Neanderthal DNA falls in our genome we see that many of the Neanderthal high frequency Neanderthal bits of DNA are nearby genes that are involved in keratin biology and so this is sort of taking it to the next step in showing not only is it enriched nearby those genes but actually in modern populations it’s having an effect on a phenotype that’s very relevant to keratin so but again here we’ll see there’s a second kind of confusing or at least more complicated to interpret association that we need to think about and that’s depression and so again I really want to be very clear that this is not what we should be thinking about Neanderthals we cannot say they were depressed we cannot blame them for any depression we have these are very complex phenotypes with major environmental components and many other genetic components and the Neanderthal influence is really quite modest in in in the whole constellation of all the ddv contributions to them so so in conclusion I want I want you to remember that interbreeding with Neanderthals has indeed left you know typical egga see in modern humans and in particular it’s it’s left effects on on many different systems in our bodies our immune systems our skin our metabolism and in fact even likely our brains and so I think largely because of the nature of the datasets we’ve been looking at we’ve we’ve we found many the cases where the Neanderthal DNA has a mildly deleterious effect in modern environments but again I want to remind you that’s not necessarily true fifty thousand years ago when we when this interbreeding likely occurred and so one of the main challenges going forward is trying to understand what knowing something about Neanderthal DNA in a modern environment can actually tell us about what was happening back then and so then the second point I wanted you to remember is that this was all enabled by using a new type of resource these large-scale databases of tens or hundreds of thousands of electronic medical records from from patients linked up to genetic information and so I think just as the ability to sequence people’s DNA at large scale that has dramatically changed our understanding of the genetic basis of human evolution over the past five or ten years thanks to many of the speakers in the symposium I think that leveraging these sorts of data and these sorts of projects that are popping up all over the world will allow us to do the same thing for the phenotypic basis of recent human evolution and so with that I would like to say thank you all very much for listening and thank all of my collaborators and yeah you you you

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