 Thank you very much. It's a pleasure to be here. I want to welcome everybody here this evening on behalf of the National Human Genome Research Institute, one of the 27 institutes and centers that make up the National Institutes of Health. As you heard, this is one, a part of a series of programs that are associated with this wonderful exhibition in Hall 23 of this great museum, Genome Unlocking Life's Code, which really reflects this great new partnership between the NIH and the Smithsonian Institution. And it's a real pleasure to be a part of this program tonight, but also this entire series. And it has proven to be remarkably enjoyable and productive to be working so closely with the Smithsonian Institution and also the Smithsonian Associates Program for putting together programs such as this, which really have brought in some spectacular guests and speakers to help round out what you can learn from visiting the exhibition itself. So my role here was simply to welcome you and tell you it's really a pleasure for our institute and for NIH to be involved in programs such as this. And also to introduce Dr. Rick Potts, who's going to in turn give a more detailed introduction of tonight's special guest. Just by way of background, as you heard, Rick Potts directs the Human Origins Program here at the Smithsonian's National Museum of Natural History, where he holds the Peter Buck Chair in Human Origins. His research investigates Earth's environmental dynamics and how human adaptations have evolved over the past six million years. Bridging many research disciplines, Rick leads field projects in the East African Ridge Valley and in southern and northern China. He's also a curator and a visionary for the Smithsonian's Hall of Human Origins and is the author of the companion book, What Does It Mean to Be Human? So with that as background, please welcome Dr. Rick Potts. Thank you very much, Eric. And I don't know what it is, but as I stepped out into the lobby and came back in here, there's such a feeling of excitement about tonight. Maybe it's snow, but I have a feeling it's Neanderthals or something like that. Anyway, I wish to offer my gratitude to Dr. Eric Green and the extraordinary partnership that's already been alluded to, the partnership that develops surrounding the Human Genome Exhibition, a partnership between the Smithsonian's National Museum of Natural History and the National Human Genome Research Institute, which Eric leads and directs at the NIH. A great thanks also to the Smithsonian Associates for organizing tonight's event, which is absolutely thrilling to me as it would be to anyone who was involved in the study of human origins. Dr. Sponte Pable has led the effort to create a new field of discovery directly relevant to the subject of human evolution. The study of ancient genomes has offered a novel means of delving into the actual genetics of early human lineages. Beginning with the Neanderthal Genome Project, Dr. Pable's research team wowed his fellow scientists and the public by mapping the molecular foundation of what it means to be a Neanderthal. And with that, with those findings, those findings have shed a great light on the genomes of many people alive today, as well as the complexity of the later phases of human evolution. And for his work and for his earlier research in genetics, Dr. Pable has received numerous recognitions and awards. In 2007, Time Magazine named him one of the most 100 influential people in the world for that particular year, and I think that continues because that was three years before his team produced the first draft of the Neanderthal Genome. More recently, he received the Theodore Bucher Medal from the Federation of European Biochemical Societies, and last year, Svante received the Gruber Prize in genetics for his pioneering research and leadership in the field of evolutionary genetics. In addition to the Neanderthal Genome Project, the further discovery of the Denisovan Genome is equally amazing. Svante is here to tell you about it all himself, one of the great adventure stories in modern science, told at the molecular level, and guaranteed to inform our evolutionary history and the distinctiveness of being human. It is my considerable honor to ask you to welcome Dr. Svante Pable. First of all, let me thank you very much, Rick, for that very kind introduction and for the invitation to come here and also see this amazing exhibition that I actually heard a lot about all the way to Europe. And what I wanted to do today is then use my time so that I first talk a little bit about our efforts in general to retrieve DNA from old fossils, in particular from Neanderthals then, then discuss the Neanderthal Genome more in detail and what it has taught us and also the genomes of this relative of Neanderthals from Siberia. And in the last third of my time or so, I'd like to discuss where we're going from here, how we will exploit the knowledge we now have to go further. And please tell me if it's not loud enough, you don't hear me. I can't judge how loud I am. But before starting all this then, I just want to remind you about what I think you all already know, that our genome, our genetic material is stored in almost all cells in our body, on the chromosomes, and it's stored in this famous double helical DNA molecule. And when a new cell divides, a ticklet of interest is then in our germ line where new germ cells are formed so new individuals may appear, there are enzymes that unwind these two strands and synthesize new strands with the old as templates. So there appears two molecules which are more or less exact copies of the earlier copies, the version of our genome. And this is a very exact process, but nothing is of course absolutely perfect in nature. So now and again, an error is made. For example, instead of building in what should have been a G here, an A is built in. And if that's not repaired fast enough before the DNA replicates again, it will appear as a mutation in the next generation. And you can then discover these mutations, the sort of consequences of these mutations when you compare DNA sequences from two individuals. So if you compare the genomes of two people in this room, we will find a difference every 1,200, 1,300 such letters or nucleotides approximately. If we add in a chimpanzee here, we will find a lot more differences, one every hundred nucleotides approximately. And we can then use our models for how we think these mutations occur to reconstruct the history of the whole genome or a part of the DNA sequence, and we generally depict that in the form of trees like this. In this case, it's very simple. The two human sequences go back to common ancestor quite recently. Much further back is the common ancestor shared with the chimpanzee sequence too. So our genome, as you also know, is over three billion base pairs. So we have something in the order of three million differences between any two people in the audience or between the two versions of the genome that you inherited from your mother and from your father. So there's a lot of information there to begin to reconstruct human history. And if you do that on a worldwide scale, what you will find is that most variation is found in Africa. So although there are a lot less people living in Africa than outside Africa, the total amount of variation outside is less when you find inside Africa. And not only that, for most of the variants you find outside Africa, you have closely related variants of DNA sequences inside Africa. But there is a component of the variation in Africa that you don't find outside. And the interpretation of this is that modern humans, that are essentially as us, evolved in Africa and a part of the variation that existed there sort of went out and colonized the rest of the world. And by some genetic tricks, for example, looking at how associated variants are with each other along the chromosome, you can also estimate approximately when this happened. And it's in the order of 100,000 years ago, so quite recently in terms of human evolution. So this is the recent African origin of modern humans. But there is a problem, if you like, with this model. And that is that 100,000 years ago, there were not only modern humans around, there were many other forms of humans. And outside Africa, most famously Neanderthals in Western Eurasia and in Eastern Asia, other forms that are less well described. So a big question, I've always been, what happened with these other forms of humans? Did they contribute to people who live today? Or did they go extinct without any sort of followers? And most interest that we focused on Neanderthals here is a reconstructed skeleton of a Neanderthal compared to a modern human. As you may also know, Neanderthals appear in the fossil record, depending on how you define a Neanderthal, maybe 300,000, maybe 400,000 years ago. And they exist till about 30,000 years ago, where they become extinct about the same time in different areas when modern humans appear. So there have been these two ideas around in paleontology for decades about what happened when modern humans appear in Africa. When they come out, one idea is a sort of total replacement idea where Neanderthals in Europe and other forms in Asia become extinct without any contribution to present-day people. Another one, ideas and assimilation called here, where modern humans come, mixed with Neanderthals before they become extinct so they contribute to people in Europe today, and the same in Asia. So you can regard these two ideas as a sort of sliding scale. The total replacement would be zero contribution from these earlier forms, and you can have more and more of contribution until total continuity that I think no one really believed in until quite a while ago already. So we got the first chance to sort of test this with molecular means back in the mid-90s when we got access to this fossil, which is not last any Neanderthal, the sort of the Neanderthal that was found in Neanderthal in 1856 and gave its name to this group of humans. So we got a sample from the arm bone here, you then extract the DNA under really clean room conditions to avoid contamination from yourself or from dust in the air or from chemicals into your experiments. And with great effort, at that time with the methods we had at hand, studied a particular variable part of the tiny piece of the genome, the mitochondrial genome, which is inherited from mothers to offspring. So it gives a very one-sided version of history, if you like, just a female side, and it's also a tiny little piece inherited as a unit, so very much influenced by chance. But it has a advantage that occurs many copies of this per cell, so it's a bit easier to retrieve. It's a bit likelier that some fragments of it have survived. So with cumbersome, we reconstructed a piece of this, by shorter little pieces we could retrieve, believing the things we could reproducibly find, and reconstructed such a tree that I showed before. And if you look at the mitochondrial genomes of present-day people, now the pointer has died, but it shouldn't be. Of the modern humans there, they go back to a common ancestor between 100 and 200,000 years ago. The Neanderthal mitochondrial genome was found to go back much further in time, about half a million years ago or so. And since then, we and others have looked at other mitochondrial genomes from other sides, and they all go back to common ancestor outside the variation of modern humans. So, you see, there's no battering this, it doesn't forward either. So in this scale of thing, it's quite clear that no one today runs around with a mitochondrial genome from Neanderthal, so it's total replacement. And this mitochondrial genome also gave us another piece of information. It suggested that the split between Neanderthals and modern humans, wow, that is really wonderful, thank you, thanks a lot. Great. And split about half a million years ago or later, because that was the time we had between the mitochondrial genomes there. So, this was what you could see from this tiny little piece of the genome, but it was of course clear to us and everyone else that the full story would be hidden in the nuclear genome. Because then we could really study all parts of the genome and also find things that would have appeared more recently in humans since we separated from Neanderthals here. And I think I'm on the published record something like eight years ago saying we will never see a nuclear genome of a Neanderthal. It's too degraded, it's too little there, it's impossible. And you should of course never say things like that, because generally you're overtaken by technology. And in this case it was quite clear it was high throughput DNA sequences, sequencing that changed it. Machines and techniques that came around to sequence million of DNA molecules really rapidly and inexpensively. So you could then instead of trying to find a particular little piece of DNA you're interested in simply extract all the DNA from a fossil and sequence all the fragments you had there, all the pieces of DNA, make up a little database and then start looking through that database and see which parts fit to the human genome. So they might come from Neanderthals, which parts, which fragments are from bacteria and so on. And the first place where this worked was in Croatia, a beautiful site in southern Europe and from this little bone which is 38,000 years old, this part of the bone there. And the first thing one sees then when one looks at the DNA sequences is that we're indeed very short. It's tiny little pieces, hardly anything as big as 200 base pairs, average 50, 60. The other thing you will see is that the vast majority of the DNA in such a piece of bone is not at all from the Neanderthal. Our very best bones have something like up to three, maybe four percent of Neanderthal DNA. The rest is all from bacteria and fungi that colonize the bone after when it was deposited in the cave. So we started a project where we over a couple of years worked a lot on improving the efficiency with which we come from the DNA in the bones to something we can feed into the sequencing machines. The machines got more efficient in that time in terms of how many molecules they could sequence. We looked through many, many sites and many bones to find the ones with most Neanderthal DNA in them, found three ones from that site in Croatia that we then used and sequenced a little over a billion DNA sequences from them. The vast majority of these then do not come from the Neanderthal, but from bacteria. But so we sort of matched these fragments to the human genome until we had gotten together about three billion base pairs of Neanderthal DNA. So that means we had random fragments here that together would add up to three billion base pairs the size of the human genome. But these fragments were of course from random places in the genome. So sometimes we had fragments that we saw piece twice. Sometimes even three times. But were lots of pieces we also just missed by chance. So the genome we had back in 2010 covered around 55% of the Neanderthal genome. But it allowed us to have a first overview over it and start to ask some questions. And one of the first questions we interested in was of course this question. Was there interbreeding with modern humans when they came out of Africa? We tried to ask that question in many different ways. I'll just present one here. And that is saying that if modern humans come out of Africa and would mix with people with Neanderthals in Europe, we would expect people in Europe today to share more genetic variants with Neanderthals than people in Africa where there never been any Neanderthals. So we're then looking for tiny little signals in the genomes. So we're very worried about errors in our sequences. So we went out and sequenced five people that live today to compare with so we would know the spectrum of errors would be exactly the same in them. So one person from Europe. And to us, oh, sorry, that is actually the Neanderthal. We sequenced one person from Europe here. And to us, of course, the archetypical European is a French person. So this is a French person here. We have two African individuals, one person from China and one from Papua New Guinea. And then we did a very simple analysis where we just took two of these modern genomes to test it first, the two Africans, and looked for all positions where those two present-day Africans differ from each other. We take the Neanderthal and count how often does the Neanderthal match that African or that African. And it should be 50-50, right? Because Neanderthals have never been in Africa. There is no reason to assume that it would be closer to one African than the other. And indeed, it's about a little less than 100,000 matches to this one and to that one. Then we do the same analysis with a European individual and an African individual. And to my surprise, I would say, we actually found statistically significantly more matching to the European individual than the African individual. Even more surprising to me was that when we looked in the Chinese individual, there was again more matching than to the African. And even in Papua New Guinea, that was also the case. So I was actually biased when we started doing this, thinking there had been no mixture with Neanderthals. But if there was one, I would expect that in Europe, where Neanderthals had actually lived. But we now found it in China and in Papua New Guinea. So the model we sort of proposed to explain that, that has since been borne out by work by others, is that if we assume that modern humans come out of Africa, they probably passed through the Middle East. And we know there were Neanderthals in the Middle East. So these modern humans there mixed with Neanderthals and then went on to become the ancestors of everyone that live today outside Africa. They would have sort of carried with them this Neanderthal contribution out to the world, also to parents, the parts where there were no Neanderthals. To the extent that then up to maximum, perhaps two and a half percent or so of the genomes of people outside Africa come from Neanderthals. We could also calculate with various tricks about when this gene flow from Neanderthals had happened between 40 and 90,000 years ago, fitting with a time when we believe modern humans come out of Africa and start spreading seriously over the world. And there has since been a lot of follow-up work of this by other scientists. But I can sort of never stop myself from pointing out that the public is also very interested in what we do and started writing to us in 2010. Many people wrote to us and self-identified as Neanderthals. And after a while, I started seeing a pattern in this correspondence. It was almost exclusively men who wrote to me. And there were very few women who self-identified as Neanderthals. So I do no real lab work myself anymore. So I presented this to my group, a sort of my research counting emails. And they're of course very critical, particularly when I present something. So they said this is just a sub-payment. Women are more interested, less interested in molecular genetics. And men, so only men will write to you. But I went back to my correspondence and found that that was not at all true. Because there were plenty of women who wrote to me and said their husbands were Neanderthals. Whereas not a single man has written and said that his wife is a Neanderthal. And this is of course extremely interesting for a geneticist. So that's sort of something I have to look into. But we'll of course do a few other things than counting emails. So something we're interested in is other forms of extinct humans. There are of course many, many forms of humans that we don't find in the fossil record. And we don't really know how they're related to present day people and to Neanderthals. And we are particularly lucky to work together with Professor Derev Janko and his associates, Professor Shunkov in Novosibirsk, who excavated many sites in Siberia. Particularly the excavated sites in southern Siberia on the border to Mongolia and China. It's a beautiful place. And they excavate there since the number of years. And in 2008, they were actually very skilled I think to find and recognize a tiny little bone and realize that it might come from a human. So it's a fragment of the last phalanx of a pinky. So we extracted the DNA from this bone and found our surprise that it was extremely well preserved. As I said, our best Neanderthal bones are 4% and the audience DNA is at 70%. So it allowed us to produce a genome from this individual about the same quality as the Neanderthal genome. And to our great surprise, we found that it was not really Neanderthal. It went back to common ancestors shared with Neanderthals. But far, far back, Neanderthals since had a long independent history. Longer than, say, the history, deepest divergences we have among present day people. So we defined this as sort of a new group of extinct hominins then based just on the genome sequences. And we named them Denisovans after Denisovacade, where they were first found. Just like Neanderthals are then called Neanderthals after Neanderthal, where they were first found. What has then happened in the last three years since that time is that we have improved our methods for retrieving tiny amounts of damaged DNA very much. There are many parts to that, but one particularly interesting one is that you extract, of course, a double-stranded DNA from your fossil. And normally, you then try to modify the ends here so that you can go on and sequence it. But many of these molecules are chemically modified so that you cannot actually replicate them or sequence them. So something that Matthias Meyer in the laboratory invented was that he actually starts by separating the two DNA strands then ligate on a synthetic piece of DNA and immobilize it here so that each of the two strands independently have a chance to end up being sequenced. So that means if you have a chemical modification of one strand that inhibits analysis, the other strand can still make it. So with this method and other modifications, we've been able to go on in the Denisovagino first that we had this slight overview over many pieces we missed, to now sequence it so deeply so that we actually see all the positions to which we can map these short fragments, which is about two-thirds of the genome, but with great accuracy. So you can do a lot of things then when you have a very accurate genome. You can, for example, distinguish the two variants that this individual inherited from its mother and its father. Just to illustrate that, there is a genetic variant at high frequency in Asia and Native Americans that's responsible for straight hair and some other sort of texture of the hair. It's very common among people in China and East Asia today. It's not in Europe or Africa. And when we now look at this Denisovan individual, it doesn't care of it either. And that's actually a common pattern this individual doesn't seem to have any special relationship to people in Asia today. But you can do much more than that. Since we have the sequence of the two chromosomes, we can sort of estimate for a part of the genome here the time back to common ancestor by making a little tree like that. And you can then go across the genome and do that for many, many parts of the genome. And you can then use by method developed by Heng Li and Richard Durbin, this to estimate population size over time. Because when you have two chromosomes like that, when they go back to common ancestor, it will be more likely to go back to common ancestor at a time when the population was small. So in this example here, we would expect the population size to have been small at this time where many of the chromosomes have a common ancestor. So from a single individual, the two genomes in that, we can estimate the population history of the entire population from which this individual derives. So if we do this for present day people, you will see very nicely, it's past here, you go to the present here, that everybody, no matter where we live on the planet, share a reduction in population size, an increase in population size, and only in the last 100,000 years or so do we start seeing a difference between Africans who have more variation than non-Africans due to this bottleneck of coming out of Africa. And we could now add this denissive and individual and look what its population history was. You then find that if anything, it's a bit bigger population size here for a time, but then it crashes and goes down and becomes extinct. So this was very fascinating to me. This individual had a very different population history from anybody who's around today on the planet. Something else you can do when you have very accurate genome sequences is that we can begin to see that this individual lived long ago, so it's actually missing mutations when we compare to present day humans. So we could see that it missed something like 1 to 1.3% of the mutations relative to present day humans here. So we can then, if we assume that the common ancestor where the chimp is 6.5 million years, we miss 1.2% of the mutations here, we can estimate how old this bone is, and in this case it would be something like 60 to 80,000 years old. Now there are many caveats about this, particularly about sequencing errors among the present day human genomes. They actually vary in age by about 20% of this here, although we know they all live today. But I think it's an indication of what will come in the future, that when we handle genome sequencing even better than now, that from bones when we can retrieve a genome, we can actually date them. And in this case, even more from a bone so small that you could actually not use carbon dating, for example, on it. So we can, of course, with the genome, ask, just as for the Neanderthals, have these denissivants contributed to present day people? And indeed they have, but surprisingly, not in Central Asia or Siberia, but out in the Pacific, particularly in Aboriginal Australians, Papua New Genomes, and so on. So this then suggests that probably these denissivants were more widespread in the past and was also in Southeast Asia. So this is a copy again of this bone, and I think it sort of indicates something that will become more common in archeology in the future, from tiny little remains like this. You can reconstruct a lot of population history, even date them, and often frustratingly, like in this case, we don't know how these denissivants looked morphologically, or what stone tools they made, or any other things we would traditionally know. So yes, to summarize before coming to the last part here, what we think we know then about the Oridine Neanderthals and modern humans, and denissivants, we think that Neanderthals and denissivants have a common ancestor, sometime in the order of half a million years ago in Africa. They come out, they evolve in Western Eurasia to what we call Neanderthals, in Eastern Eurasia, somewhere, to what we call denissivants. This is not to say that this widespread, also not that they were the only hominins there at that time. We know they were the hobbits, the homophoresiensis in Indonesia, for example. We also don't know the border between these two groups. We do know that in this region, in the Altai mountains, at some times there were Neanderthals at another time, denissivants. Then modern humans evolve in Africa, come out, and presumably in the Middle East, mix with Neanderthals. They continue to spread around, and there is now a paper that appeared in January that convincingly showed that it seems to have been a second occurrence of mixing with Neanderthals in somewhere in Central Asia or so, because people in China, for example, have slightly more Neanderthal contribution in their genome than people in Europe. There is then this mixed with denissivants, presumably somewhere in Southeast Asia, by people that then spread out into the Pacific. And these archaic humans then become extinct, but they live on a little bit in people today, if you like, so that something like one to two, two and a half percent of the genomes of people in Eurasia comes from them, and you add on another five percent from denissivants in the Pacific. Now we sequence two genomes from extinct hominins, found two cases of admixture. I wouldn't be surprised if, for example, in China one found other cases. I also don't think there is an absolute difference between Africans and non-Africans in that Africans would not have a contribution. Clearly Neanderthals, sort of modern humans, appeared somewhere in Africa and also spread across Africa, and there's some indication from present-day variation that there might have been a contribution from earlier forms of hominins also there. So we clearly rejected this sort of total replacement model for modern human origins. We have up to seven and a half percent contribution from other forms, but the big picture is still one of replacement. So just to sort of have a name for this, I find sort of leaky replacement, perhaps a good idea. So I would then like to bring up three things that are sort of in the works. The first one is actually now accomplished. We need a good Neanderthal genome, and we now have that since January when we published it. It's again from the same site in the Altai Mountain from the Niseba Cave, where we found the finger bone and deeper down, two years later, they found a toe bone that looks like this. And we sequenced a DNA from it, and again to our surprise, it was not the Niseba, but it was very close to other known Neanderthals here. So this is the Neanderthal, and we sequenced the genome to high coverage, again very high quality, and we can compare it to present-day people. For example, we can look over all how much variation is it between the two genomes these individuals have inherited from their parents. So here are Africans that have more variation than non-Africans today, and these are the Denisovan finger bone and the Neanderthal toe bone. So they have a grammatically less variation. But not only that, we also found something very surprising. When we walked along the chromosomes in this Neanderthal genome on the bottom here, we found large stretches, one here of 19 million base pairs, where the two chromosomes were absolutely identical. And this of course indicates that the parents of this individual were closely related. So we find much less of that in the Denisovan finger. So you can then model what relationships must have occurred in the case for the parents of this individual here, the Neanderthal individual, and the parents have been either, say, half-sibs or grandfather, granddaughter. Don't ask me to explain what double for a cousins is. We're going to count. But one of these four scenarios must have been the case. So you begin to get some idea about socially what happened in that cave quite a long time ago. And I think it will be very interesting in the future to see in other Neanderthal sciences, this is a typical pattern for Neanderthals or something special here. You could again do the same analysis with the Neanderthal here, comparing it to present-day humans and denisovans. And its population history matches that of the denisovans very closely. This difference here is probably just due to that this bone is actually older than the Denisovan bone, but we don't know how much older it is. We now then have two good genomes of the Denisovan of the Neanderthal. We have some sort of overview genomes from Croatia and from a place in the Caucasus. So we can now begin to look at interactions, not only with present-day people, but also with among between Neanderthals and denisovans. So if we do that, we find this contribution from Neanderthals to present-day people outside Africa that we know about the one to 2% contribution from denisovans to people out in the Pacific of about 5%. We now find a tiny contribution from denisovans also in mainland Asia, in China, for example, of 0.2%, a lot less. But we also see a contribution from Neanderthals to denisovans. And quite interestingly, we see an old component in the denisovan genome that we do not see in the Neanderthal genome that comes from something else that diverged much earlier than these guys one to four million years ago from the human lineage. So it's very tempting to speculate that this is Homo rectus or something like that in Asia that contributes to the denisovan genome. And I think future work will look more into that. So a conclusion from this is that human forms have always mixed with each other, at least to some extent. We find no sort of wholesale contributions of 30%, 40% from one into the other. It seems to be generally small extent. What you can also do now then, and there were two papers that appeared in January, one of them we were involved in and the other one was from Josh Ake's group in Seattle, where they had looked at contributions in present-day European genomes and East Asian genomes from Neanderthals. And they then find in some regions, high contributions from Neanderthals were a high percentage of present-day people carry fragments from Neanderthals in certain regions of the genome. And if you look what genes are particularly present in such areas, one group of such genes are those that are involved in structural proteins in the hair and the skin. So it seems to be that Neanderthals have contributed something in the skin or hair to quite a lot of people that exist today. And now the group of genes that come from Neanderthals and the Nisimans was shown already in 2011 by Peter Parham's group that they are involved in regulation of the immune system. So one can imagine that there were sort of Neanderthals had resistance to certain infectious diseases that they had adapted to over hundreds of thousands of years. And when modern humans from Africa picked up these variants, they were of an advantage to them so they increased in frequency. I was quite fascinated by a paper that appeared by it from David Altshuler's group, a big consortium that appeared in December where they found a new risk allele for type two diabetes. So the type of diabetes you get in old age. And that risk allele existed at high frequencies in East Asia and in Native Americans. And when you look at this tree of this risk allele versus non-risk alleles, you find that the Neanderthal allele is right in here. So this is a variant that one has picked up probably in Asia from Neanderthals and have risen to high frequency perhaps because these variants were of an advantage and a situation of starvation. And today when we have ample nutrition all the time it results in type two diabetes. So some of these sort of contributions may actually have consequences, also medical consequences today. What you can also look across these genomes or present-day people is then for areas where there is no contribution from Neanderthals. So areas that seems to be resistant to Neanderthal contribution where we would expect statistically to see Neanderthal DNA in some people but we don't see it. They are of course interesting because they might point to things that we sort of don't accept from Neanderthals in the modern human gene pool. And if you look in such regions of the genome for what genes are particularly present there, it turns out that that is genes that are expressed in the male urn lining testicles. So it makes it very tempting to suggest that in the hybrids, Neanderthal human hybrids, they may have been a problem with male fertility. And that's actually not uncommon when closely related species or populations come together and make hybrids, be that say donkeys and horses. It's a male offspring that's infertile and the female offspring generally is fertile. So it may actually be that there was some biological problems when this happened. So something else that we then work on is to apply these super sensitive techniques now, particularly that single strand library techniques to all the remains of hominins. So far we've always said that we have to stay within the last 100,000 years or so of human history but we now apply this and try older things and we've been very lucky to work at a site in Spain called Sima de Luces in Atapuerca. It's a deep cave 30 meters down, so it's very constant conditions where they find very many bones of something that most people would call homohydric burgancis or maybe an ancestor of Neanderthals. And from this femur here, we were able to get, we got samples, we extracted DNA and there are very degraded, very short pieces. We have so far been only able to retrieve this mitochondrial genome that exists in many copies per cell. And just to give you a feeling for this, we've sequenced about 500 million DNA frequencies from this bone and sieved them down so we can then analyze in the order of 10,000 of them to reconstruct the mitochondrial genome. But we were able to do that and quite surprisingly we found that this mitochondrial genome was related not to the mitochondrial genomes of Neanderthals but to the denisovan mitochondrial genomes but far back here, of course. So it's very surprising, of course, that we now find in Spain something that's related even though far back to the denisovan mitochondrial genome and not those of the Neanderthals that have been sequenced. So one explanation for this may be that 400,000 years ago were simply so far backs over somewhere in the common ancestral populations of denisovans and Neanderthals and modern humans that they have variants that are related to all of these. We may see other types of mitochondrial DNA when sequenced more individuals from there. Another possibility is that this actually comes from gene flow from some other group of humans into the ancestors here in Sima de la Vesos. And it's in the end, only the nuclear genome that would be able to clarify that and sort of working hard to try to retrieve at least parts of the nuclear genome. But what is really exciting to me is that these techniques now allow us to go further back. Somewhere, maybe, to within the last million years or so in the rare sites that are well enough preserved for this. So finally, then, the third thing that I'm very excited about is to actually look on the sort of functional implications for modern humans from what we can now see from the genomes. So for example, looking in these regions that lack Neanderthal contributions to see what hides there more than these genes expressed in the male urine line. So looking for things that has appeared in humans very recently since we separated from Neanderthals and particularly those things that have become fixed and are present in all humans today. So if we take a very strict criterion then and say, what changes in the genome can we find that exists in everybody today, no matter where we live on the planet, but where the Neanderthals and the Nisimans look like the apes. So things that changed here and spread to everybody. That's if you like a genetic recipe for being a fully modern human when we then compare ourselves to our very closest relatives. The interesting thing is that this catalog of such changes that sort of define us genetically as a species relative to Neanderthals and the Nisimans is not very long. It's a total of a bit over 30,000 single nucleotides that have changed and some insertions and deletions. You can actually look through it in an afternoon in the computer. You can then of course say some of these to have some inkling what they may be involved in. So there's something like 3000 changes in well-defined regulatory regions. And if we look at things that change amino acids in our proteins in our body and we'll focus on them for a minute just to give you a sense for how we can look at this now. It's just 96 amino acid changes that have changed and they occur in just 87 different proteins because some of them have multiple changes. So it's of course very interesting to look at this and say is there some function that hides here that may be behind what set modern humans on this very special trajectory. The fact that we are seven billion people on the planet and not in the hundreds of thousands that the hundreds of thousands that the Neanderthals were. We're particularly interested of course in things expressed in the brain. So it was quite interesting to see that if we look for those 87 proteins and see where they are expressed in the developing human brain, we actually see an enrichment of them in the proliferative zone in the developing brains when new neurons are born in fetal development. And quite surprisingly of these seven genes that are expressed there, three of them actually turn or to be part in a machinery that pull chromosomes apart during cell division. So that was quite surprising to me. I thought that was a very concerned function that would not have changed recently in human history. But there are also indications that how cells divide, how the stem cells divide in the developing brains determines what types of neurons you form and how many of them you form. So it may actually be that these three genes are particularly interesting that one should now go on and study. But that's of course work that will be very, to take a lot of work over many years by many biologists to do that. But I just wanted to end up saying how would we do that? How would we take the next step to investigate such human specific traits? Because the problem is of course we have no animal models. When we now want to study something that's unique to humans. So I've gone along sort of that is a question and I've sort of spent many years going around making jokes when I give talks and saying what we want to do is put Neanderthal variants into transgenic humans and human variants into transgenic chimps and then analyzing. And I've sort of said that obviously that is impossible. And will never be done. But this is sort of suddenly not so much of a joke anymore because there are people, there's even a very famous professor of genetics in Harvard, George Church, that goes around and suggests that one should go much further than what I suggested here. We should clone Neanderthals. We should engineer all these changes we've found in the Neanderthal genome into human stem cell and create the Neanderthal. And I think I'm sort of tired of discussing it. I think it's technically impossible and ethically totally absolutely impossible. So why are we really thinking about it? But it's anyway a serious question. How will we go on with this? And I think there are some ways that I just want to mention. I think that the human genome and I think Eric Green is the perfect person to discuss this is a small enough place that all mutations that are compatible with human life actually exist out in the population. Every baby that's born has something like 50 or 100 mutations, new mutations that are not there in a father nor the mother. The genome is three billion base pairs. We have seven billion people on the planet. Everyone has 50 or 100 mutations. So we will, in the future, when we sequence millions and millions of people when you just walk into your doctor's office, I think one will be able to find back mutations to the ancestral states and probably it will be possible to work out ethical ways to then study that. Something else that will come and we and others are already in the process of doing it is engineering these interesting changes into humans themselves and differentiate them two different forms of cells in the tissue culture, in the laboratory and study their effects in cells in culture. And I think something else one will also be able to do is sort of put them into mice, maybe several of them together to study the effects of particular biological systems. Before ending, I should also say that I've been many, many people involved in this. Many more people than I can mention. I then just want to put up one person here, Matthias Meyer, who developed the single strand library method that without which we would never have been able to get this high quality neanderthal and the nissan genomes. It's really transformed what we can do. Many people have helped in analyzing this, particularly Jim Malikin at the NHGRI here in Bethesda. And before ending, I should also say that some of the things I've described is also in a book where I sort of also described the dirty little secrets of how this all happened. And I thank you very much for your attention. We get to now call my English. Yeah. Just my role. Fancy. Would you like to sit here? Oh, I can sit here. Very good. Am I on? Do you hear me? Okay. Excellent, excellent. Terrific, Svante. And my head is swimming, not because of the complexity of the subject, but because of that it's been done and is continuing to go on. And I just can't, personally, I can't wait to see what a neanderthal mouse looks like. So what we'll do here is we'll have about 20 minutes of conversation and maybe before, as we're winding that part of it up, I'll mention that if you have questions, we have two microphones that are available. Don't get up now and get there and line up for your question yet, but I'll announce when we're going to start to take questions from the audience. I love the idea of leaky replacement with regard to the variety of models that you've suggested. And you know, I'm a bones and stones person. And those of us in that area of paleoanthropology, we love our categories. We like to slap a species name on things. And I think that most people also enjoy, what box do I put things in? Whether it be a woman putting her husband in a neanderthal category or whatever, which is terrific. In any case, to what degree would you then say that the neanderthal lineage and the lineage of living people were reproductively isolated? Because I think this is one of the questions that as in our Hall of Human Origins that I get, our volunteers who are the docents who work there get a lot. Do we call neanderthals Homo neanderthalensis as a separate species? And particularly of interest to me is that for about, what was it, be about 10,000 years or maybe 15,000 years that neanderthals and Homo sapiens were both in Europe. But apparently you see no evidence, no echo of interbreeding during that time? Yeah, so I mean, we see this, what I found it fascinating this thing that we do see something that the most reasonable explanation is that there was some problem with fertility in the offspring, probably that the men had reduced fertility. So it wasn't just the sort of two groups that totally, they were perhaps even on the verge of becoming reproductively isolated when they came together. Then it's another thing that we as humans and perhaps particularly less professors and academics who want to put things into boxes and feel very uncomfortable if you can't put everything in boxes. To some extent I would say it's a sterile discussion. Are we calling them a species or a subspecies if we now describe that they contributed one or two percent to the enos of people today? In a way that is the interesting information. I think it's up to everybody if you want to call them one or the other. We actually, I never use these Latin names because then I have to take a stand on it. I have the feeling if I say neanderthals, if I said denisolence, modern humans, people know pretty much what I talk about and I don't need to have a long discussion but it's shaking me out. So noted as a paleoanthropologist. I'm interested in the matter of the chromosomal evolution that has occurred in humans since the separation from our last common ancestor with a living species chimpanzees. And all of the great apes have 48 chromosomes, 24 pairs. Humans have 46 chromosomes, 23 pairs. And as I understand it, the change that occurred was where two chromosomes, both that have, that are the strands are joined together at the end, merged into one that joins at the middle. A fusion of two chromosomes into one. Are we pretty certain that the neanderthals had 23 pairs of chromosomes as you've shown and how would we be able to detect and do you have ideas about when that possibly very important change in genetic evolution but at the chromosomal level occurred? Yes, you are actually now sure that that fusion that created our chromosome too had happened before we separated from neanderthals because we can find this junction fragment that of course created a piece of DNA that's unique to humans relative to the apes where one chromosome ends and the other one starts and fuses to each other. And we can look in our high quality genomes about the reeds we have there for this junction fragment and we find it many, many times over. So that had actually, from that point of view, if two groups of different chromosome numbers have offspring, you often also have problems of infertility in the hybrids but that is not a reticillator. And are you quite certain at this point that in the atapuerca material that goes back to about 400,000 that again the chromosomal fusion occurred before then? That we don't know, that there we have so little information, we only have the mitochondria. But there are studies of that sort of fusion region that suggest that this is at least 700,000 years ago or more. The number that you put up here, and there are a lot of numbers that we've heard tonight, but one of the ones that I think may be surprising to many people I find when I crib from your articles and things like this and mention this to people that people are quite amazed at the number of base pairs in our DNA and that as I understand it, between any two individuals there would be about three million base pair differences. Could you put a number on the number of base pair differences between any two Neanderthals? And what does that indicate about the genetic diversity of Neanderthals compared with the genetic diversity of human beings today? So as I showed there, there is much less genetic diversity among Neanderthals than among present-day people. Now that said, we sort of study late Neanderthals here. So it may be, but they have something like, I shouldn't put the number on this because I don't really have it in my head, but they have something like a third of the variation that we have today. They're among the least variable groups of organisms we have among mammals so far. But again, these are late Neanderthals. Some of it is rather extreme as we saw the parents of this in Neanderthal would like have sips, right? And there's also indication that had been close relatives further back in the generations of this individual also. Well, that's interesting because one of the things that as I understand, to come out from the study of genetics of all living people is that the genetic diversity of living humans is actually quite small relative to other primates. And it has been speculated that, not speculated exactly, but one part of the spectrum of thinking on that is that there was a genetic bottleneck in the evolution of our own species. Others might see that it was a low population size over a long period of time. Do you think that the Neanderthals also underwent a genetic bottleneck and might this be a fairly common phenomenon for the precarious nature of human evolutionary history? Yes, but sort of with the caveat that I don't know if that bottleneck had to do with the origin of Neanderthals or say the last glaciation that they lived through. We also see that we have now Neanderthals from Spain, we have them from Croatia, we have them from the Caucasus, we have them from the Altai Mountains. But not only do they have little variation, they also are quite distinct from each other. I mean, our interpretations really, they live in quite small but separated isolated groups from each other. The idea of cloning on the Neanderthal, I'm glad you mentioned what you did and had your thoughts about this. There's a gentleman named, who's quite famous named Stuart Brand, who's also very strongly in favor of, well, let's bring back the extinct forms of organisms. And one day about three years ago at dinner, he said, you're a paleoanthropologist, don't you want to see a Neanderthal? And I said, well, yeah, I would love to see a Neanderthal, but give me a time machine to go back rather than trying to bring one up to speed. Now, I'm interested that George Church at Harvard also is in favor of this. You mentioned that you thought not only is it ethically questionable at best, but is it technically possible given that every aspect of biology needs an environment? Even the genome needs a molecular environment in which to actually produce the organism for which those instructions have evolved. And is it possible to actually take the genome of the Neanderthal that you and your team and others around the world have produced and is it technically possible to bring back a Neanderthal? So first of all, as I said at one point there, what we study is actually the single copy part of the inner part of genome that occur only once. That's where we have this very accurate sequence now. For about a third of the genome is actually repeated. So the sequences occur twice or more times. And there, of course, don't know with our small fragments where they fit to which copy they fit. So we can only statistically say there were at least many numbers of this version, but we don't know how they're arranged. And we know that those parts of the genome are also very important in any respects. So for a third of the genome, we cannot do it at all. For the other parts, I mean, in reality, we struggle just to put in two or three changes today accurately in a stem cell. You can do it with one, with great effort, putting in more is much, much harder. And we're now talking about putting in, say, 30,000 back to the common ancestors, and another 30,000 to make the Neanderthal, and put them in on both chromosomes. I mean, there's this way, even what George Church can do. Have you just said never? I haven't said quite never, but yes. I thought I should ask. Okay, I'll have perhaps one or two more questions. If you'd like to think about questions, you'd like to ask Dr. Pabo. We have the two microphones here, and you can please stand up, don't be shy, and go to a microphone and ask your question. And one of the final questions I have that's on my mind is that as a person who does his research largely focused, not entirely focused, but largely focused in Africa, we tend to think that Africa is the happening place for changes for the developments in human evolutionary history that have been so important related to the origin of our species. And yet there are problems, as I understand it, in warmer climates with regard to DNA degradation. Are there some steps? Do you see some technologies that you see clearly or vaguely down the road that can help deal with that and allow the rich fossil record of Africa and other tropical areas to be decoded? So of course with these new sensitive methods, some things work that have previously not worked for us. I think it's still the situation that there have been very disappointing to try things in the Middle East, for example. I would really hope for areas of Africa with a colder climate, be that Southern South Africa or Ethiopian highlands or deep cave sites if there are such things, but there are constant conditions and probably the best things. Right, right. I had the pleasure of visiting Vasvante's lab several years ago and bringing a fragment of our Shenadar III Neanderthal from Shenadar Cave in Northern Iraq to his lab. But unfortunately there were only contaminants or hardly any DNA in it at all and what was there proved to be contaminants. So that's the fossil that you can see out in the Human Origins Hall there. But with the kinds of remarkable developments that you and your team and others around the world have been able to make, I remain at least hopeful that that and other bones from more southerly locations or more near the equator locations will someday be susceptible to study in this way. So why don't we begin and we'll just go back and forth and why don't we start over here, please, sir? Yes, you showed the nice little pinky bone from the Denisovans. Can you say something about what fraction of that tiny bone you actually had to destroy in order to do this experiment and will there be plenty of that left in the future for let's say a decade from now when even your techniques will be more highly developed? Yes, so we used almost all of that. So we used sterile dentistry drill and we drill inside. So we just barely kept the surface of it. Of course, we do micro-OCT of the things before so that the morphology is at least sort of preserved. Now actually there is another part of the story too that I don't know if I dare tell, but it's in the book so I can just as well say it. There was another part of that bone that was given to another laboratory and so there is, but nothing has really come out of that, but there is another part of that bone that could perhaps be used for other analysis. We have also, there has also been two teeth found in the cave that we have shown contain Denisovan DNA by much, much less than the finger bone. So we have some idea about the dental morphology of this Denisovans. Please. Thank you for a lovely talk. In written human history, we know that infectious disease has had a major role in forming societies and really having major impacts on different populations around the world and I was really heartened to see that you were analyzing aspects of the Neanderthal and Denisovan genomes that involve the immune loci. Can you maybe tell us what you can extract those information for how perhaps infectious disease may have impacted these early hominids as well? Yes, sort of it's a good question. We can of course imagine that infectious diseases have played a big role. We really have not anything really to say about this. It's quite hard to study these immune responses because they're so repeated. It's sort of really hard to see which fragments come from which and Peter Parham's group at Stanford are really the experts in these groups of genes and it's their study I had that figure out from there. The problem is that to see these genes that regulate immune responses that account to high frequency but you do not know what pathogens or so that were responsible for this. There has been work recently from a previous student of mine who is now a professor who studies the DNA of infectious diseases of the Gershina pestis for example and of other pathogens. So it might be the chance there are for example some neanderthal remains with what seems to be tuberculosis lesions. So it may well be that one will be able to study the evolution of these pathogens even back to our CA communions but unfortunately nothing really concrete to say. I was wondering if the geographic range of the neanderthal extended into areas that were then and maybe still are permafrost. What I'm getting at is, is there a finite but maybe infinitesimal possibility that a preserved body could be found or maybe an otzi or maybe a bog person in a temperate climate. I guess someone would find in a permafrost neanderthal is the question. I think there is a realistic chance of that. Unfortunately one have not done that yet but it's of course things are melting and we've actually started collecting bones from people who collect mammoth ivory from the river systems in Siberia. They find a lot of bones on the banks of the river. They are there for the ivory but one can sort of get them to pick up what looks like human bones and it might even find things there that are of interest for example. That's not permafrost but yes. I actually as a follow up to that I'm wondering is there any possibility ever do you imagine of finding DNA on say the place where you hold a stone tool? Yes, maybe. I would be skeptical or from blood stains on stone tools or things like that. Maybe. Dr. Pavo thank you again for such a lovely talk and it's very now interesting to think about what it means to be a modern human considering your findings and I was wondering in reference, this is more of a philosophical question I guess. In reference to the findings that you identified that there are contributions of Neanderthals and Denisovans that have been made to our modern genome and considering that some of the sub-populations of modern humans have these while others don't, I was wondering what sort of implications if any does this have for the definition of what it means to be a modern human? Yes. To me the definition of being a modern human must be in the parts that we don't have from Neanderthals. In those regions where Neanderthals don't seem to contribute and Denisovans also don't contribute. It must in a way be in this catalogue we presented there that is now a very strict catalogue saying this should be genetic changes that are there as far as we can tell today in 100% of humans on the planet. Can of course relax that to say 90% and that catalogue is about a bit more than twice as long but it's in that catalogue I would see the genetic definition of a being a fully modern human because all of us as you say we are all modern humans even if we don't have any Neanderthal contribution if we are from Africa and don't have any Neanderthal contribution. But this is a surprisingly short list to me. It's extremely interesting if some of these have functional consequences I think. And I think many people will work on this other than us in the world. When I was a student, Neanderthals were depicted as being these hairy, shambling brutes with low brows and corresponding low IQs. But I was wondering from your studies, and this is highly speculative, if you cleaned them up and put them in a suit and so forth and put them on the metro, would they stand out? What would people say, this is a human being? Or this is a, I don't know what this is. Yeah, I mean, probably you are back to the nice answer. I would tend to think one would look twice on the Neanderthal. I would agree with that. Yeah. But maybe not in the New York subway. Thank you. I happened to have bought your book and read it and it's fascinating. I would advise everybody to, and I have no link, but I would advise everybody to buy the book and read it, it's very interesting. Thank you. My question is more on the statistical side, both in your presentation and in your book. And what you say, it appears that you have very, very fine statistics. And we are talking about one out of 10,000 or one percent, half a percent. I come from the engineering side and financial side. And these are just, in my universe, just non-significant. The likelihood of error or the lack of certainty on such a fine number of differences over a very large population, I don't know a bit of statistics, leads me to think that the statistics that you use must be very, very precise or powerful. So my question is very simple. Do you really trust your statistics and why you trust them when they are so fine as to be infinitesimal? So yes, one can, of course, should be skeptical about this. Of course, in the statistics, we sort of try to have as good models as we can. But it's of course not just the statistical thing we have. You can also go in the genome and find pieces of DNA that are 30, 40, 50,000 base pairs long that are almost identical to the Neanderthal genome, where I, for example, is almost identical to the Neanderthal genome, and very different from other people from Northern Europe. So you can sort of actually see with your own eyes that there is evidence of this and that you don't find this in African genomes. So that is sort of probably the most intuitive, direct answer to your question. We can also do formalize that more where we, for example, do analysis where we see that if you walk across a genome of me and I sort of plot when I get closer and closer to the Neanderthals, most of that is simply a counter part of genome where the mutation rate is low. But then I see that in those regions where I get closer and closer to Neanderthal, I also get closer and closer to you because we just have a low mutation rate in those parts. But then when I get to the regions where I'm very close, almost identical to Neanderthal, I'm suddenly very different from you. So that also convinces us that there is a population of sequences there that is really derived from Neanderthals. So there are several lines of evidence like that, actually. And I mean, this is so debated, I've almost waited for someone in the world to publish something and say it's wrong. No, there's a challenge, isn't it? Please. Thank you for coming tonight. I really enjoyed your talk. And first off, I'd like to tell you the Arkansas definition of a double first cousin. Brothers, Mary's sisters, their siblings are, their offspring are double first cousins. Two brothers marry two sisters. They each said has children. The cousins are then first cousins from both sides. These are double first cousins? The Arkansas double first cousins. Oh yeah, yeah. Cool. My question is... Someone write that down, please. A lot of the mutations you said, or the transpire from Neanderthal to modern human being with the immune system, do you think there's any way we can maybe pull some more out and have maybe some new therapy, gene therapies and stuff to fight disease and Alzheimer's, cancers, whatever? I don't... So the question is, do we think that we can somehow learn from these variants? Maybe even manipulate modern human to go back to the end of all the fight-off things, maybe, you know? Yes, I would be extremely, yes. I mean, for all these reasons that we don't clone Neanderthals, I would also not go and manipulate the genomes even with a view to fighting diseases like that. So that may be something that's an earlier branch of the Cuban lineage. So we have sort of attempted to do that after lots of discussions and negotiations. We have six, seven years ago, we've got to drill a little bit in the root of the tooth, and we couldn't get any DNA out of that at that time. Now, that said, we are better at it now, but it's also very humid and very warm. I suspect it's actually not preserved. The majority of fossils, especially from such climates, don't contain any DNA. It's not that this can be applied to everything, unfortunately. I have a question about another human ancestor that's also a recent newcomer to our whole hominid species, Australopithecus sediba. So I've been teaching anthropology at the high school level for eight years, and it's been really exciting because we keep getting new species like sediba. And so I heard it's almost like rumors that there might be some of those fossils, some actual flesh, or they think there might be a little bit of something like that, and so would you be able to get DNA out of that if that sort of rumor is actually true? So what was the rumor? So I've heard, I just took actually a course through Coursera with John Hawks at the University of Madison, and so he interviewed somebody who was working with the sediba fossils, and they think there might be some bit of actual material. Soft tissue. Yeah, soft tissue. And that rumor is true in that it is a rumor. Yes, I mean, I would still think. So how old is the sediba? 1.9 million years. I would be very skeptical. I don't think it would be justified to sort of sacrifice any of it to try to get DNA, but animal remains from similar places. I could of course attempt, but I would almost think it's a waste of your time to do that today. So we know the Neanderthals buried their dead. We know that they created musical instruments. We know that they painted. Do you have a sense of that portion of the non-African population? What the DNA, the genomes contributed to modern people? So blonde hair, blue eyes, musical ability? No, actually, all we know almost is what I presented there, unfortunately. I think there will be a lot more knowledge in the future. I know that there are studies underway, for example, where one look at cranial forms where both know something about what Neanderthals and what Neanderthals looked like from fMRI studies, medical studies, where you also have genome sequence from the individuals you look at, and now look at what Neanderthal proportion and part of the genome that people have and how it correlate with features in the cranial morphology. So I think there will be some things like that that will be known in just the next few years. But there has been the claim that red hair comes from Neanderthals. There's even a sort of study, but those mutations in the Neanderthal genomes, we have, we don't see the mutations that now give red hair in Europeans so far. So it's a kind of a parallel evolution of red hair, is what you're suggesting? Parallel? I mean, we don't know if Neanderthals have red hair. Ah, right. Okay, please. Hi, my question may be a little bit similar. I'm actually a cultural anthropologist, so I'm a little out of my room here. But is there any potential benefit to having either Neanderthal or Denisovan DNA? And for example, if I'm looking for a husband, should I seek out or avoid men with Neanderthals or Dysenome? Just, just, just. It's more about if there's any potential benefits. Is there any something different about people who have the Neanderthal role? So everyone we've looked at outside Africa have a Neanderthal contribution, but we have different pieces in each of us, right? So you can actually walk around people in this room and puzzle together the Neanderthal genome by jumping from person to person, so to say. And you can get something like 35% of the Neanderthal, you know, that way. But yes, we're just at the beginning of associating any of these variants with anything in how we look or behave or things you might look for in your husband. That may not have been a question a scientist would ask, but it's certainly a very human question. Please. My understanding is you worked primarily with mitochondrial DNA? Not anymore. Whenever we can, we really try to look at the new Plutinum because it gives us so much more information. I wondered, is it possible to use the male chromosome? Is that accessible? I mean, is it preserved enough to use? Yes. By a funny quirk of nature, these are females, the Nisovan high-caverage genome and Neanderthal high genome, high-caverage genome, but when we find a male and we have one in Spain now, one will be able to study the white chromosome. At least those parts of them are single copy, the large part of them that are repeated that will have problems with. Thank you. We'll take two more questions, Eric Green has a question. So I'm gonna actually ask the question of the moderator because I actually have something that I think you might be able to answer to shed some light on. What everything Sfante talked about has been made possible because of remarkable technological breakthroughs in DNA sequencing to allow exquisite sensitivity to be able to reconstruct genomic information from highly degraded bits of DNA. But he'd be the first to admit you even heard in some of his answers that what limits him now will be some technical advances and the computational methods will get better. But really what limits him from doing some things that even come up in the questions and answers of wouldn't it be great if, are better specimens and better preserved materials. And one can't help wonder if somewhere in this earth is our better preserved samples where the DNA is more intact and we can get much more accurate and complete genomic information from those specimens but we can't find it. So just as we've seen genomic technologies advance this field significantly, are there new technologies on the horizon for finding better specimens that can then be analyzed? Yeah, that's a good question. Well, if you look at the comparison of the extent of genomic coverage of the Denisovan DNA compared with those from a Vindia cave, even what caves are a good place to look. Caves in colder environments so far have been very good to look. I know that in our excavations right near the equator in Kenya that there have been times when I have been excavating, for example, the fossil elephant butchery site that's featured in one of the snapshots and through time in our exhibit on human origins. Whereas we were digging, we were actually seeing oxidation of plant roots, of ancient plant roots right before our eyes as we were digging. At that point, we turned over, we changed over to excavating with gloves, on sterile gloves and implements that we had not excavated with before or handled in order to try to see, is there something from the stone tools that we could recover? And we were able to actually see amino acids related to keratin and hair on them. So that's an example of something where if you, and this has gone on in one of the Spanish sites where you've worked in on the Neanderthals. Elsidron, is that the name of it? Yes, where people went in there, the excavators went in there with gloves and sterile conditions in order to recover these things. I would say that the best place to look would be caves. And the question is whether there are caves that have been sealed enough in areas that are closer to the equator, places in Africa, for example, where one might try to look. But it's, I think it's, your work has shown that it's a little bit like looking at for a needle in a haystack. Are there better imaging technologies that are becoming available that can allow you to find the sites to then try to dig or where to dig? Satellite technology has been great to be able to see exposed sediments, exposures of sediments places where the vegetation coverage is such that you can actually go and you can see eroded hills and gullies to recover things. But those, even there, when you get to outcrops where you can dig, where nature does the first excavation and you go in and you help nature along by excavating a bit further, we find the degradation of pollen, we find the degradation of organic materials. And so one of the questions that could be really, you know, that would get around that is if you could drill down, like we've drilled a core for environmental purposes out of the East African Rift Valley. But the chances of hitting a hominin bone in a drill core that's four centimeters in diameter going down are quite remote. So there's going to have to be some continued luck on the paleoanthropological side and where possible the use of sterile techniques. Yes, last question. Thank you very much for an excellent presentation and also for an excellent book that you wrote that talked about the decades of effort that took to develop these techniques, especially dealing with such small fragments of DNA and the extensive amount of contamination. Early in your book, you talk about the examination of Otzi, the Paleolithic man that was found in Europe. But you don't follow up with what we've learned later and I assume we've learned a great deal. One of the interesting questions perhaps you can shed some light on is to what extent is Otzi different from us? He's clearly not in the Anderthal, he's much closer to us, but is there a field of study of worth in looking at human beings using the techniques you've developed since the last breaks 3,000 plus years ago now that you've got these techniques to the point where they can look so specifically at individual genes and get pretty good cell, pretty good DNA registers and apply them perhaps on things in the last five to 7,000 years. Yes, I think that's a sort of area that's expanding very drastically, that many laboratories now that study sort of Neolithic, Paleolithic, the transition to agriculture in Europe. So I think that will be extremely illuminating and are all rather first insights that coming suggesting that it was quite an influx of populations that came with agriculture but in northern Europe there's also big contribution from earlier hunter-gatherers to present day populations. So I think there will be a lot of things in that timeframe that will come. Otzi is obviously very, very close to us today compared to Neanderthals, right, he could. Had we sequenced his genome in a person today we would not have reacted. So this couldn't be a person on the street today. In addition to the fossil Neanderthal from Shandadar Cave that we have on display we do have here in the Department of Anthropology in this museum one other fossil hominin from a site in Afghanistan. And I'm glad to say that Svante is going to, I think, go away with it in his luggage. You're going to get most of it back. In a couple of days. We don't know how old it is. It comes from a site called Darii Core and there's a plan to date the specimen and to have Svante's group sample the bit of cranial bone and see what it means for, not only for our collections but for the study of human evolution. As a follow up to that I just have a question. How many fossil human specimens do you have in your lab right now that you're working on? So we, of course, we have sort of milligrams of bone material from hundreds of specimens that we have had, yes. But many sites or, of course, many, many bones, for example. Right, right. Where can one get your book? In a bookstore. And there is a bookstore in this museum. And, of course, all around. Are you doing a signing by any chance while you're here? Not that I know of. Not that you know of, okay. So in any case, well, I hope that we have it in our bookstore. Does anyone know whether we do? Okay, good, good, excellent. That's a thumbs up on that. So, well, in any case, I can say it, Svante can't. Go buy his book. I want to thank you all for coming out on a snowy evening and contributing to a great evening here together. And a tremendous thanks to Dr. Svante Pable.