 Okay, hello. It's my real great pleasure to welcome you to the first international Steenbach Symposium. I'd like to just take a couple minutes to talk to you about the origins of this lecture series, starting with Harry Steenbach. So, Harry Steenbach was a Wisconsin native. He was born in Calumet, Wisconsin in 1886. He went to the University of Wisconsin-Madison. He got a bachelor's degree here in agricultural chemistry, a master's degree, and a PhD, all from this university in agricultural chemistry. He was recognized by his professor colleagues as being an outstanding prospect and was immediately hired into the faculty. When he began work in an environment where people were discovering vitamins at a university where the first experiments with rats were being carried out. And it was so in this environment, Professor Steenbach made a simple but really astounding discovery. That irradiation of the food fed to a rat suffering from vitamin D deficiency. It was not known that it was vitamin D at the time. The irradiation of the food, not the rat, cured the disease. This set the stage for a series of discoveries that extend clear to our time. Professor Steenbach was a very practical man and realized both the immense importance of this discovery for health and disease, but also the commercial potential. Some of you know this part of the story. Professor Steenbach sought to patent this discovery and did receive that patent and attempted to assign it to the university. That was an unusual event for academics at that time and the university declined that assignment of the patent. And so Professor Steenbach formed an organization called War for the Wisconsin Alumni Research Foundation with some of his friends and assigned that patent to war. Shortly after that, the Quaker Oats Company licensed that patent and paid $2 million. At that time, it was a very large sum of money. And I mentioned as I look through some of the history, Professor Steenbach's annual salary when he started here was $720 a year, eight and 10 installments. So he had basically a C basis appointment. So as we walk about this campus, we can see many, many examples of how this partnership and inspiration of Professor Steenbach to start war has enriched this campus. It's spread everywhere as you look. Now, as is true now, inventors who have a patent that receives royalties to war get a personal share of that income. That was true when Professor Steenbach was here. And so Professor Steenbach returned that income, his personal income to the university in many, many ways. This lectureship is one of those. And so we have this to recognize his generosity and to honor that thought and contribution to the university. I'd like to now pass the microphone to Professor Asim Ansari who will introduce our guest of honor for this first international Steenbach lecture. Thank you, Brian. Today's speaker, of course, needs no introduction. His work in identifying the Neanderthal genome is well known in 2009, I believe. They announced the full draft of the Neanderthal genome. 2010, the Denisovan genome. And that really captured the imagination. He has woven together many strands of intellectual pursuit that engage us all in the deepest abiding mystery. We want to understand where we come from of human origin. He's going to talk to you about that today. It brings together archeologists, anthropologists, molecular biologists. You could have seen the sort of people that requested to meet with him. It spans the entire campus. And he's done it in a way that is understandable to each one of these disciplines, people who follow each one of these disciplines. And today he's going to tell us what he has used, innovated, and applied from a variety of different disciplines to understand the genome. Tomorrow is a second talk at the historical society where he'll give us a sense of a more public view, an understanding of the genome. I want to also point out that he comes here today from San Francisco for having given out the Breakthrough Awards. These are the new awards that have been launched just like the International Steam Box. He's the inaugural speaker. He handed out yesterday Breakthrough Awards at San Francisco. And he received one last year. And before that, he was in Tokyo receiving yet another award. And before that, he was in Leipzig where he's the director of the Max Planck Evolutionary Anthropology... Yeah, let me get this right because it's got exactly... Molecular Anthropology Institute at Leipzig, Germany. Now, I mention this because a friend of mine just decided to give up her Howard Hughes to move to Munich as a member of the Max Planck. She tells me that being a director of the Max Planck is a beautiful thing. Those are her words. So if you give up a Howard Hughes to move there, you can imagine. And with that, he has brought together a collection of amazing scientists. And before that, he was... Let me see. He was listed as the most influential scientist, 100 most influential scientists by Time Magazine. He's won the Gottfried Libnitz Prize, one of the highest awards from the German Academy. He's a member of various academies, national academies of the US and Sweden, Helsinki, Finland, Croatia, Japan, Russia. I can just go on. Members of the Academy of all these scientific agencies. Before that, he was a professor at Munich and a postdoc at Berkeley. And while he was in transition, his first paper that caught the collective imagination of scientists across was sequencing them, amplifying, and sequencing the Mamed DNA, Egyptian mummies in 87 in nature. And since then, it's just been a trailblazing to the force and has defined this field and is perhaps going to help us nucleate the molecular archaeology group here at Wisconsin. And with that, let me hand it over to Professor Pebo. Welcome him to Wisconsin. Okay, thank you very much for this very generous introduction. Please tell me if the loudspeakers work or not. They do work. Okay, good. So I should just start by sort of saying that I feel very honored and happy to be here finally to give the very first, as I understand, Steenbock lecture. It's an amazing place that I've heard a lot about and it's wonderful to finally be here. So what I then wanted to do is to begin with a bit about how we retrieved the Neanderthal genome, what we may learn about interactions between Neanderthals and modern humans from studying the genomes and then for the second half of the talk, then more volume. Talk about what we might learn about human origins in the sense of sort of functional adaptations in humans that are there in modern humans and not seen in the Neanderthals. So that would be the second half. But I just want to start with sort of reminding you sort of what you all know that our genome is like 3 billion base pairs and that we have a difference about every 1200, 1400 nucleotides or so when we compare to human genomes. So it means we have in the order of 3 million differences or so between genomes. So we have a lot of information with which we can potentially reconstruct human history. So if we now do that in a very bird-sized view, we just look on the variation among present-day humans. What you also know is that what we then find is that most of the variation is found in Africa. If we take the entire world outside Africa, the amount of variation there is less and not only that, most haplotypes or sequences out here have close relatives inside Africa. But there is a component of the genetic variation in Africa that doesn't have any close relatives outside Africa. So the interpretation of that is then that modern humans the direct ancestors of everyone today evolve in Africa, accumulate variation there and a part of that variation go out and colonize the rest of the world. And with genetic tricks by looking at sort of the extent of linkage disequilibrium and haplotypes out here, you can approximately estimate when that happened and it's sort of less than 100,000 years ago or so. So that's sort of the genetic evidence for this recent African origin of modern humans. But if you like, there is then a problem of that with that and that is that 100,000 years ago there had of course been other forms of humans there for a very long time. And most well known are then the ones we have in Eurasia, particularly the Neanderthals in western Eurasia and other less well known groups in eastern Eurasia. So as you also know I think Neanderthals are then this robust forms of humans. They appear in a fossil record depending a bit on how you define a Neanderthal now between three, 400,000 years ago. They exist in western Eurasia until about 40,000 years ago when they become extinct, generally in connection with that modern humans appear in an area. So you may then ask why should we be so interested in Neanderthals? And I think there is to me one big reason for it if you like and that is that they are the closest evolutionary relative to all present day humans. So if we should sort of define ourselves as a group it's really them that we should compare ourselves to. So in some sense they sort of define us as a group. There are other reasons too to be interested. They were here quite recently just 3,000 generations ago or so there were Neanderthals in western Eurasia so you can ask how are they related to us what happened when we met and so on. And this last question then what happened when we met has been debated a lot in paleontology. So essentially there is one extreme opinion that says modern humans come out of Africa meet Neanderthals and replace them with no mixing whatsoever meaning there would be 0% contribution from Neanderthals to present day Europeans. Another extreme view that no one really holds I think is saying Neanderthals are the direct ancestors of Europeans. They would be direct continuity but you can imagine anything in between here. So we got the chance to test this with molecular means then in the 90s when we got sort of access to the first Neanderthal fossil not just any Neanderthal but the Neanderthal from Neanderthals to say that was found in 1856 and was really the first time I realized there were other forms of humans around before present day people. So a sample from the upper arm there at the time we needed quite a lot of material to do this kind of work and we could profit from already like 20 years almost of experience in how you work with ancient DNA that you're very scared of contaminations you dress up in funny clothing and work in special lab and do a lot of stuff. And at that time with the technology one had the polymerase chain reaction you needed to focus on some certain part of the genome you're interested in so we focused on the mitochondrial genome simply for the fact that there are many copies per cell so it's a bigger chance that some fragments will survive we focused on a particular variable part of the mitochondrial genome and then determined that an estimated phallogenetic tree for the mitochondrial genome. And what we found was rather surprisingly to us at the time the Neanderthal mitochondrial genome go quite far back to common ancestor shared with modern humans about half a million years whereas all present-day mitochondria go back just between a hundred and two hundred thousand years and there have been a lot of humans tens of thousands of humans studied by now and it's very clear there's no present-day human that runs around with a mitochondrial genome from an Neanderthal. So in this scheme of things then is sort of total replacement. But it's of course also true that the mitochondrial genome is a very tiny part of our genome inherited as one unit so it's a big element of stochasticity and it's only inherited from mothers to offspring so any woman that has only male offspring for example her mitochondria will become extinct. So it gives a very limited view of our history that the real picture isn't a nuclear genome and it was again sort of technology that came around and made it possible to start studying the nuclear genomes and that was high throughput sequencing that came around in the beginning of this millennium. So instead of then focusing on some certain part of the genome you could just start doing an extract of the DNA and sequence all the DNA that's there in this fossil make your own little database compare it to the nuclear genome other of humans and others and sort of start working with this. Ooh, it got dark. That's okay. Perhaps it's good with dark. People can sleep. So the first place then where this worked for Neanderthals was the site in Croatia, in southern Europe and this bone, this fragment of the bone here around 40,000 years old and the first thing you will then notice if you sequence DNA from this is that it's indeed very short fragments. It's degraded 50, 60 base pairs hardly anything above 200. Let's see. The other thing that you will notice is that only a tiny part of the total DNA is coming from the Neanderthal and the vast majority is from bacteria fungi that have lived in the fossil when it was deposited in the ground. So our very best Neanderthal bones at the time had like 3, 4%. That's exciting. Now it's good, isn't it? No. No? Wow. Wow. Lecture. I'm sorry. Yeah, that's fine. Can we take away this thing at least? How do we get that to work? We do right. Lecture. I don't want to turn that light off. Yeah. Lecture. Now I hit the lecture. That's it. Lecture. Lecture capture. This is very exciting. We do dim. I like that. Ha! Ha! Okay. Let's see. Interesting. So we were then, this was about 2005 or so and we were very lucky then to get funded for five years to really work when we sort of could show that it would be a chance to reconstruct the Neanderthal genome. We could get money to sort of improve our method for extracting DNA from such bones, turning them into a library that you can feed into these machines in a more effective way. So we got a lot better in doing that. In the process, we also learned a lot of other things. For example, that if you now look in the sequence of these fragments and map them to the human genome, you will find a striking thing that you have a lot of apparent C to T substitutions and that they are particularly towards the ends of the molecules. And that turns out to be due to the amination of cytosine residues. So you lose this amino group, you get uracil. And of course, the uracil is read by DNA polymerases as a T when you replicate these molecules. And that happens particularly towards the end of the molecules where you have single-stranded overhangs that are more sensitive to the amination. So we also looked through many, many sites and bones. Finally, the focus of three neanderthals from three different individuals at that site in Croatia sequenced a bit over a billion DNA fragments, most of them then of bacterial origin from those bones, and then designed computer programs to map these short fragments to the human genome taking into account that you have this apparent C to T substitutions that particularly accumulate towards the ends of the molecules. So we then did that and sequenced about 3 billion bases from the human genome. So on average, each position had been seen once, but that then means that we had covered with one or more fragments a little over half of the genome. But we could then for the first time begin to ask questions. And one of the questions we were interested in was and this. What happened when one met? Was there interbreeding or not? When modern humans came to Europe and met neanderthals. And we addressed that in many ways, but the most obvious direct one is sort of this, saying that if there had been interbreeding, we would expect Europeans today to share more genetic variance with neanderthals than people in Africa today, because there never been neanderthals in Africa. So there's no reason to assume any special relationship between Africans and neanderthals. So it's just this idea, if there is no contribution here, then the neanderthal is just as far from people in Europe as from people in Africa. If there is a contribution, then on average, the neanderthal will be closer to Europeans than to Africans. So we had a neanderthal genome. We went and sequenced five genomes from around the world, Europe, two in Africa, China, Papua New Guinea, and did a very simple test first. Simply saying, if we now compare two present-day genomes and to test this idea, we take two Africans, find places where they differ, and then we have the neanderthal genome. And we can just see how often does the neanderthal match this African or that African. And that should be 50-50, right? Since we don't expect neanderthals to have contributed more to one African than the other, since they've never been there. And indeed, that's the case. We found, statistically speaking, 50-50. But when we then looked at the European individual and one African individual, to my surprise actually at the time, we found significantly more matching to the European individual than the African individual. Even more surprising was that we went to China versus Africa. We again find more matching to the Chinese individual, although most people would say there had never been neanderthals in China. And Papua New Guinea, where everyone would agree there had never been neanderthals, we also find more matching. So the sort of idea that came out of that was then to say that, well, when modern humans come out of Africa, they're probably passed by the Middle East. We know there were neanderthals there. So if these early modern humans that then went on to become the ancestors of everyone outside Africa mixed with the neanderthals, they would sort of carry with them this neanderthal contribution out into the world, also to regions where there had not been neanderthals to the extent that somewhere 1-2% of your DNA, if your roots are outside Africa, will come from neanderthals. So we've then gone on and worked, particularly with archaeologists in Russia, particularly at a site in southern Siberia on the border to Mongolia and China, the Nisava Cave, this beautiful site, where they in 2010 found this toe phalanx, which turned out to come from a neanderthal. By that time, we had then designed a new way to doing DNA libraries. That's much more sensitive than the ones we had before. So other methods rely on having the double-stranded DNA, manipulating the ends so you can ligate on adapters here, amplify and sequence your thing. This new development then relied on separating the two strands. You have single DNA strands. You do single strand ligation here, immobilize your fragment on a surface, and then synthesize the other strands. Each strand in a double-stranded molecule have two chances to make it into the library, so to say. And that turned out to be a big breakthrough for making really sensitive libraries. Often you have chemical modifications that affect only one of the strands, so that's lost, but you don't lose the whole molecule. You can get the other strand then. So we could go from then having just a little over half of the genome covered to covering this from now a single individual actually 50 times on average over, so we have a 50x neanderthal genome. So you can then begin to do much more things. You can, for example, walk over the genome and look for heterozygosity in windows. And one striking thing that we saw immediately was that there were huge segments in this genome without any variation at all, big regions of homozygosity. So this, of course, indicated that the parents of this individual must have been closely related. So you can then estimate the relationships that these parents must have had. So they could have been either of these four scenarios. They could have been half siblings. They could have been grandfather and granddaughter. They could have been, don't even ask me what double first cousins are, but sort of something went on in the cave there anyway. So it will be very interesting in the future to see if this is sort of typical of neanderthals or not, or this is sort of only at this site. I should say we now have a second high-caverage genome from Croatia, and at least this closely related is the parents are not there. So this is sort of not totally typical. You can then also, in present-day people, say, example one chromosome here, go over the chromosomes and identify with greater accuracy than it could before segments that come from neanderthals. And indeed, it's sort of one to 2% of the genome, just quantitatively to give people a feeling for this. But it's, of course, a case that that sort of, in total amount of DNA, it sort of represents as if you would have one neanderthal ancestor, six generations back. But of course that would be distributed in large chunks. This is in small chunks, thanks to recombination. You can also then ask how much remains today of the neanderthal genome in present-day people. You can sort of go from person to person and puzzle together longer segments like this. And it's a bit unclear, but in the order of, say, 40%, maybe 50% of the neanderthal genome still then exists in people today. And there are more interesting things that people, that they find there in this site in Russia. In 2008, they were very skilled, I must say, to realize that this little fragment might come from a hominin and it turns out to be a part of the last phalanx of a child, the fragment of the last phalanx of a child. If you want to know if there are archaeologists here, I should probably not say anything. I should say that, at least. I mean, there is a tendency in Western archaeology, I think, to talk down about Russian archaeology and say they excavate like we did 30 years ago. They just want to find the big things. Not really scientific excavations, but it was very skilled of them to realize that this might be a hominin bone, I think. So we actually were able to sequence a good genome from this little bone too and were very surprised to find that it was not a neanderthal, not a modern human, but something else, something that goes back a long way to common ancestor shared with neanderthals. So if the deepest population split among human populations today is in the order of 100,000 years, this is about four times deeper. And as always with these things, this depends on what mutation rates in humans you believe in and things like that, but this ratio of 4 to 1 will sort of remain. So we debated a lot about what to call these things and decided they are called the Denisovans, just as neanderthals are named after the first site they were found. These are named after the Denisovac cave. You can ask, have they interbred with modern humans? And yes, they have. And you find contribution particularly out in populations in the Pacific, a bit in mainland Asia and nothing in western Eurasia. And up in Papua New Guinea, for example, up to 5% of the genomes of present-day people then come from these Denisovans. And that's on top of the neanderthal contributions, so to say. You can look at heterosagosity, begin to look at that. In present-day people you see Africans and more heterosagosity than present-day people. And the neanderthals and Denisovans then have even less, about a third or so of the heterosagosity that you find in Europeans, for example. And you can then look for contributions from these extinct forms to present-day humans, but also in other directions. So there is this contribution then from neanderthals into the ancestors of all non-Africans. But what you find is that Asians actually have slightly more neanderthal DNA than people in Europe. So there is rather good evidence that there is later contribution to the ancestors of Asians that add on a little bit on that. There is also in the other direction contribution from neanderthals into Denisovans of a few percent. And there is a contribution from Denisovans then to Asians, mainland Asians, and a much bigger contribution to people in Oceania. And quite interesting, there is a sort of old component in the Denisovan genome that is not there in the neanderthal genome. So there is a contribution from something else into Denisovans that separated more than a million years or so ago from the human lineage. It's very tempting to say this is homo erectus in Asia or something like that, but we don't know what it is, of course. And it's even more complicated than that. There is now also some evidence that there might be info that they've gone on in the other direction from really early modern humans into neanderthals. And I just want to give you a feeling for the evidence for this. So if you sort of go in windows across the genome and look for windows where you have sort of one archaic group, say, neanderthals falling way back in the tree much further than the other archaic than the Denisovans or vice versa. So this is regions where not neanderthals and Denisovans have a common ancestor, but one of them go much further back. Then you will see that there is an excess of these deep lineages in Denisovans. This is this indication of this very archaic, very early diverged contribution into the Denisovan genome. But if you now go in the other direction and look for places where one archaic individual falls in with present-day Africans and there are other archaic falls outside, sort of having young haplotypes, if you like, in the archaic group that is similar to some people in Africa today, then there's an excess of that in neanderthals. So the interpretation of this is then that yes, there is this contribution from this early diverged thing into Denisovans, but there seems to also be a contribution from really early, more than 100,000 years ago, modern humans into neanderthals. And it's quite interesting what that is if there is some sort of early out-of-Africa population that is then not ancestral to present-day people outside Africa, but that mixed with neanderthals. And I think in the future one will probably learn more about that if that is true. But so one message of this is then that we have always mixed as humans also with these other forms of humans and at least to some extent. And we have a recent indication of that. That is a fact from this site in Romania where one has found this mandible that looks like a modern human mandible. It's 40,000 years old. So it's among the earliest modern humans we know of outside in Europe, outside the Middle East. And when we studied the genome of this individual we were then very interested to ask since this person lived when neanderthals were around had it already mixed with neanderthals or not. So this is a number of other modern humans on one chromosome, colored lines indicate there are fragments coming from neanderthals. So the question is, do we see any such contribution in this individual? And indeed we do. And a lot more actually than in present day humans. And in fact where it's black here or sort of areas where we have no information. So there is really this case that more than half of this chromosome is solidly of neanderthal origin. Across the genome there are then seven such regions. So this again suggests there is a neanderthal ancestor here quite recently in a family tree. So with this sort of size and number of fragments we can sort of say that six, five or four generations back there was a neanderthal ancestor to this individual. There is sort of almost caught someone in the act of mixing. So we then know that when modern humans come out there is this sort of early mixing, ancestors of Asians and so on but there is then also mixing locally in Europe. So very clearly then we have rejected this total replacement idea. There is a contribution from other groups but it is rather minor. It's certainly below 10%. I doubt one will find anything more than that in present day people. The vast majority of our genetic variation still comes out of Africa. So to sort of not lose track of that we sort of like to call this model say leaky replacement or so. The big picture is replacement out of Africa but there is some contribution from these other groups. So we can then ask does this matter? Does this mean anything? Is there any functional consequences of this contribution from neanderthals? So you can say go over the genome, whole genome of Europeans or Asians and find places, generally these contributions from neanderthals are a few percent but there are some regions where 60, 70, 80% of people carry something from neanderthals. So it seems to have been positively selected and you can ask overall what group of genes are in such regions and that turns out to be keratins. So structural proteins in skin and hair. So we don't know what that is but we will probably learn in the future then of some sort of functional aspects of skin or hair that comes to Asians and Europeans from neanderthals. There are also other things. There was a group that found this gene variant, the variant of a liquid transporter which is associated with risk for type 2 diabetes. And this risk allele is prevalent particularly in Asia and Native Americans and if you make a tree you then see that the risk allele is closely related to present day risk alleles and not to the preposterous alleles. So you may then ask why would something that causes disease type 2 diabetes come over from the neanderthals and rise to high frequency. And I think there is at least the speculation that this must then have been of advantage in the past and it's sort of possible that that advantage could be survival in starvation. That those alleles that sort of give us type 2 diabetes today when we eat too much during our whole life may have been an advantage in the past. It may be some neanderthal adaptation to starvation. Denisovans also contributed something, yes they have. So in Tibet populations live at very high altitude where there is little oxygen in the air. It was already known that an important genetic adaptation for that was in a gene called EPAS1 that has to do with being able to take up a lot of oxygen without getting very many red blood cells per volume in your blood. The lead frequency of this variant is very high in Tibet, very rare at other places. And Rasmus Nielsen's group at Berkeley showed that this variant of EPAS1 comes over into the ancestors of Tibetans from Denisovans actually. So it's fascinating that it may not be that we would have had so large populations on the high plateau in Tibet if it wasn't for this contribution from Denisovans. There's many things coming out now sort of with sort of functional consequences of this variance. One thing is a cluster of toll-like receptors, receptors that have a function in innate immunity that actually come over both from Neanderthals and Denisovans into present-day people. If you look at people that are homozygous for these Neanderthal variants they express more of these toll-like receptors. And if you look at association studies with phenotypes for this, these variants from these two groups are then associated with increased resistance to helicobacter pylori infections. So if you don't have an ulcer, you may perhaps thank Neanderthals for that. But these same variants are then associated with increased sort of risk for allergic problems. You may blame them if you have allergies. So there are quite a few things. This is just a review that came out a few weeks ago of things that seems positively selected in the human genome that have come from Neanderthals. So several of these things are involved in immunity and actually also in skin and pigmentation. And quite a few things are not known what they've done. So there is a sort of this view emerging then that these modern humans come out of Africa, meet these other groups that have lived for hundreds of thousands of years in the environment in Eurasia that may have evolved sort of some advantageous variance there and they then transmit to modern humans and they then increase in frequency. So this is something you might call adaptive radiation or so. But it's still the case of course that most variants we find in present day people from Neanderthals that have some function are simply associations with risk for disease or being protective alleles. So many things such as hypercoagulation, many skin diseases but also things like depression or so that comes up now. So finally then what I wanted to also discuss was in a sense what was not contributed by Neanderthals to modern humans. So you can go over the whole genome in Europe in red, Asia in green, look at the frequency of things coming from Neanderthals and then ask are the regions where we would statistically expect Neanderthals to have contributed but we find nothing. It's like we select against the contribution and there are indeed such regions and we are so interested in them because we sort of imagine that it might be then the genetic background for sort of functions unique to modern humans that hide here. So things changed after we separated from Neanderthals and became prevalent among present day humans. And we are so interested in them because there are of course some things that are sort of behaviors or things that seem unique to modern humans. It's after all true that if you compare modern humans to Neanderthals, Denisovans, all other forms of now extinct humans that existed. It's only modern humans that start developing technology, it changed really rapidly and become regionalized in the world. Only modern humans start doing figurative art that really depict something we can recognize. It's almost like political correctness today to sort of find as an archaeology some Neanderthal art but I'm sometimes a bit sort of saying that it looks like very modern art to me because you cannot see what it sort of depicts sort of things that really show something that counts with modern humans. And of course only modern humans start becoming really numerous millions of people and spread across open water and colonized entire world, come to Americas, come to Australia. So the idea is then that looking at things that are there in everybody today no matter where we live on the planet but not in Neanderthals would be interesting. So we can make this catalog now because we have the Neanderthal genome and it's not a very long list. So it's an order of 30,000 changes in the genome. So whereas two genomes between people today differ at sort of three million differences, if we make the requirement that everyone should share something today but the Neanderthals differ then it's just 30,000 changes. You can look through them in an afternoon in a computer. The problem is of course that you don't really know what you look at, what it means. And I think that is where there will be a lot of interesting things for the next five or 10 years. So we have to give you a feeling for how we begin to scratch the surface of this. We can think about these 96, there are only 96 amino acid changes fixed in humans and ancestral chimp-like in the Neanderthals. And they fall then in 87 proteins and you can then ask which ones of this would be important and we have a bias from what I said about modern humans that we think it should have to do with cognition or brain function in some form. So you can then ask for example in the developing brain by looking in the Allen brain atlas, is there some region of the developing brain where these proteins are over expressed, more expressed than as a control the genes that have silent changes that are ascertained in the same way, fixed in all humans, ancestral in Neanderthals but doesn't change amino acid changes. So the only region is then in the subventricular, matricular zone of the epithelium where neurons are born in the developing brain. And this now is a weak effect. It relies on very small numbers. In total 87 genes, right, this is like six genes that are expressed there, but very surprisingly to me three of them are involved in the spindle and the kinetic core so the machinery that pull chromosomes apart in mitosis. So we speculated when we saw this saying maybe this has to do with how stem cells divide and the geometry in which they divide determines how many neurons you form perhaps also what type of neurons. This was just speculation, but I sort of want to hint that one can now start studying this functionally and this comes from work with induced pluripotent stem cells that as you know you can differentiate into different types of cells, different types of neurons for example, but also into organoids like three dimensional structures that sort of mimic developing tissues. So you can make brain organoids, little bubbles in tissue culture where you sort of have this sort of same architecture with epithelium. So a group in our lab has sort of done sort of studied and compared between fetal developing brain and organoid brain and shown that this sort of patterns and gene expression in single cells here are very similar. We also can now do from chimpanzees, stem cells, chimpanzee brain organoids and compare now brain organoids from chimps and humans. In general they are very similar, but you do find some interesting differences and one of them actually involves precisely these cells that go through mitosis in the apical part of the epithelium here. So if you look by time-lapse photography on how the cells now, the chromosomes line up in this metaphase plate and the chromosomes are then put apart, you will find if you compare the chimpanzees to the humans that this period phase is longer in the humans than in the chimpanzees. And that turns out to be specific to these stem cells that form neurons in other mitosis that we look at between chimps and humans. We don't see this difference. So now it's sort of very tempting to say maybe it has something to do with these amino acid changes that affected the proteins in the mitotic spindle and kinetochore. So the next thing we want to do is then to introduce these changes into stem cells and make organoids now ancestralized for these proteins or to say and see if we see any effect of this. So this sort of, I think, where this field will be going in the future, one direction will be to ancestralize stem cells and study in vitro cells and organoids. The other approach will actually be to do the same thing in the mouse and we try to do the same thing for these proteins in the mouse. For the last two, three minutes, I just want to illustrate one other such project, the gene that we work on since 10 years now to indicate that mouse models or suggested mouse models may also be useful for human-specific traits. And this gene was found by Tony Monaco's group in Oxford in a famous family where a severe language and speech problem segregates over three generations. So they were able to identify the gene. It's a gene called Foxp2 encoding a transcription factor. And interestingly, the encoded protein is very conservative among mammals but has two amino acid changes in humans that's not there in apes and other mammals. So we were, of course, very interested then when we started getting the Neanderthal and Denisovan genomes, what were the states at these positions? So these are the two positions in the gene. So when we then get the Neanderthal and get the Denisovan, what we found was that they were identical to present-day people. So these changes clearly happened here before we separated from Neanderthals. They are still interesting, but whatever we find about them is shared with Neanderthals. And as I said, this protein is very conservative all the way to the mouse. It has only one other change that's hopefully very conservative there. So what you can do is humanize the mice. So you change the genome of the mouse to carry these human-specific changes. So you then end up with a mouse that essentially makes a human protein from its Foxp2 gene. And this idea is this should have something to do with speech and language. You try to speak to the mouse, and it doesn't answer. Probably it sort of lifespan is too short to really acquire fully human language. But you at least have a sort of model where you can then start looking at this. So for example, you can find that in the humanized mice when you compare to their littermates, neurons in some parts of the brain make longer dendritic trees, bigger dendritic trees. And this is then seen particularly in parts of the brain that are part of these corticobasal ganglion circuits that have to do with motor learning. So this stimulated the graduate student and the laboratory finished, Kristianne Schreiweis, to go to MIT and work with Ann Graybill, went there with these humanized mice to study motor learning in the mice. And then they do experiments like this where the mouse has to go in a maze and find something it really likes, which is chocolate milk. And you give it a cue, say a light or a signal saying it should go to the left to find this. And you can then train the mouse to sort of follow this cue. And there's no difference for the humanized and wild type mice in how quickly they learn this. But it then comes a time, if you always give the signal, say to go to the left, where you can take away the cue. And the mouse sort of internalized this. I just go to the left and I get my chocolate milk. And that switch comes in seven to eight days in the humanized mice and their siblings that are wild type take 11 to 12 days to sort of figure this out. So there is a clear difference in sort of how fast you sort of do proceduralize something like this. So I'm not a neurobiologist, but the neurobiologist sort of explained this to me by saying this is a model for sort of motor learning in humans. For example, when you learn to bicycle, when you start to learn to bike as a kid, you're really bad at it, right? You think about what you do and it's very complicated. And if I tip to the left, I should stare to the left actually to compensate that. But then comes the time and you can't really make it clear for yourself when you stop thinking about what you do. And the moment you stop thinking about what you do, you get really good at biking. And this goes together then with a switch in activity from the middle part of the striatum to the lateral part of the striatum. One of these parts where we see this bigger dendritic trees. So that may stimulate us to go back to the mouse and look for long-term depression. So sort of a model for learning and memory where you give a high-frequency stimulation and measure how much less excitability you get after that in these neurons. And in the lateral part, we see this effect much more pronounced in the humanized mice than in the wild-type littermates. Whereas in the medial part of the striatum then we don't see any such effect. If there is an effect, it's even in the opposite direction. So this matches then with the idea that it would be a stronger switch to a lateral part to automation of this motor behavior. So you then at least have a hypothesis suggesting that these human-specific amino acid changes may have something affect these corticobasal ganglion circuits to make for faster automation, if you like, or motor coordination tasks. And it's of course very stimulating or sort of tempting to speculate that the sort of most sophisticated motor learning, motor coordination I should say that we do as humans is articulation. We need millisecond control between vocal cords, lips, tongue to produce articulate speech. No other primate can do that to that extent and it actually takes two, three years for us as kids to learn this. So it may well be then that this has something to do with that. So I think that sort of very, very optimistic that one may actually be able to use a mouse as a model also for some human-specific traits. We might be able to humanize and neanderthalize if you like, pathways in the mouse or organelles even in the mouse in the future. And I think that's sort of where I think this sort of field of sort of modern human origins is going that we now have the neanderthal genome. We can determine what happened earlier on the human lineage and what happened very recently. And the next challenge is now also to try to understand this functionally, which will be a lot of work, but it will involve, I think, stem cells that you manipulate and also then mice that you humanize. So with that then, I should say, many more people that have been involved in this than I can mention. Many paleontologists, archaeologists, many people in the lab. I mentioned one person in particular, Mathias Meyer, who developed this highly sensitive, single-stranded method for making libraries. Without this invention, we would not have high-caverage genomes of neanderthals and denisovans today. I should also mention Jesse Daveney, who is now here and thus ancient DNA at this famous university. And there are a lot of people also involved in this functional, in population genetics work, interpretation of this, I should say. I mentioned particularly Janne Kelsen, Keif Rufler, who sort of coordinate all this bioinformatics and David Reich at the Broad and Harvard, and Montes Latkin for population genetic work. Functional work, many people are also involved. I mentioned particularly the single cell genomics group in our institute, Barbara Troitlein. And Jiland Hotner's group for the sort of mouse brain development work that we do with them. And with that, I then thank you for your attention. We do questions, right? So we can pass the bike around, or perhaps you could repeat the question. We also will limit the questions. There's a reception after this in the neighboring building in the atrium, the latest glass building on the other side of the oak. It's Hecht Deluca Laboratories. So you go until six. So if you have questions, reserve them. I didn't get your question right now. With that, let's start. Can we turn the lights on? No, we do that. Lecture, let's... You can wake up now, questions. Please. So the question is, 40,000 years ago, the Neanderthals were already mixing with humans? Yes, they had mixed. Some Neanderthals had mixed with humans at that time. Yes, so well, those Neanderthals that we have studied, also 40,000 years ago, they have not mixed with Neanderthals or their ancestors yet. I think that mixing happened in the Middle East somewhere. It didn't have in Siberia or in Europe where we studied this. But we also have older Neanderthals, yes, that are more than 60,000 years old. But we have not yet... We would actually be very interested in finding a Neanderthal where we found gene flow in the other direction more recently. And we have not found that yet. Ah, yes. So when did the Neanderthal ancestors leave Africa? We don't quite know that, but the ancestors of... The common ancestor of the Nisimans and Neanderthals presumably lived in Africa and came out. There is something called Homo heidelbergensis that the paleontologists recognize that are seen both in Africa and outside Africa. That's probably the ancestor of these people. We have... The oldest DNA we now have from hominins is around 430,000 years old in Spain. And that's already... It's early, but it's only Neanderthal lineage. So by 430,000 years ago, the ancestors of Neanderthals were already in Europe, so to say. But it's probably a bit before half a million years ago or something like that. Yes, the question is, was it primarily males who contributed? So Monteslatkin has sort of... We have been very tempted to claim that. But Monteslatkin had simulations on the reasonable population sizes and things that this could happen just stochastically. You could lose the mitochondrial DNA just by chance. There is another expectation. If it was primarily or only males, we would expect less contribution on the X chromosome, right? Because the males would only contribute an X chromosome to half their kids, to their daughters. And in fact, we see less contribution on X. So then we were again very excited and said, yes, it's indeed so that modern human females found Neanderthal men attractive. But then we have found this sort of negative selection in other parts of the genome, in the autosomes. We see this sort of deserts. So then we got very scared and said, well, it could be that you also have selection on the X for this. So we sort of don't dare really claim that it is like that. But if I should bet on something, yes, it was the men that were attractive. Do you see a similar appetite as that? Yes, so it's a good question. It's of course, what about the mouse background? So we have not done that. We should probably do that. I mean, I would perhaps then more go and do it in a marmoset or something like that, where you would have more vocalization, more human-like things. There is actually a group at Keio University in Japan that is putting in these things in the marmosets. So we will know in a year or two. We have not seen anything that's fixed. The question is, do we see anything in European donations that's fixed that come from Neanderthals? And I'm now thinking, do we have some kind of ascertainment bias in that we wouldn't really discover it immediately. But I think we should have seen it because the way we identify these things are looking for things outside Africa. That's not in Africa, but that is Neanderthal, similar to Neanderthals. They should have popped up. There are things that are 80, 85 percent. Yeah. Shall we do that first? The question is, do ex-chromosomal depletion suggest that hybrids will less fit? I think yes, probably. There's another thing that I didn't mention if we just say in these deserts where we seem to select against Neanderthal contribution, the genes in those regions, where are they expressed in the body? And the only sort of significant thing there is testicles, male urnite. So that sort of suggests that yes, it may be a whole day in cirrhubal that when closely related population species mix, it's often the heterogenetic sex that has problems. And that applies then for some of these things on ex-chromosome, too. So yes. It may well be that one mixed both sexes, but it's actually the male offspring had problems. Yeah. So you have this mixing between Neanderthals and modern humans in Asia and Middle East. But back at Africa, apparently, there's multiple hominid groups involving at the same time. And presumably, there's some mixing there and maybe some of the genetic diversity in modern Africans is due to that. Is there anyone looking at that and trying to put together some of that evolution that's happened in Africa? Yes. So the question is what about Africa? Is there contribution from other groups in Africa to modern humans, archaic groups? And yes, absolutely. I think that may very well happen. We don't have any really old genomes from Africa. We have now one genome from Ethiopia that I think is 3,000 years old or something like that. There are some other things coming in the literature that is in the Holocene, all of them. But I think the situation is also a bit more complex in Africa because outside Africa, we have these sort of Neanderthals and these other forms, and there's a period of separation, and then one meets again. So we can sort of really detect it. In Africa, there were probably different forms of humans, perhaps more continuously in contact with each other. So it might be a bit harder to figure out, but it may well be exactly as you say that the bigger variation in Africa is also due to. So I've been tempting to say only Africans are the fully modern human population. Everyone else has this primitive thing from these other groups, but I would think that that exists also in Africa in the end of the day, when one has looked. Perhaps you can stop here and head over to the reception and get some food as well.