Print BCTV: Ancient Echoes -- Svante Paabo on Neanderthal, Denisovan contribution to modern human DNA

Ancient Echoes

Transcript of BioCentury This Week TV Episode 190




Svante Pääbo, Director, Department Of Evolutionary Genetics, Max Planck Institute For Evolutionary Anthropology




1000 Genomes Project

Dr. George Church

Anatoly Derevianko, Director, Institute of Archeology and Ethnography of the Russian Academy of Sciences



Steve Usdin, Senior Editor




STEVE USDIN: I'm Steve Usdin. Paleogenomics has made it possible to sequence the genomes of Neanderthals. A paleogenomics pioneer joins us to discuss what it means to be human. I'm Steve Usdin. Welcome to BioCentury This Week.


NARRATOR: Connecting patients, scientists, innovators, and policymakers to the future of medicine. BioCentury This Week.


STEVE USDIN: Svante Pääbo, a Swedish scientist, has developed techniques for extracting and analyzing ancient DNA. Pääbo led a team that sequenced the genome of modern human's closest relatives, the Neanderthal. To the astonishment of many paleontologists, Pääbo's research shows that Neanderthals mated with modern humans, and echoes of those encounters live on in the DNA of many people who are alive today.


Just as scientists began to study what physical or behavioral traits we've inherited from Neanderthals, Pääbo's team announced another discovery that changes conceptions of human evolution. They determined that ancient DNA from a tiny bone fragment discovered in a cave in a remote region of Russia came from a new human species. This species, Denisovans, also interbred with modern humans. And like Neanderthals, Denisovans live on today in the DNA of people who live in Papua New Guinea and in the genomes of Australian Aborigines. Beyond rewriting the story of human origins, Pääbo's team and other paleogenomics researchers are studying Neanderthal and Denisovan genomes for insights into what makes humans different from other primates.


To discuss his work sequencing DNA from Neanderthals and other early humans, and how it changes our understanding of what it means to be human, I'm pleased to be joined by Dr. Svante Pääbo. Dr. Pääbo, your team spent a great deal of effort in sequencing Neanderthals. And there was a lot of technical work that was involved in that. But I want to talk to you today about kind of what it means and what we've learned from it. To start with, what did we learn about human origins from sequencing the Neanderthal genome?


SVANTE PÄÄBO: Well, so we learned that modern humans do come out of Africa, but first of all in Africa, come out of Africa. And then we meet, somewhere around 40,000, 50,000 years ago, we meet other forms of humans, for example, Neanderthals in Europe and western Asia, and other forms in Asia. And we don't just replace them. We mix with them. So as a result, if you're ancestry today comes from Europe or Asia, somewhere between 1% or 2% of your DNA actually comes from Neanderthals.


STEVE USDIN: So that's really fascinating. And about the origin story, so before your work, there was kind of a debate about origins, about whether humans came out of Africa originally or whether they developed separately in different places, right? And you've kind of definitively shown that we all came out of Africa, but it's a complicated story. It's in two waves, right?


SVANTE PÄÄBO: Yes. So Neanderthals also, of course, have an origin. And the most likely place of that origin is in Africa. So somewhere half a million years ago or so the ancestors of Neanderthals come out of Africa and in Europe and western Asia evolve into what we call Neanderthals today. And they actually have relatives in Asia that evolved to other forms there.


And then modern humans, somewhere between 100,000 and 200,000 years ago evolve inside Africa. And somewhere around 100,000 years ago, we find the first fossils of modern humans in the Middle East. But they really start spreading seriously out of that area only around 50,000, 60,000 years ago.


STEVE USDIN: And during that period when they were together, humans and Neanderthals then, they mixed. The other thing that you found, which is really incredible, is you found a whole new species of early humans. Can you tell us how did you find them? And what do we know about them?


SVANTE PÄÄBO: Yes. So we worked together with Russian archaeologist in Novosibirsk, Anatoly Derevianko and his team. And in 2008, they excavated in a cave on the border between Russia and Mongolia in southern Siberia and found a tiny little bone, a fragment of the last phalanx of a pinkie of a child. They were actually very skilled in realizing that this might be a bone from a human.


And we got this fragment of this bone and were convinced that it would be either a modern human or a Neanderthal and were extremely surprised when we started sequencing the DNA and found that it was related to Neanderthals, but very far back, at least 200,000 years ago or so. So Neanderthals and this other form of humans had a long, independent history from each other. So we thought a lot about what we would call this new form of humans, and settled on Denisovans, after Denisova Cave, the place they were first found. Just as Neanderthals are named after Neandertal.


STEVE USDIN: So the really kind of interesting thing also, to follow the story forward, is that not only did you find this new form of human simply from this little tiny bit of a pinkie, but then you also later found that there are people who are alive on earth today who have incorporated the DNA or have the DNA from this Denisovan people, right?


SVANTE PÄÄBO: Yes. So when we then sequenced their genome, we could ask the same questions as we had done with the Neanderthal genome. Have these Denisovans contributed to any people that live today? And to our surprise, we found a contribution, but not in central Asia or Siberia, but mainly in the Pacific, so in Papua New Guinea, Aboriginal Australians, Fiji, and so on.


STEVE USDIN: And the other thing also -- I'm sorry -- to get back to the Neanderthals that's really interesting is that most people who are in Europe and in Asia have got a little bit of traces of Neanderthal DNA in them. But since humans came out of Africa, people from Africa don't have that DNA, right?


SVANTE PÄÄBO: Yes. So we find no evidence of Neanderthal DNA in Africans. Or the little, little bit one can detect is actually due to the infill back to Africa from Europe or western Asia. But that's not to say that there are no contributions in Africans from any of these earlier forms. There are some indications from studying variation today that there are some old lineages also in Africa. So presumably, modern humans evolved somewhere in Africa, spread across Africa, and probably then mixed with other early forms that existed there. But we have no genomes of those forms.


STEVE USDIN: Dr. Pääbo's research has implications beyond human origins. When we return, what does Neanderthal DNA mean for us?


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STEVE USDIN: We're back with Dr. Svante Pääbo discussing ancient DNA. Dr. Pääbo, I sent my results off, like a lot of people do, to a personal genomics service. And it came back and said I'm 2.8% Neanderthal. First, is that accurate? Is my DNA really 2.8% Neanderthal? And second, what should I think about that.


SVANTE PÄÄBO: Well, first of all, I think that sounds a little high. And I think most of these companies in reality actually measure in addition to the Neanderthal contribution a lot of statistical noise. Some of them come out, for example, finding Denisovan contribution in Europe, which doesn't make sense.


There are better methods on the way. There were two papers published in January from two different research groups. So I think we will be able in the future to tell much better how much of you is Neanderthal.


STEVE USDIN: And what's the difference? I mean, what should people think about that, besides the fact that it's tremendously cool?


SVANTE PÄÄBO: Well, I think we're beginning to learn that sometimes this can have consequences, some consequences for how we sort of look or behave, maybe. But for most of it, I think it's just DNA as any other part of your DNA that you needn't think have any special consequences at all for you.


STEVE USDIN: So you've done some research, though, looking at the DNA that's different, kind of the contribution of Neanderthals to modern humans. And some of it's focused, surprisingly, on type 2 diabetes. Can you talk about that?


SVANTE PÄÄBO: Yes. So there's a group in Boston who did a big study in Native American groups in Mexico and found a new risk allele, a variant of a gene that transports lipids across the cell membrane. And the risk variant there turns out to come from Neanderthals into the ancestors of Native Americans, presumably when those ancestors were in Asia. So that's quite fascinating to me, because that's sort of an example of something that comes from Neanderthals and actually has consequences for us today.


STEVE USDIN: And you're not only looking at ancient DNA. You've also looked at primate DNA. And you're doing comparisons with humans. Some of your work is also looking at what might be responsible for creating speech and language. Can you talk about that and what you've seen? Well, for example, did Neanderthals speak?


SVANTE PÄÄBO: So speech and language is obviously a very complex trait. And many, many genes are involved. But there is one gene that is known to have effects, because when one copy is damaged in a present-day human, we have a severe and specific language and speech problem. That gene is called FOXP2. And it's transcription factors. Its function is to turn on and turn off other genes.


And the protein it encodes have two changes in amino acids specific to humans. And they are in no other apes or monkeys. We have actually shown that those two amino acids are important, because if we engineer them in into a mouse, the mouse actually peeps differently. It vocalizes differently. And it has consequences for aspects of motor learning in the mouse.


So we are very interested to see, in the Neanderthal and Denisovan genomes, if they share these changes with us or not. And they do, actually. So they looked like us.


STEVE USDIN: So can you go back farther and find earlier humans that don't have it? Can we find out when that evolved?


SVANTE PÄÄBO: Hopefully in the future. So we are applying our very best new techniques now to older fossils. And we've just succeeded late last year to retrieve DNA from a 400,000-year-old probably ancestral Neanderthals or so. But so far we have very little of the genome, just a tiny little part of mitochondrial genome. But I think that will happen, yes. We will be able to go further back within the last half million years or one million years.


STEVE USDIN: So you think there's a limit, though. At some point, the DNA degrades. You're not going to be able to go back and get dinosaur DNA or something like that.


SVANTE PÄÄBO: Yes. I do think that sort of the furthest back we can go is probably in the permafrost, where things are constantly frozen since they died. And there's a group that retrieved from a horse 700,000-year-old DNA. But somewhere there is a limit. I would say on this side of one million years.


STEVE USDIN: Well, thank you. Does sequencing extinct beings mean they can be brought back to life? If that's possible, should it be done? We'll talk about that in a moment.




NARRATOR: Now back to BioCentury This Week.


STEVE USDIN: We're back with Dr. Svante PÄÄBO. Dr. PÄÄBO, George Church, when we had him on this show, he talked about bringing back carrier pigeons and mammoths from extinction. Is that possible? And do you think it should be done?


SVANTE PÄÄBO: I would actually say it's not possible in any real sense. So for example, the Neanderthal genome now is the best genome we have of anything extinct. We still, though, have only about 2/3 of the genome, that single copy that exists only once, where we can map these short little fragments to it.


Then there is another 1/3 of the genome that's composed of repeated sequences that occur twice or more times. And there, of course, when you have tiny little fragments, you don't know from which copy they came. So there's 1/3 of the genome that contains important things too that we will never know the exact organization of. And in reality, when we try to engineer in single changes into stem cells today, we struggle to put in even a few changes correctly. And say, if we talk about the Neanderthals, we're now talking about engineering in tens of thousands of changes in those 2/3 of genome we know. So I would actually say within reasonable time frame that we can overlook, it's impossible.


STEVE USDIN: So that's a Neanderthal. And what he talked about about the mammoth, for example, is not really, when you get down to it, bringing an extinct mammoth back, but trying to tweak the genome of an elephant to make it a bit more like a mammoth.


SVANTE PÄÄBO: Yes. I mean, what I do think can happen is that you in the future with great effort make an elephant that's a bit hairy, a bit different color. But it will then be an elephant masquerading as a mammoth. It's not a mammoth.


STEVE USDIN: So I want to switch onto another topic, and getting back to kind of the social meaning of your work. When you talk about human origins and DNA, really at some point sooner or later people start talking about race, racial differences among humans today. What has your work shown about the significance of racial differences at the level of the genome?


SVANTE PÄÄBO: Well, that's not only our work. It's actually work of many, many groups who study genetic variation, for example, the 1000 Genomes Project, which have sequenced over 1,000 complete genomes from all over the world. And I find it fascinating that if you look at those data, you really see that there are no absolute fixed differences I would say between what we call races.


So the biggest sort of genetic difference between populations I think we have is between Africans and non-Africans. And if you look in those data over tens of millions of variable positions, you don't find a single position in the genome that's a real difference, like my mother would think of a genetic difference, where everybody in Africa has something, everybody outside Africa has something else. If we take a less stringent criteria and say 95% in Africa, 5% or less outside, it's 12 differences. So it's really nothing. So this really means that from looking at the particular part of our genome only, you cannot with 100% certainty say if a person comes from Africa or outside Africa.


STEVE USDIN: So another thing, now kind of jumping around to another topic, you started your work looking at the DNA from mummies. And one of the things I'm wondering about there is, have you been able to determine, the people who were Egyptians at the time of what we think of the classical Egypt of the pyramids and the pharaohs, were they the same people as there are in Egypt today?


SVANTE PÄÄBO: That was really a dream I had when I started doing this. And the sad thing is really that preservation conditions in Egypt are very bad for DNA. It's really related I think mainly to climate and how one prepared the mummies that we have not been able to retrieve yet, but it will come, really reliable DNA sequences from whole genomes at least from Egypt. So I can't really answer that.


STEVE USDIN: Well, that'll be a very interesting one. And another one, kind of jumping around to another thing that I found very interesting in your book, is that you talked about using genome sequencing to learn some basic things about evolution. And you give the example of the sloths, of the tree sloths. Can you tell that story? Yes.


SVANTE PÄÄBO: So there are cases, many cases in evolution where animals have evolved to similar lifestyles. So for example, there are two forms of tree sloths in South America, two-toed and three-toed tree sloths. And there used until 15,000 or 10,000 years ago, to be many forms of sloths that were ground-dwelling, big sloths. So there were really two ideas about this. Either the two tree sloths were very closely related to each other and survived until present day due to some physiology they have in common, or they were not closely related to each other and simply survived because they were in the trees, so when humans came, they killed off the ground-dwelling sloths but couldn't get into the trees.


STEVE USDIN: And that seems to be what -- in short, that's what you found.


SVANTE PÄÄBO: Yes. And that is what we have found. So this is a case of independently two animals evolving to the same sort of morphology and way of behaving. Now, many examples of that sort of parallel evolution, suggesting that selective forces are very strong and can form how we look quite quickly.


STEVE USDIN: Dr. Pääbo, one of the things I think that's confusing, I'm wondering if you could clarify a little bit. A lot of people, when they went to school, they learned that a species, the definition is a group of animals or people who can't breed with others, that can only breed with themselves. And obviously, that's not what happened with humans and Neanderthals.


SVANTE PÄÄBO: Yes. I think species is a complicated thing, because there's no definition of a species that applies to all cases of different groups in nature. So for example, polar bears and brown bears can indeed breed with each other and have fertile offspring, yet are very, very different. It would be ridiculous to call them the same species.


So I think it's actually a very academic thing to discuss what is a species or a subspecies. If we now describe what happened when Neanderthals and modern humans met, that one did mix with each other, Neanderthals ended up contributing about 1% of the DNA to people today, we have described what is interesting. And others can fight about if we are two different species or not.


STEVE USDIN: And the other thing that's interesting, so they contributed about 1% or maybe in some people a little bit more. But there are also parts of the Neanderthal genome that didn't get incorporated into humans. Can we learn something from that?


SVANTE PÄÄBO: Yes. So there are two studies that recently appeared that looked across the genome of hundreds of humans to see where Neanderthals had contributed and where we seem to be resistant to it, where one would expect statistically to see Neanderthal contribution but you don't. And then we asked, in those parts of the genome where we don't accept Neanderthal contributions, what genes are particularly located there? And it turned out to be genes that are expressed in the male lines and testicles.


So this suggests that the hybrids, Neanderthal-human hybrids, may have had some problems with fertility in the males. And that's actually quite a common thing, where closely related species or populations hybridize with each other, say horses and donkeys, that it's the male offspring that has problems with fertility, whereas the female offspring generally can have.


STEVE USDIN: So does that suggest that in the kind of inner-mixing between modern humans and Neanderthals, that most of what's come to us would have been from the maternal side?


SVANTE PÄÄBO: Yes. So it suggests that it would be the female offspring that then went on, had children on their own, and contributed to people today.


STEVE USDIN: Great. Well, thank you. We're going to continue our conversation with Dr. Svante Pääbo in just a moment.


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STEVE USDIN: We're finishing up with Dr. Svante Pääbo. Dr. Pääbo, I want to jump back to something we talked about earlier. When you said that there are no clear genetic differences between, for example, Africans and people in Europe, people who are watching the show might say, well, what does that mean? We can look at people and we can see racial differences. Are you saying that there's no underlying genetic causes?


SVANTE PÄÄBO: So what I'm saying is there are no absolute differences in terms of everyone has one variant in one region, everyone has another variant elsewhere. There are differences in frequencies in many, many genes that have consequences, for example, for skin color, hair texture, facial features. There is a very accomplished study of just body height, which is a very simple trait to measure and that is also largely inherited that shows there are hundreds of genes involved in this. So there's no absolute difference between short people and long people, but small differences in many, many genes.


STEVE USDIN: Wow. So another kind of common perception, it's gone into the language even, people say that something is in my DNA or even companies even say that something's in their DNA. It suggests a certain level of genetic determinism. How much of our behavior, of our social traits, really is in our genes?


SVANTE PÄÄBO: Well, that's of course a billion dollar question that no one can answer I think just straight off. I do think, though, that almost any trait of interest we think about is determined both by genetics and by environment. And I find it sort of sad that we come to a situation where we will stress the DNA and inheritance so much that we perhaps don't focus on what we can change in our society.


STEVE USDIN: So that also kind of -- getting back to the Neanderthal, I think one of the ways to kind of get at these things is to ask, what is it that made modern humans prevail and succeed where Neanderthals, and Denisovans, and other kinds of early humans didn't? Do you think we might actually know the answer to that some day?


SVANTE PÄÄBO: I hope we will one day. And we have a tool for it now with the Neanderthal genome. We can make a catalogue now of all of the absolute differences where all people today, no matter where we live, have some change in the genome but the Neanderthals look like apes. And that's a very short list. It's around 31,000 changes.


So we can begin to look at these. And biologists can now start making experiments to find out what those changes do. And some of them may be behind the fact that in just 50,000 years, we spread all over the world, colonized every part on the planet. We're flying to Mars now. And we are 7 billion people instead of in the hundred thousands.


STEVE USDIN: And what about the difference between the Neanderthals and modern humans? How many differences are there there?


SVANTE PÄÄBO: So absolute differences would be in the order of 60,000 or something like that. But we don't know the variation among Neanderthals yet, so we can only really say that there are a little over 30,000 differences to Neanderthals that all humans today have in common.


STEVE USDIN: And how many of those differences code for a protein, something that we think actually would have an effect?


SVANTE PÄÄBO: So in protozoas, 97 changes in 87 different genes.


STEVE USDIN: And do we know what that means, what the actual functional meaning of that is?


SVANTE PÄÄBO: Well, the dirty little secret of genomics is really that we are very, very bad at looking at single changes we pick out in the genome and saying what consequences they have. So we just make guesses. There are genes in there, for example, that does have to do with development of nerve cells in the brain that may be particularly interesting. There are others that have to do with skin and skin morphology, for example.


STEVE USDIN: Well, thanks very much. We could talk all week about this. But that's all the time we've got today.


I'd like to thank Svante Pääbo. Remember to share your thoughts about today's show on Twitter. Join the conversation by using the hashtag #BioCenturyTV. I'm Steve Usdin. Thanks for watching.