 My name is Larry Thompson. I'm the Communications Director of the National Human Genome Research Institute at the National Institutes of Health. With me is Dr. Jim Mulliken, the Acting Director of the NIH Intramural Sequencing Center and a Computational Geneticist. Dr. Mulliken is the co-author of the May 7, 2010 paper in Science Magazine in which an international team of researchers have sequenced the complete genome of the Neanderthal, the closest extinct relative of modern humans. So Dr. Mulliken, let's start at the beginning and just tell me what this study was about and we'll start to go through what you found. Well, it's been an amazing journey with the group led by Dr. Sante Pavo at the Max Planck Institute in Leipzig, Germany. He's been working on the study of ancient DNA for quite some time and has analyzed the DNA from the bones of Neanderthals. And earlier on, before this study, he had found that you could sequence the mitochondrial DNA, which is a small subunit of the cells. But in this study, what he also found was that you could sequence the nuclear part of the DNA and get information from that as well. And that's what they did. They kind of threw a tour de force. They took the small fragments that they got out of the bones and sequenced it to enough coverage to cover much of the genetic material of the Neanderthal genome. And how? I mean, the bones that were studied, how old are they? I mean, how can you get DNA out of that? So the bones have been found range in age from about 80,000 years old to around 40, 35, 40,000 years old. So they're quite old and they've been in these caves buried under layers and layers of sediment for all those tens of thousands of years. And when they unearthed those bones, they used a, in clean room environments, they were able to take some of the bones and take a small bits of the bone and make it into a powder. And then from that, they could extract the DNA from that powder material. And some of it, not much of it, but some small fraction of it was actually from that Neanderthal that had died in that position in the cave. And so that's really quite remarkable. And so you would sequence this DNA the same way you would sequence modern DNA from, I'll say, a patient? Well, no, it's a lot harder than that. One of the problems with this particular research is to also understand that you don't want to contaminate with modern human DNA. So they had to make extra special care in handling the DNA prior to sequencing it. But the sequencing part of it, once they were able to turn the molecules of DNA into something that they could sequence, they could look for the pieces that looked like Neanderthal DNA, that they were short fragments of DNA that had been altered by the eons of time that they had been underground. They change in a distinctive pattern so that we know which ones are the ones that are real, that are the old pieces from the ones that might be contamination. But contamination was one of the main focuses of understanding what might be contaminant and what was real Neanderthal DNA. And we tried to remove as much of the contaminant as possible from the sequence. We got it down to about below 1% of error rate. Yeah, that's really remarkable. So I mean, just being able to do it all by itself is quite remarkable. But how would you sum up sort of what the significance of the study? Right. So after we were able to sequence it and essentially map it back to our two other closest living relatives, the Homo sapiens and chimpanzee, we aligned the sequence back to both of those species and we're able to find the differences that are unique to the Neanderthal. And more important, what are similar between Neanderthal and modern humans and modern chimpanzees. So it was kind of a three-way analysis of the DNA from Neanderthal. And from that, what we could find is an interesting genetic history from the last 400,000 years since our ancestors, our common ancestor with Neanderthal, split and went their separate ways. And that's a very interesting time period that we don't have a lot of information on and now we've highlighted that information through this study. So what does it tell us about human evolution? The other studies that we've done without the Neanderthal sequence, like the international haplotype map project that I was also involved in, that can see things that are at a different time scale than what you see from the 400,000 year kind of time point that you see from the Neanderthal study. And in particular, we were able to see that since the split that in one or both branches of this tree, we've differed in our sequences in a way that changes skeletal bone structure, metabolism, cognitive ability, those sorts of things. We don't know which way they went for which species, but they were different. And it's interesting that those genes were highlighted in this study. So what you're saying is that you lined up the Neanderthal genome to the human genome, and you could see what the differences were in the genes that are responsible for bone formation or for, I think one of the things in the paper was wound healing as a difference in the genes that are involved in it. We don't know whether it's good or bad. The way that we did that was we were able to look at the variation in modern humans that have a fixed difference relative to chimpanzees in all modern humans. And then when we look at the Neanderthal, we see that they are either the ancestral form just like the chimpanzee, or maybe they were variable at those sites, but they've been fixed in the human lineage, and thus must be important to have that particular genetic profile. So are these genetic insights, do they provide any explanation as to why Neanderthal has gone extinct? We don't see them around anymore, but does that explain it? It does not explain why they went extinct. That's still a great mystery. I don't know if the genetic information will tell us anything about that, though. So I understand from the paper one of the great surprises was that we found some Neanderthal footprints, you might say, or fossil genes in our own DNA. Tell me about that a little. Yes, the study from the bones and the fact that the Neanderthals overlapped with modern humans in the same geographical locations at the same time between 40,000 and 80,000 years ago was intriguing, and everyone always wondered if there was a chance that there may have been some interbreeding of those two species, or modern humans and Neanderthals. And so it's been controversial, both sides have been debated just from the bone evidence, but now with the genetic information we see a clear signature that there was a breeding event that happened probably in the Fertile Crescent, probably around 50,000 years ago, 60,000 years ago, something like that, from the early ancestors that moved out of Africa into the Fertile Crescent area, but before they split into the Eurasian continents. So it's a very interesting time point where this happened, and we know something happened. We'll get more details as to whether it was just one chance event that happened or whether it was many events over many thousands of years. We don't know those details yet, but we definitely know that there's Neanderthal DNA. As I said, when they split the 400,000 years, we went our different ways, but modern humans and Neanderthals met back up again about 60,000 to 80,000 years ago and exchanged some DNA, and there was some breeding that went on, and we see that clearly in the signature now. So some portion of modern humans have some amount of Neanderthal DNA, and what's the percentage? We see about 2% of the out of Africa populations, at least the ones that we studied, and those would have been the individuals we studied are Europeans, an individual from France, an Asian individual, a Papua New Guinea individual, and then we also studied two individuals, DNA, from Africa, from West Africa and from Southern Africa, and did these comparisons, and it showed that the African individuals do not have any signature of this mixing, and all of the limited number of individuals that we studied outside of Africa do show a similar mixing level of about 2%, and that's a significant number. If we have 30,000 genes in our genome, that would be 600 genes have a signature of Neanderthal in them, so it's a significant, it sounds small, but it's significant and we can see it in the data. So does that change our current understanding of the origin and migration of modern humans? Is that modern humans arose in Africa, migrated up through the Middle East and then radiated out across the planet? But does this information sort of change our understanding of that story of modern origins? That's still the way things went. It's just the extra bit of information that we've seen now is that there was intergression, a return of DNA from the Neanderthals into the out of Africa populations, just a sprinkling. It's not a huge amount, and we'll find out more as we sequence more modern humans from both within Africa and outside of Africa to see how widespread it really is across the out of Africa populations, but also if there's anything that any signatures that we've missed so far because of limited sampling within Africa, we could get better information about that in the future. So it's a small sampling right now, and we have just sort of sentinel chunks of DNA that we've looked at, but right now it does not look like Neanderthal re-migrated back into Africa or mixed genes in Africa, but stayed in the North and populations passing through that area picked up the DNA. That's right. Neanderthals do not seem to have migrated back, or the DNA that was transferred into the modern humans didn't come back into Africa until much later as now modern day people can move anywhere around the planet. But back 60,000 years ago it was pretty limited in travel. But this is still a first peak, so there's much more to be learned as we go forward and looking at Neanderthal DNA and looking at many populations of modern humans across the planet. That's right. So is there any evidence that genes flowed from modern humans into Neanderthals? We can't see that yet. We have a very limited amount of data from Neanderthals. The data we have now comes primarily from three different individuals, three different Neanderthal individuals. We know that because of the sequence that we got from these three different bones. We have DNA from a lesser amount of DNA from a few other bones that we've sequenced from other parts of Europe. But what we'd really need to have is almost a population study of Neanderthals from Neanderthal bones, so that would be a much bigger sequencing effort. It may be undertaken. That may be something that Solante Pado and his team continues with. But that's the kind of information we need to find out if there was gene flow back into Neanderthals. So, and that leads me to my last question. So what is next for the Neanderthal genome research? Well now that the data will be released, everyone can have a look at it and apply their new methods or any methods that come along to analyze the data. It's going to be freely accessible by anyone. And I wouldn't imagine Solante is going to stop in this effort. I think there's going to be more coming from his group. Very interesting stuff. Dr. Jim Mullikin, acting director of the NIH Intramural Sequencing Center and a co-author of this paper on the Neanderthal genome. Thank you very much for joining us and explaining this really fascinating study. Thank you, Larry.