Neanderthal genome reveals interbreeding with humans
* 19:00 06 May 2010 by Ewen Callaway
* For similar stories, visit the Neanderthals and Genetics Topic Guides
How closely are Neanderthals related to us?
They are so closely related that some researchers group them and us as a single species. "I would see them as a form of humans that are bit more different than humans are today, but not much," says Svante Pääbo, a palaeogeneticist at the Max Planck Institute in Leipzig, Germany, whose team sequenced the Neanderthal genome.
The common ancestor of humans and Neanderthals lived in Africa around half a million years ago. After that, the ancestors of Neanderthals moved north and eventually made it to Europe and Asia. Our ancestors, meanwhile, stuck around Africa until about 100,000 years ago before eventually conquering the globe. Neanderthals died out around 28,000 years ago.
How did they sequence the Neanderthal genome?
Bone contains DNA that survives long after an animal dies. Over time, though, strands of DNA break up, and microbes with their own DNA invade the bone. Pääbo's team found ways around both problems with 38,000 and 44,000-year-old bones recovered in Croatia: they used a DNA sequencing machine that rapidly decodes short strands and came up with ways to get rid of the microbial contamination.
They ended up with short stretches of DNA code that computers stitched into a more complete sequence. This process isn't perfect: Pääbo's team decoded about 5.3 billion letters of Neanderthal DNA, but much of this is duplicates, because – assuming it's the same size as the human genome – the actual Neanderthal genome is only about 3 billion letters long. More than a third of the genome remains unsequenced. "It's pretty darn good for something that's 38,000 years old," says Edward Green, a team member now at the University of California, Santa Cruz.
What did they find?
Any human whose ancestral group developed outside Africa has a little Neanderthal in them – between 1 and 4 per cent of their genome, Pääbo's team estimates. In other words, humans and Neanderthals had sex and had hybrid offspring. A small amount of that genetic mingling survives in "non-Africans" today: Neanderthals didn't live in Africa, which is why sub-Saharan African populations have no trace of Neanderthal DNA.
It's impossible to know how often humans invited Neanderthals back to their cave (and vice versa), but the genome data offers some intriguing details.
"It must have been at least 45,000 years ago," says David Reich, a geneticist at Harvard Medical School who was involved in the project. That's because all non-Africans – be they from France, China or Papua New Guinea – share the same amount of Neanderthal DNA, suggesting that interbreeding occurred before those populations split. The timing makes the Middle East the likeliest place where humans leaving Africa and resident Neanderthals did the deed.
Does this mean that Neanderthals didn't interbreed with Europeans more recently?
Not necessarily – it's just that earlier interbreeding is more likely to leave a mark on our genomes than more recent trysts, largely because of population expansion. With a more complete Neanderthal genome and DNA from other Neanderthals, it will be possible to find out if Europeans and Asians interbred with Neanderthals after those groups went their separate ways.
Archaeological evidence suggests that humans and Neanderthals overlapped for about 10,000 years in Europe and some fossils have even been interpreted as Neanderthal-human hybrids, though not all palaeoanthropologists agree on this.
Can we trace any human traits back to Neanderthals?
Probably not. Some researchers had hypothesised that some human genes, including one involved in brain development, originated from interbreeding with Neanderthals, but Pääbo's team found no evidence for this. In fact, no Neanderthal DNA sequences are consistently found in humans. "Each person has a different bit of Neanderthal in them," says Reich.
However, Sarah Tishkoff, a geneticist at the University of Pennsylvania in Philadelphia not involved in the project, says it is possible that interbreeding introduced traits into a few human populations. "It will be interesting to look at other ethnic groups and other Neanderthals," she says.
Does the Neanderthal genome explain what makes us different from them?
That is the hope, though this first scan emphasises the overwhelming similarity between humans and Neanderthals. Pääbo's team found just 78 amino acid peculiarities – differences that change the shape and potentially the function of a protein – which all humans have in their genes but Neanderthals didn't. To put that in context, the genome encodes about 10 million amino acids. They also identified more than 200 regions of the human genome that look like they have evolved since we split from Neanderthals.
These changes occurred in genes linked to cognition, skin and bone development, and reproduction, but they don't explain what makes us human, because they occurred after humans split from Neanderthals 500,000 years ago.
"There is no compelling story where you say, 'Ah, ah, this difference means this,'" Green says. "'It let us write poetry instead of making stone tools' – there's nothing that jumps out like that."
That means a lot of hard work for researchers, examining the genetic differences between humans and Neanderthals one by one, and in some cases genetically engineering bacteria, mice and other organisms with these genes. "This is really a gold mine for finding recent changes in human evolution," Green says.
Does this mean we could clone a Neanderthal?
No. "Resurrecting" a Neanderthal based on its genome sequence poses a number of scientific and technological problems, not to mention ethical dilemmas.
The most straightforward way to bring Neanderthals back to life would be to alter the DNA of a human cell to match that of Neanderthals and then transplant its nucleus into an unfertilised egg and implant it into a surrogate mother, a process called somatic cell nuclear transfer (SCNT). No one has accomplished this feat for humans, and it may not be possible.
Even if we could clone humans, another challenge would be introducing the millions of genetic differences that exist between humans and Neanderthals into a human cell. As it stands, the Neanderthal genome is incomplete and riddled with errors.
More problematic, though, is making many genetic mutations at once instead of one at a time, as is conventionally done. A technology exists to introduce dozens of mutations at a time into bacteria but this doesn't come close to the complexity required to make a Neanderthal.
Journal reference: Science, DOI: 10.1126/science/1188021
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There is some neanderthal in us
Neanderthal genes 'survive in us' | |||||
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 Many people alive today possess some Neanderthal ancestry, according to a landmark scientific study. The finding has surprised many experts, as previous genetic evidence suggested the Neanderthals made little or no contribution to our inheritance. The result comes from analysis of the Neanderthal genome - the "instruction manual" describing how these ancient humans were put together. Between 1% and 4% of the Eurasian human genome seems to come from Neanderthals. But the study confirms living humans overwhelmingly trace their ancestry to a small population of Africans who later spread out across the world.
The most widely-accepted theory of modern human origins - known as Out of Africa - holds that the ancestors of living humans (Homo sapiens) originated in Africa some 200,000 years ago. A relatively small group of people then left the continent to populate the rest of the world between 50,000 and 60,000 years ago. While the Neanderthal genetic contribution - found in people from Europe, Asia and Oceania - appears to be small, this figure is higher than previous genetic analyses have suggested. "They are not totally extinct. In some of us they live on, a little bit," said Professor Svante Paabo, from the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany. Professor Chris Stringer, research leader in human origins at London's Natural History Museum, is one of the architects of the Out of Africa theory. He told BBC News: "In some ways [the study] confirms what we already knew, in that the Neanderthals look like a separate line. "But, of course, the really surprising thing for many of us is the implication that there has been some interbreeding between Neanderthals and modern humans in the past." Science Explained: What is a genome? John Hawks, assistant professor of anthropology at the University of Wisconsin-Madison in the US, told BBC News: "They're us. We're them. "It seemed like it was likely to be possible, but I am surprised by the amount. I really was not expecting it to be as high as 4%," he said of the genetic contribution from Neanderthals. The sequencing of the Neanderthal genome is a landmark scientific achievement, the product of a four-year-long effort led from Germany's Max Planck Institute but involving many other universities around the world. The project makes use of efficient "high-throughput" technology which allows many genetic sequences to be processed at the same time. The draft Neanderthal sequence contains DNA extracted from the bones of three different Neanderthals found at Vindija Cave in Croatia. Retrieving good quality genetic material from remains tens of thousands of years old presented many hurdles which had to be overcome. The samples almost always contained only a small amount of Neanderthal DNA amid vast quantities of DNA from bacteria and fungi that colonised the remains after death.  Svante Paabo (pictured here with a Neanderthal skull) led the research effort The Neanderthal DNA itself had broken down into very short segments and had changed chemically. Luckily, the chemical changes were of a predictable nature, allowing the researchers to write software that corrected for them. Writing in Science journal, the researchers describe how they compared this draft sequence with the genomes of modern people from around the globe. "The comparison of these two genetic sequences enables us to find out where our genome differs from that of our closest relative," said Professor Paabo.
The results show that the genomes of non-Africans (from Europe, China and New Guinea) are closer to the Neanderthal sequence than are those from Africa. The most likely explanation, say the researchers, is that there was limited mating, or "gene flow", between Neanderthals and the ancestors of present-day Eurasians. This must have taken place just as people were leaving Africa, while they were still part of one pioneering population. This mixing could have taken place either in North Africa, the Levant or the Arabian Peninsula, say the researchers. Professor Stringer added: "Any functional significance of these shared genes remains to be determined, but that will certainly be a focus for the next stages of this fascinating research." The Out of Africa theory contends that modern humans replaced local "archaic" populations like the Neanderthals. But there are several variations on this idea. The most conservative model proposes that this replacement took place with no interbreeding between modern humans and Neanderthals. Unique features Another version allows for a degree of assimilation, or absorption, of other human types into the Homo sapiens gene pool. The latest research strongly supports the Out of Africa theory, but it falsifies the most conservative version of events. The team identified more than 70 gene changes that were unique to modern humans. These genes are implicated in physiology, the development of the brain, skin and bone. The researchers also looked for signs of "selective sweeps" - strong natural selection acting to boost traits in modern humans. They found 212 regions where positive selection may have been taking place. The scientists are interested in discovering genes that distinguish modern humans from Neanderthals because they may have given our evolutionary line certain advantages over the course of evolution. The most obvious differences were in physique: the muscular, stocky frames of Neanderthals contrast sharply with those of our ancestors. But it is likely there were also more subtle differences, in behaviour, for example. Dr Hawks commented that the amount of Neanderthal DNA in our genomes seemed high: "What it means is that any traits [Neanderthals] had that might have been useful in later populations should still be here. "So when we see that their anatomies are gone, this isn't just chance. Those things that made the Neanderthals apparent to us as a population - those things didn't work. They're gone because they didn't work in the context of our population." Researchers had previously thought Europe was the region where Neanderthals and modern humans were most likely to have exchanged genes. The two human types overlapped here for some 10,000 years. The authors of the paper in Science do not rule out some interbreeding in Europe, but say it was not possible to detect this with present scientific methods. | |||||
[Neanderthals] are not totally extinct, in some of us they live on - a little bit 
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