FOR THOSE trying to reconstruct our evolutionary history, a little fossil often has to go a long way. A fragment of jaw or skull here, part of a thigh bone there, is often all palaeontologists have to go on. Tools and other cultural artefacts help fill in the gaps, but itâs like viewing our history through a keyhole. Our hominin predecessors didnât bury time capsules for later species to pick through. Not deliberately, at least. They did, however, leave a huge package of coded information behind. And now weâre going to try and read it.
In July a team led by Svante Pääbo, an evolutionary geneticist at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, announced audacious plans to reconstruct the entire genome of the Neanderthals, our closest relatives in the fossil record. If they pull it off, and they are confident they can, it will be a remarkable technical feat. âThis would be the first time we have sequenced the entire genome of an extinct organism,â Pääbo says. It could also transform our view not only of Neanderthals but, perhaps more importantly, of ourselves.
Neanderthals have been at the centre of many of the most intense debates in palaeoanthropology ever since the discovery of their bones spawned the field 150 years ago. A popular caricature portrays them as beetle-browed brutes, but this is far from the truth. âNeanderthals were sophisticated stone-tool makers and made razor-sharp knives out of flint,â says Richard Klein, an anthropologist at Stanford University, California. âThey made fires when and where they wanted, and seem to have made a living by hunting large mammals such as bison and deer.â Neanderthals also buried their dead, which, fortunately for researchers, increases the odds of the bones being preserved.
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Bones and artefacts leave a whole range of questions wide open, though. How exactly are Neanderthals related to us? Did our ancestors interbreed with them, and if so, do modern Eurasians still carry a little Neanderthal DNA? Just how âhumanâ were they? Thereâs only one way to be sure: âBy sequencing their entire genome we can begin to learn more about their biology,â says Eddy Rubin, a geneticist at the Lawrence Berkeley National Laboratory in Walnut Creek, California. Whatâs more, if we can answer the genetic questions we might solve the biggest mystery of all: why did Neanderthals die out while modern humans went on to conquer the globe?
It wonât be easy. Although ancient DNA has been extracted and sequenced from Egyptian mummies, 5000-year-old maize plants and a menagerie of extinct mammals including mammoths, cave bears and ground sloths, in all these cases only minuscule fragments of badly degraded DNA have been recovered.
Formidable obstacles
Pääbo and colleagues probably know better than anyone how hard it wil be. They pioneered the genetic study of Neanderthals by extracting and decoding fragments of mitochondrial DNA (mtDNA) from the bones of the original specimen, discovered in 1856 in the Neander Valley in Germany. The mtDNA that Pääbo sequenced suggested that humans split from Neanderthals roughly 500,000 years ago, which fits neatly with the fossil record. It also indicated that Neanderthals did not interbreed with our ancestors.
Although mtDNA can yield important information, the really significant information is in the cell nucleus, where the vast majority of genes reside. Extracting and sequencing this DNA, however, is much harder. Cells can contain thousands of mitochondria but they have only one nucleus, so nuclear genomes are far scarcer than mitochondrial ones. What is more, there are a number of awkward biological and chemical facts standing in the way of studying ancient DNA. Firstly, enzymes in recently dead organisms chop DNA into small pieces. Then, over time, a steady onslaught of oxidation and background radiation further degrades these fragments, and causes the nucleotide âlettersâ of the DNA code to change from one to another or into ones that are not naturally found in DNA. To make matters worse, ancient DNA is invariably contaminated with the DNA of hundreds of types of bacteria and fungi that invade a dead organism. Finally, in the case of Neanderthals, any modern human DNA that contaminates a sample causes tremendous problems, as it can so easily be mistaken for Neanderthal DNA.
Despite these formidable obstacles, the task is not hopeless. Dry or cold conditions can help preserve DNA, and in some exceptional circumstances it might be possible to retrieve useful DNA from bones 100,000 years old, Pääbo says. Whatâs more, the changes in DNA sequence that result from nucleotide conversion follow a relatively stable pattern, which means that the original sequence can often be deduced. In fact the very presence of these changes can be a useful sign that youâre working with ancient DNA, not more recent contamination with modern DNA.
Pääboâs team have selected two Neanderthal specimens to work on, based on the fact that both are have âcleanâ DNA that is relatively uncontaminated. One is a 38,000-year-old fossil from Vindija, Croatia. The other is the original specimen, which, despite being extensively handled, has unusually clean DNA in its right upper arm bone (during its lifetime the individual lost the use of its left arm after breaking it and had to rely on the right arm, causing the bones to grow thicker and denser than usual. After death this shielded the DNA from contamination). Pääboâs colleagues are also hunting for new specimens that can be sampled before other people get their hands on them.
Thereâs a further problem with trying to reconstruct the genome of an extinct animal, however. Conventional genome sequencing requires large quantities of DNA, which is fine when youâre dealing with a living species, but is a huge problem when all youâve got is a few precious bones that have to be ground to dust to extract the DNA.
âThe Neanderthal genome could help us to understand what it means to be humanâ
Draft sequence soon
Enter 454 Life Sciences, a genomics company in Branford, Connecticut, that has invented a new sequencing technique especially suited to the Neanderthal genome. It takes fragments of DNA 100 to 200 base pairs long â coincidentally about the length of DNA fragments extracted from ancient bones â and reads them directly. This cuts out the normal intermediate step of amplifying DNA in bacteria. The method is also extremely powerful. âConventional sequencing generates 96 sequences in a single run,â says Michael Egholm of 454. âWe generate 250,000 sequences, each about 100 bases long â thatâs 25 to 30 million bases in a run.â
This is crucial. Up to 95 per cent of the DNA extracted from Neanderthals will be from microorganisms and therefore irrelevant. To have a decent chance of capturing the whole Neanderthal genome â which, like the human genome, is expected to contain about 3 billion bases â from random fragments, 454 will have to generate at least 60 billion bases of sequence. âOnly when you generate as much sequence data as we do can you even think about throwing out 95 per cent of the sequences you decode,â says Egholm.
Using this approach, Pääbo and colleagues have so far sequenced roughly a million base pairs of nuclear DNA from the Croatian fossil. They hope to publish a draft of the whole genome in two years.
How plausible is this? âIt is definitely possible to sequence the entire genome from such well-preserved specimens,â says Eske Willerslev, an expert in ancient DNA at the University of Copenhagen, Denmark. âPerhaps the biggest difficulty will be verifying that the sequences obtained are genuinely from the Neanderthal genome and not a contaminant, as so much of it will be identical to the human genome.â
The genome, once in hand, will provide insights into two key questions, Rubin predicts. âThe first thing it can tell us is where the human genome is unique â places where the Neanderthal genome looks like the chimp genome. This will help us identify changes in the human genome that are of recent origin and which may contribute to the biology that distinguished us from Neanderthals.â In other words, it could help us understand more about what it is to be human.
âThe other, more difficult thing is to look for areas where the human genome is similar to the Neanderthal genome, which may help in making inferences about Neanderthal biology,â Rubin says, although itâs hard to say in advance just what the genome will reveal. He draws an analogy with Egyptian hieroglyphics: âBefore understanding hieroglyphics we werenât sure what they would tell us, though we knew theyâd tell us something,â he says. âI think the Neanderthal genome will do the same thing.â
The genome is sure to fuel the particularly intense controversy that has surrounded a much-vaunted aspect of human uniqueness: language. âThereâs been a debate going for more than 30 years about the speech capabilities of Neanderthals,â says Philip Lieberman, a cognitive scientist at Brown University in Providence, Rhode Island.
Computer models of the mouth and vocal tract give us some idea of what sounds Neanderthals could make. âIt is clear from the fossil record and comparisons with modern humans that Neanderthals, and probably their common ancestor with humans, could speak,â Lieberman says, though perhaps with less sophistication than us. Yet fossils cannot tell the whole story. âThe shape of the skull doesnât tell you whatâs inside the brain,â Lieberman says.
Genes, however, might provide clues. In 2001, FOXP2 became the first gene to be tied to a specific language impairment. People with an error in FOXP2 suffer from a severe speech disorder involving difficulty pronouncing words and with some aspects of grammar and cognition. Genetic analyses indicate that FOXP2 reached its modern form in humans within the past 200,000 years â well after we and Neanderthals had parted ways. The Neanderthal genome will help to verify that date. âNeanderthal FOXP2 is likely to be the same as the chimpanzee version,â says Simon Fisher of the Wellcome Trust Centre for Human Genetics in Oxford, UK, a member of the team that discovered FOXP2. âBut if it turns out that Neanderthal FOXP2 is identical to that found in modern humans, these dates will have to be revised.â Another possibility â unlikely, in Fisherâs view â is that after splitting from our shared ancestor Neanderthals independently evolved the same version of FOXP2.
It will take more than examining Neanderthalsâ FOXP2, however, to settle debates about their speech capabilities, as it is extremely unlikely to be the only gene relevant to the evolution of language. Even if Neanderthals didnât have the human version, it is hard to say what this would have meant for their speech capabilities.
FOXP2 wonât be the only interesting gene. âWeâre on the verge of sequencing many [individual] human genomes, and from this weâll begin to see associations between sequences and biology,â says Rubin. âAt the moment there are a limited number of questions to ask, but very quickly we will crack aspects of the human genome and find associations that weâll want to look at in Neanderthals.â
So much for understanding Neanderthals. What about ourselves? âWhat is really interesting is what makes us specifically human,â says Klein. And this is where having the Neanderthal genome could really pay off.
At the moment, geneticists trying to answer questions about human uniqueness often compare the human genome with the chimpanzeeâs. Even though the species differ in DNA sequence by just 1.2 per cent, lining up the genomes side by side reveals 35 million genetic differences.
Many of these differences fall in non-coding areas and have no obvious effects, which makes finding the differences that really matter a formidable challenge. The Neanderthal genome will provide something of a short cut. Humans and Neanderthals split much more recently than humans and chimps (500,000 versus 5 to 7 million years ago), which means there will be fewer genetic differences to sift through. âThis comparison is helpful if you are interested in the more recent evolutionary changes that might define distinct biological features of Homo sapiens,â says Fisher.
Perhaps the biggest open question about human evolution is why and how we became so globally successful as a species. Palaeoanthropologists generally make a distinction between anatomically modern humans and behaviourally modern humans: the former began to emerge around 200,000 years ago, the latter around 50,000 to 80,000 years ago in a cultural âbig bangâ. Until then, humans and Neanderthals made the same sorts of artefacts and went about business pretty much the same way. Then, suddenly, people with complex culture, elaborate social systems and sophisticated technology started migrating out of Africa into Eurasia. Within a few thousand years the Neanderthals had breathed their last. Why? Solving the puzzle of the cultural big bang bears heavily on answering this long-debated question.
Some palaeoanthropologists have proposed that Neanderthals were wiped out in a genocide by invading Cro-Magnons, the first behaviourally modern humans in Europe who we know briefly coexisted with Neanderthals, or that they were pushed to the margins by the invadersâ more sophisticated social systems and culture. Others have suggested that climate was the decisive factor. Whatever the cause, though, a still more fundamental question remains: why were humans more culturally advanced than Neanderthals? If they were biological and cognitive equals, was it just some new cultural trick that humans happened to stumble on first that got them ahead? Maybe, but that just raises another question. âWhy didnât the Neanderthals simply copy the successful strategies of the modern humans?â Klein asks. After all, such imitation is common throughout recorded history.
To Klein, the lack of evidence of cultural transfer between humans and Neanderthals suggests that a biological and cognitive abyss separated the two species. Not everyone agrees. âI think it is very unlikely that some biological or cognitive difference caused the replacement of the Neanderthal population,â says Terrence Deacon, a neurobiologist at the University of California, Berkeley. The lack of evidence does not prove there was no cultural transfer, he points out.
âWe could argue back and forth endlessly,â Klein says. âThe idea that there was a genetic change related to brain development 50,000 to 80,000 years ago has been problematic when all weâve had is the artefacts and the fossils.â The Neanderthal genome could help end this game of intellectual tennis.
âCould the genome be a recipe for resurrecting a living Neanderthal?â
But could it do more than that? Could the Neanderthal genome be the blueprint for resurrecting a living Neanderthal, Jurassic-Park style? That would raise enormous ethical quandaries: who would act as a surrogate mother, who would care for it and what rights would it have? And if it was capable of understanding its situation, how would it feel to discover that the rest of your kind has long been extinct? Pääbo thinks these ethical issues rule out any attempt. In any case, the technical barriers are also too high, he says: a human egg with Neanderthal DNA would be unlikely to develop. âWe would be able to create a physical Neanderthal genome but we will not be able to recreate a Neanderthal,â he says. âEven if we wanted to.â
âHow would it feel to discover the rest of your kind has long since been extinct?â
