Published online 6 May 2010 | Nature | doi:10.1038/news.2010.225

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Migrating humans interbred with Neanderthals after leaving Africa.

Some Neanderthal lives on in the genomes of many modern humans. M. ANTON/ SCIENCE PHOTO LIBRARY

The genomes of most modern humans are 1–4% Neanderthal — a result of interbreeding with the close relatives that went extinct 30,000 years ago, according to work by an international group of researchers.

The team, led by Svante Pääbo, a geneticist at the Max Planck Institute for Evolutionary Anthropology in Leipzig, is reporting only 60% of the Neanderthal genome. But sequencing even this much of the genome was thought to be impossible just a decade ago.

"This will change our view of humanity," says John Hardy, a neuroscientist at University College London who was not involved in the research but studies genetic neurodegenerative diseases.

The drive to sequence the complete Neanderthal genome began about five years ago following the invention of better, faster methods for sequencing DNA. From three Neanderthal bones found in Vindija Cave in Croatia, the team extracted a total of about 300 milligrams of bone. The bones date to between 38,300 and 44,400 years ago, and some have been broken open possibly to remove their marrow — a sign of cannibalism.

Countless fragments of degraded ancient DNA were extracted from the bones, used to create libraries of sequences and then reassembled by computer into the draft Neanderthal genome comprising nearly 2 billion base-pairs. The researchers used the genomes of modern humans and the chimpanzee as references to get the sequence in the correct order. They publish their work in Science this week1.

Quality control

After the Pääbo group published an analysis of 1 million base-pairs of Neanderthal DNA in 20062, it was found that the sequence was contaminated with modern human DNA. A separate analysis put the level of contamination at nearly 80%3, whereas Pääbo and his colleagues contend that it was 11–40% contaminated1.

Based on that experience, Pääbo and his team developed methods for tagging the multitude of ancient sequence strands, which allowed them to reduce contamination to 0.6% in this study.

Most of the Neanderthal DNA sequenced was from three bones found in Vindija cave, Croatia. Max-Planck-Institute EVA

But the fact that the team has so far read the draft genome only 1.3 times on average raises questions about the reliability of the code, which can be altered by degradation or sequencing processes. For instance, the first ancient genome of a 4,000-year-old palaeo-Eskimo from Greenland was read 20 times4.

However, study author Richard Green, who recently moved from the Max Planck Institute to the University of California, Santa Cruz, says that work will continue until the genome has been sequenced an average of 10–20 times.

Sergio Baranzini, a geneticist at the University of California in San Francisco who was not involved in the research, says that the low number of sequence reads makes the Neanderthal genome "of limited value". Nonetheless, he adds, "it is a fascinating study".

After Africa

A year ago, Pääbo and his team announced that they had largely sequenced the Neanderthal genome. During the process of comparing it to that of modern humans, they decided to sequence the genomes of five modern individuals from France, Africa, China and Papua New Guinea in the south Pacific.

It was by comparing the Neanderthal sequence with these genomes that the group was able to surmise how and where the Neanderthals had interbred with modern humans around 45,000 to 80,000 years ago.

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Examining the five contemporary genomes, they saw Neanderthal genetic regions in the three genomes of modern humans who had migrated across Europe or Asia, but not in the genomes of the two African populations: the San from southern Africa and the Yoruba from western Africa.

This suggests that Neanderthals bred outside Africa with Homo sapiens, who migrated out of that region about 100,000 years ago. On the basis of the fossil record of human migrations, the team proposes that this took place in the eastern Mediterranean.

Therefore, they say, modern humans from Europe and Asia are closer genetically to Neanderthals than are those from sub-Saharan Africa.

This agrees with the findings of a separate study presented at a conference last month. That study examined 2,000 modern human genomes that showed two interbreedings with Neanderthals: the first about 60,000 years ago, also in the eastern Mediterranean, and then again about 45,000 years ago in eastern Asia (see 'Neanderthals may have interbred with humans').

"They found exactly what we saw in our study," says Jeffrey Long, a genetic anthropologist from the University of New Mexico in Albuquerque, who was part of the team that presented the findings last month. "I call it molecular stratigraphy."

Under pressure

Using the Neanderthal genome for comparison, Pääbo and his colleagues were also able to identify genes that occur frequently in modern humans, suggesting that such genes are the result of selection pressure.

The report notes genes that affect metabolism, cognition and skeletal development show similar signs of such positive selection in modern humans. And there was positive selection for three genes, that when mutated, have been implicated in Down syndrome, autism and schizophrenia1.

The Neanderthal draft genome provides "a powerful method to shine a light on our evolutionary history", says Green — a technique that will reveal the genomic regions and genes that are keys to our human identity.