The first modern humans to leave Africa about 80,000 years ago encountered Neanderthal settlements in the Middle East and, on at least some occasions, chose to make love instead of war, according to an international team of scientists who have pieced together the genetic code of humanity's closest relatives.
Traces of that ancient DNA live on in most human beings today, the researchers report in Friday's edition of the journal Science.
The finding, which was made by analyzing DNA from Neanderthal bones and comparing it with that of five living humans, appears to resolve a long-standing mystery about the relationship between Neanderthals and Homo sapiens, who coexisted in Europe and Western Asia for more than 10,000 years until Neanderthals disappeared about 30,000 years ago.
"We can now say with absolute certainty that we've got these Neanderthal genes," said John Hawks, an evolutionary geneticist at the University of Wisconsin who was not involved in the study. "They're not 'them' anymore; they're 'us.'"
Svante Paabo, the geneticist at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, who spearheaded the study, said he now sees his ancestors in a new light. His initial research on a different type of DNA that contains far less information had concluded — incorrectly, it turns out — that Neanderthals have no genetic connection to people today.
Now, Paabo said, "I would more see them as a form of humans that were a bit more different than people are from each other today."
Most important, scientists said, knowing the precise structure of the Neanderthal genome will help answer the fundamental biological question: What makes us human?
Neanderthal DNA is 99.7% identical to that of people, according to the analysis, which involved dozens of researchers. Something in the remaining 0.3% must make us unique.
"It's not about understanding Neanderthals," said genome biologist Ed Green, who led the study as a research fellow in Paabo's lab and is now at UC Santa Cruz. "It's understanding us."
By lining up the Neanderthal genome with DNA from humans and chimpanzees, Green and colleagues identified small changes that are unique to humans. Some were in genes involved in energy metabolism, skeletal structure and brain development, including four that are thought to contribute to conditions such as autism, Down syndrome and schizophrenia.
The researchers constructed the Neanderthal genome from three bone fragments found in Croatia's Vindija Cave. Using a sterile dentistry drill, the scientists removed 400 milligrams of bone powder — an amount equivalent to the size of an aspirin.
Extracting DNA from ancient bones was a dicey proposition.
For starters, 95% to 99% of the DNA the team found came from microbes that colonized the bones after the Neanderthals died more than 38,000 years ago. To address that problem, the scientists discarded DNA fragments with letter combinations that were especially common in microbes.
In addition, the Neanderthal DNA was badly degraded, which caused sequencing machines to misread some of the chemical letters in the sequence. The researchers developed a computer program to correct those mistakes.
To conserve their limited supply of Neanderthal bones, they practiced their techniques on bones from extinct cave bears first.
The researchers took special precautions to keep their own DNA out of the Neanderthal samples. Workers wore full-body suits, including masks and gloves. The air pressure inside the lab was kept high so that nothing could blow in accidentally, and the room was irradiated after the researchers went home, Green said.
After four years of work, the team identified 4 billion fragments of Neanderthal DNA and organized them into a draft genome. The sequence is 60% complete.
"It is a very poor quality for a human genome, but it is outstanding for a 30,000-year-old extinct hominid," said Eddy Rubin, who has sequenced samples of Neanderthal DNA at Lawrence Berkeley National Laboratory but was not involved in this study.
To look for evidence of gene flow between humans and Neanderthals, the researchers sequenced the DNA of five people who live in Southern Africa, Western Africa, France, China and Papua New Guinea. Because they didn't think Neanderthal genes had passed to humans, they expected to find the same degree of difference between the Neanderthal genome and all five people.
Instead, they discovered that the Neanderthal DNA was slightly more similar to the three people living outside Africa. Even more surprising, the relationship was just as strong for the individuals from China and Papua New Guinea as for the person from France, who lives in the Neanderthals' old stamping grounds.
The simplest explanation is that a small group of humans met the Neanderthals 50,000 to 80,000 years ago after they left Africa but before they had spread throughout Europe, Asia and beyond. The logical meeting place was the Middle East, which connects northeast Africa to the Eurasian continent.
"The contact must have happened early for the Neanderthals' genes to have spread so widely and uniformly," said Henry Harpending, an anthropologist at the University of Utah, who was not involved in the study.
The amount of mixing was small: Only 1% to 4% of the DNA in non-African humans originated in Neanderthals, according to the study. The researchers said none of that DNA is functional; in fact, the particular 1% to 4% is different in every individual.
Interbreeding may well have continued in Europe, but that would be harder to detect because both populations there were large and any small Neanderthal contribution would be too dilute to see, Paabo said.