New Methods Let Scientists Analyze Neanderthal DNA

By Rick Weiss
Washington Post Staff Writer
Thursday, November 16, 2006; A01

Unleashing a new kind of DNA analyzer on a 38,000-year-old fragment of fossilized Neanderthal bone, scientists have reconstructed a portion of that creature's genetic code -- a technological tour de force that has researchers convinced they will soon know the entire DNA sequence of the closest cousin humans ever had.

Such a feat, deemed impossible even a few years ago, could tell a lot about what Neanderthals were like, such as their hair and skin color and their relative facility with language, according to scientists in Germany and California who released the new results yesterday. It could also clear up what sort of relationship existed between Neanderthals and the first modern humans -- including whether the two interbred after their evolutionary trajectories diverged.

Most tantalizing, the newfound ability to reconstruct prehistoric DNA allows scientists to home in on the fraction of a percent of human DNA that will differ from that of Neanderthals, who went extinct 30,000 years ago.

Those differences, scientists said, will amount to biological snapshots of what makes humans human.

The new findings that significant amounts of Neanderthal DNA can be retrieved and read "are perhaps the most significant contributions published in this field since the discovery of Neanderthals 150 years ago," David Lambert and Craig Millar wrote in a commentary in the journal Nature, which with the journal Science is publishing the work this week.

Lambert and Millar, who were not involved in the work, are experts in molecular evolution at universities in New Zealand.

"Personally, I was blown away when I first heard wind of this," said Sean B. Carroll, a Howard Hughes Medical Institute investigator and evolutionary geneticist at the University of Wisconsin at Madison. "We're all kind of giddy with excitement."

As the most closely related and most recently departed members of the human family tree -- and as the bony-browed icons of a stonier age -- Neanderthals have long fascinated scientists and armchair anthropologists alike. They and human forebears started as equals hundreds of thousands of years ago but took very different paths.

One line went on to develop haute couture, rock 'n' roll and DNA synthesizers. The other disappeared in a wave that began in Asia about 45,000 years ago and ended with extinction in Europe 15,000 years later.

Some say climate change did them in. Some blame modern humans, who were spreading through Europe at the time and who, perhaps because of some fortuitous genetic mutations, were experiencing an intellectual and cultural awakening.

The quest to understand Neanderthal genetics was for a long time seen as hopeless because DNA, the instructions for life ensconced in cells, breaks down over time.

A few researchers, most notably Svante Paabo of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, had extracted DNA fragments from 5,000-year-old mummies and a few older bones, and even stitched a few pieces together in sequence. But the DNA bits from Neanderthals are so old and small that nothing has been able to fully reassemble them.

Complicating matters, prehistoric bones are heavily contaminated with DNA from bacteria and from scientists who have handled them. That is one reason no extinct animal has ever had its genome fully sequenced.

But the technology for detecting and reconstructing disintegrated DNA has evolved at a stunning pace. Machines can now tell whether a snippet of DNA came from the same organism as another snippet -- and if so, whether the two fragments were once attached. Bit by bit, an organism's genome, or full genetic code, can come into view.

To do so with Neanderthal DNA, Paabo's team focused on a bone discovered decades ago in a Croatian cave. Though more than 90 percent of the DNA was from bacteria, virtually all of the rest appeared to be Neanderthal, recognizable by its similarity to human DNA but with stretches resembling chimpanzee.

The bone had stayed clean, Paabo said, because "it's rather small and uninteresting and was thrown in a big box of 'uninformative' bones and was not handled much by people."

Paabo's team then turned to 454 Life Sciences of Branford, Conn., which is developing high-speed DNA analyzers with the goal of being able to offer affordable, personalized, full-genome analyses.

In a test run on 20 grams of pulverized bone, the machine placed in order 1 million letters -- or "bases" -- of Neanderthal genetic code, Paabo and his colleagues report in today's Nature.

That is less than one-thousandth of the entire anticipated genome. But a full cracking of the Neanderthal code should be complete in about 18 months, Paabo said.

"Clearly, we are at the dawn of Neanderthal genomics," said Edward M. Rubin of the Department of Energy's Joint Genome Institute in Walnut Creek, Calif., and the Lawrence Berkeley National Laboratory. Rubin led a second team that used a different method to sequence 65,250 bases from the same Neanderthal bone, landmark work complementary to Paabo's, described in tomorrow's issue of Science.

"We're going to be able to learn about their biology, learn things we could never learn from the bones or artifacts," Rubin said. "This data will serve as a DNA time machine."

Scientists have already identified a few lucky genetic glitches that may have helped launch humans to global dominance while our stocky cousins turned toward an evolutionary dead end. One, in a gene called FOXP2, may have facilitated language. Another may have driven a big increase in brain size.

Until now, the only Neanderthal DNA that scientists had looked at was a smidgeon of "mitochondrial" DNA, of limited value because it does not contain genes involved in appearance, intelligence or language.

The new reports confirm early suggestions that modern humans and Neanderthals split into two genetically distinct groups about 500,000 years ago. They also show no evidence of interbreeding, though a final answer to that question must await further analysis.

The most exciting thing about the new technology is its promise of allowing a first comparison of DNA from humans, Neanderthals and chimpanzees, our closest living relatives, said Chris Stringer of London's Natural History Museum.

"We should then be able to pin down unique changes in each genome," Stringer said, "to show how we came to be different from each other."

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