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After sequencing genes from 70 Neanderthal bone and tooth samples, Pääbo’s team and researchers from 454 found one sample, estimated to be 38,000 years old, that had mostly clean DNA. As they reported in a paper published last fall in Nature, they then sequenced one million base pairs from less than 200 milligrams of material, an achievement that has yielded clues about whether modern humans and Neanderthals interbred and when the two species diverged from each other. More important, the paper shows that sequencing all three billion bases in the Neanderthal genome is feasible. Doing so could help solve such mysteries as whether Neanderthals had the genetic ability to speak.

Sorting out whether humans and Neanderthals interbred or even had the capacity to talk to each other may get a lot of press and public attention, but other applications for ultra­rapid DNA sequencing could have a far greater impact on medicine and on our lives. The traditional sequencing method looks at DNA from many different cells. But if one of those cells is, say, a tumor cell, its sequence can differ slightly from those of the healthy cells. In such cases, the computers select the sequence that’s most commonly found and discard the others. Next-­generation sequencers like the ones marketed by 454 instead clone and sequence single molecules of DNA, allowing “ultradeep” probing that can unearth rare variants. (Traditional sequencers can also analyze single molecules, but it’s prohibitively expensive.) The implications of single-molecule sequencing are enormous for medicine. While it is not practical to use conventional sequencing to sniff out the DNA differences between healthy and diseased cells, the new machines can perform such experiments easily.

Matthew Meyerson, a clinical pathologist at the Dana-­Farber Cancer Institute in Boston, has published a study showing how the 454 machine can help uncover mutations linked to lung cancer. Lung-cancer drugs now available target the gene that Meyerson is sequencing, and he hopes that physicians will ultimately gain a better handle on who will respond to which drugs by learning whether the patient has a particular mutation. “I imagine in a few years all cancer patients will have their tumors characterized by single-molecule sequencing if the technology continues to decrease in cost,” he says.

In a variation on this theme, Michael Kozal, an AIDS clinician at Yale, has joined with 454 to do ultradeep sequencing of HIV to determine the presence of minor populations of drug-resistant virus. Early tests of the technique in patients detected about twice as much resistant HIV as Sanger sequencing did. This information, too, could help physicians individualize treatment regimens, which would increase cost-effectiveness. “It’s practical to do in our system,” says 454 chief scientist Michael Egholm, who is collaborating with Kozal. “Before, it simply wasn’t affordable.”

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Credit: Steve Moors

Tagged: Biomedicine

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