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How to Reconstruct the Neandertal Genome

A Neandertal, mammoth and cave bear wandered into a lab and, in the process, revealed how it might be possible to reconstruct their entire genetic makeup
neandertal-skull



© ARCHIVO ICONOGRAFICO, S.A./CORBIS
If you want to bring back from extinction the relative of modern Homo sapiens known as Neandertal man, you must first have a working copy of his genetic blueprint. But it is difficult to determine which DNA from a 38,000-year-old skeleton is bona fide Neandertal and which is from bacteria or contamination with modern human DNA. Now ancient DNA expert Svante Pääbo—who is working on reconstructing the Neandertal genome—has shown how the ravages of time are largely restricted to just a few types of errors.

Pääbo, of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, and his colleagues examined ground-up Neandertal bone as well as 43,000-year-old mammoth bone and 42,000-year-old cave bear bone to determine whether the genomes of such ancient creatures could be sequenced. Although researchers, including Pääbo, have been able to extract DNA from such bones, the entire genetic blueprint remains difficult to map due to confusing gaps in the long strand and potential contamination.

But by analyzing the available DNA, Pääbo found that such damage is most likely to occur at certain junctures in the strand near the end of molecules and, further, that such breakages are most likely to be misread as cytosine (C) for thymine (T) or guanine (G) for adenine (A)—the chemical bases that make up DNA.

"The damage seems to be limited to these two kinds of changes, and they have established that other changes can be trusted as genuine differences between ancient sequences and living homologues," says John Hawks, a paleoanthropologist at the University of Wisconsin–Madison.

Given this predictability, the researchers should be able to reconstruct the Neandertal genome—or the genome of wooly mammoths, cave bears or any other extinct creature from that period—and use far less DNA to do it, sparing more fossils from grinding. "Except for C to T, G to A and perhaps G to T substitutions, nucleotide substitutions observed in Neandertals relative to humans and chimpanzees are as reliable as if they had been determined from contemporary DNA," the researchers write in Proceedings of the National Academy of Sciences USA.

Any complete genome raises the prospect of bringing back once extinct animals and peoples by placing ancient DNA in the embryos of modern relatives, but Pääbo dismisses the possibility. "One cannot clone individuals from DNA," he says, "only from intact cells."

Nevertheless, such efforts are underway for some Pleistocene animals. "I know that people are wanting to try to clone a mammoth," Hawks says. "I predict they will fail—not because it is impossible, but because we don't understand enough about the genetic differences between mammoths and elephants yet to make it work."

The Neandertal genome is more likely to prove useful as a comparison with that of H. sapiens. After all, even though the ancient hominid died out, Neandertal can be a guide to our own genome, not unlike modern living relatives such as the chimpanzee. "Every genetic difference between a Neandertal and a living person is a potential candidate for a gene or drug therapy," Hawks says. "Every one of their genes worked in a humanlike creature. We know that none of them were lethal. So, for instance, functional differences between Neandertals and humans in muscle metabolism might lead to treatments for problems in humans like muscle wasting."
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