New York

The first nuclear DNA sequences from a Neanderthal (Homo neanderthalensis) have been reported. The results should provide clues about when certain diseases, or traits such as hair or skin colour, arose. They also have geneticists excited about the idea of sequencing a Neanderthal genome.

Svante Pääbo, a palaeogeneticist at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, began his Neanderthal Genome Project about two years ago. He and his team have probed 60 Neanderthal specimens from museums for hints that the DNA might have survived millennia of degradation. The species lived across Europe and western Asia from 300,000 to around 30,000 years ago, with the first specimen found in 1856 near Dusseldorf, Germany.

Two of the specimens showed promise, and on 12 May Pääbo's team reported at the Biology of Genomes meeting at New York's Cold Spring Harbor Laboratory that they had managed to sequence around a million base pairs of nuclear DNA — around 0.03% of the genome — from one of them. This is a 45,000-year-old male specimen found in Vindija Cave outside Zagreb, Croatia.

Typically, DNA to be sequenced must be cloned in bacteria to produce large enough amounts for study. But because the Neanderthal DNA had broken down into tiny fragments, Pääbo and his colleagues used a new sequencing technique, developed by 454 Life Sciences in Branford, Connecticut, that allows genetic fragments in an emulsion to be sequenced directly in tiny wells. They are now analysing the results to work out how the different fragments fit together so that they can be compared with the modern human genome sequence.

One finding so far is that the Neanderthal Y chromosome is substantially more different from human and chimp Y chromosomes than are other chromosomes. This suggests that little interbreeding occurred, at least among the more recent Neanderthal species.

Neanderthal (right) DNA should shed light on the human genome. Credit: G. J. SAWYER & B. MALEY; PHOTO D. FINNIN/AMNH

Edward Rubin, director of the Joint Genome Institute in Walnut Creek, California, works with Pääbo. The two are also working to sequence Neanderthal DNA by the traditional method. James Noonan, a postdoc in Rubin's lab, reported at the Cold Spring Harbor meeting that preliminary analysis of the 75,000 base pairs sequenced so far shows that Neanderthals diverged from the lineage that led to modern humans about 315,000 years ago — around the time that had been thought. Homo sapiens is known to have evolved at least 200,000 years ago (I. McDougall, F. H. Brown and J. G. Fleagle Nature 433, 733–736; 2005).

Back in 1997, Pääbo reported sequencing the first mitochondrial DNA from a Neanderthal (M. Krings et al. Cell 90, 19–30; 1997). That sequence also suggested that Neanderthals split from the common lineage well before modern humans evolved and may not have contributed any mitochondrial DNA, at least to modern humans.

But the more extensive nuclear DNA sequences should pin down the timing of the split more precisely, and comparing genes for particular traits could help researchers work out which characteristics were shared by Neanderthals, and when such traits arose. Such comparisons could also confirm whether Neanderthals did contribute isolated genes to the human lineage. For example, John Hardy, a geneticist at the National Human Genome Research Institute in Bethesda, Maryland, has hypothesized that Neanderthals may have contributed a gene that is linked to several neurodegenerative diseases, because it is found in people of European ancestry, where the Neanderthals lived. Proving that theory would require finding this version of the gene in the Neanderthal genome.

Researchers are confident about the prospects for sequencing much more Neanderthal DNA. “Our goal is to sequence a large amount of the Neanderthal genome,” says Pääbo. That task will probably require identifying new fossils. “We should do it,” agreed Francis Collins, director of the National Human Genome Research Institute, after attending Pääbo's lecture on 12 May.

Rubin says he envisages creating a bank of Neanderthal DNA, so that representative samples can be compared with the thousands of H. sapiens genomes that are expected to be sequenced in the future. “In ten years, we hope to have ten Neanderthal genomes,” says Rubin.