Neandertal genome sequence published in Science

The researchers, led by Svante Pääbo of the Max-Planck Institute for Evolutionary Anthropology in Leipzig, Germany, compared the Neandertal genome with the genomes of five present-day humans from different parts of the world. The results reveal a variety of genes that are unique to humans, including a handful that spread rapidly among our species after humans and Neandertals split from a common ancestor. These findings thus offer a shortlist of genomic regions and genes that may be key to our human identity.

The scientists also found that modern humans and Neandertals most likely interbred, to a small extent, probably as modern humans encountered Neandertals in the Middle East, after leaving Africa.

"Having a first version of the Neandertal genome fulfills a long-standing dream. For the first time we can now identify genetic features that sets us apart from all other organisms, including our closest evolutionary relatives," said Pääbo.

"We have so many questions about the Neandertals, not the least of which is, how much were they like us? The Neandertal genome promises to be a fruitful source of information about the evolutionary events that produced modern humans and Neandertals," said Andrew Sugden, Deputy and International Managing Editor at Science.

Neandertals are our closest evolutionary relatives. They first appeared around 400,000 years ago, ranged across Europe and western Asia, and became extinct approximately 30,000 years ago.

The draft Neandertal genome sequence being reported in Science represents about 60 percent of the entire genome. The genetic material that was sequenced came from single bones from three individual Neandertals.

The sequencing effort involved multiple steps to deal with the challenges of sequencing ancient DNA. The researchers removed as little material as possible from the bones, using a delicate dentist's drill so as not to damage the fossils, and they conducted their lab research using sterile "clean-room" conditions, to avoid contaminating the material with DNA from present-day humans and other organisms. They also weeded out the much more abundant microbial DNA that had colonized the bones since the individuals died.

Modern humans and Neandertals are so closely related that a comparison of their genomes must take into account the fact that for any particular part of the genome, a single modern human and a single Neandertal could be more similar to each other than two modern humans would be.

Most of what we know about genetic variation among humans today is based on European populations. Seeking a broader picture, Pääbo and his colleagues sequenced the genomes of five present-day humans from southern Africa, West Africa, Papua New Guinea, China and France, and compared the Neandertal genome to the genomes of these individuals.

The Neandertal genome sequence proved to be slightly more similar to those of the non-African individuals.

More specifically, at any randomly chosen point in the genome where the sequence of two of the modern-day humans differed, there was a slightly higher chance that the Neandertal genome matched that of the non-African individual than the African one. (In a supporting line of evidence, the authors report that Craig Venter's recently published genome sequenced contains segments that are closer to those of the Neandertal genome than to those of the human "reference" genome, which includes a mixture of DNA of African and European ancestry.)

Though other explanations are possible, one of the simplest scenarios is that early modern humans interbred with Neandertals in the Middle East, after leaving Africa and before spreading into Eurasia.

Approximately 1 to 4 percent of the modern human genome seems to be from Neandertals, the authors estimate. Population models have suggested that when a colonizing population comes across a resident population, even a small amount of interbreeding can be widely reflected in the colonizing populations' genome, if that population then expands significantly. Thus, the relatively low percentage of Neandertal DNA in the modern human genome may suggest that interbreeding was actually fairly limited.

The comparisons between the Neandertal and modern humans also produced many other results that may ultimately be more important than the admixture discovery when it comes to giving us a better understanding of ourselves.

"It's cool to think that some of us have a little Neandertal DNA in us, but, for me, the opportunity to search for evidence of positive selection that happened shortly after the two species separated is probably the most fascinating aspect of this project," Pääbo said.

His team devised a method to look for regions of the modern-human genome where new genes have spread through the population since the two species diverged. These genes are likely to have somehow improved early humans' odds for survival or reproduction.

The researchers screened the genomes of five modern-day humans from around the world to look for genomic regions with sequence variations that occur frequently in humans but not in Neandertals, suggesting human-specific selection. Any variation shared with Neandertals would presumably have been lost from these regions as the new genes swept through the early modern human population. The team found 212 regions with such variation. Among the 20 regions with the strongest evidence for positive selection were three genes that, when mutated, affect mental and cognitive development. These genes have been implicated in Down syndrome, schizophrenia and autism.

Other regions in this list of 20 included a gene involved in energy metabolism, and another that affects the development of the cranial skeleton, the clavicle and the rib cage.

"In all these cases it requires much, much more work. This is really just hints at what genes one should now study, and I'm sure we and many other groups will be doing that," Pääbo said.

The researchers also used the Neandertal genome to produce the first version of a catalog of genetic features that exist in all humans today but are not found in Neandertals or apes. This catalog will be valuable for scientists who study what sets humans apart from other organisms.

In a companion paper appearing in the same issue of the journal, another research team with many of the same authors and also led by Pääbo present a new technique to sequence select regions of the Neandertal genome from especially degraded Neandertal remains. Using a "target sequence capture" approach, the authors sharpened their focus on the protein-coding regions within several pieces of the genome of another Neandertal individual from Spain. They identified 88 amino acid substitutions that have become fixed in humans since our divergence from the Neandertals. More research will be necessary to determine how these changes may have affected human biology.

An online presentation highlighting the Neandertal genome, including video interviews, explanatory text, and images will be available on 7 May at www.sciencemag.org.

The main genome-sequence paper, by Green et al, was funded by the Max Planck Society, El Ministerio de Ciencia e Innovación -- Inicio, the Janggen-Pöhn foundation, the National Human Genome Research Institute, National Institutes of Health; and the Burroughs Wellcome fund. The companion paper, by Burbano et al, was funded by the National Science Foundation, the National Institutes of Health, the Stanley Foundation, Howard Hughes Medical Institute and the Max Planck Society.