Neanderthal DNA sequenced

Early findings suggest Neanderthal and human DNA diverged about 500,000 years ago

Nov 15, 2006
Charles Q. Choi
More than one million base pairs of Neanderthal DNA have been sequenced, according to findings appearing this week in Nature and Science that could begin to shed light on whether humans and Neanderthals interbred and when they diverged genetically."These are just proof-of-principle findings, but they're very exciting in how they demonstrate the feasibility of a larger-scale Neanderthal genome project, which if successful will provide a key reference for understanding human evolution," Bruce Lahn at the University of Chicago, who did not participate in the studies, told The Scientist.The researchers investigated fragments of nuclear DNA roughly 100 to 200 base pairs long, which were extracted from a 38,000-year-old Neanderthal bone from Vindija Cave in Croatia. Ninety-four percent of the hominid DNA from the bone appeared to be of Neanderthal origin.In their Nature paper, Svante Paabo at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, and colleagues sequenced more than one million base pairs of putative Neanderthal nuclear DNA using pyrosequencing, which has a roughly 100-fold higher throughput than traditional sequencing methods. DNA fragments were attached to beads that were placed in wells, where the DNA was sequenced directly. These were then matched against similar sequences in the human genome. The Neanderthal DNA represented about six percent of the sequences the researchers found, with the rest coming from contamination from bacteria or handling by human bone collectors or lab workers."It is surprising that one million base pairs could be recovered," said David Lambert at Massey University in New Zealand, who was not a coauthor. In fact, Pääbo told The Scientist the researchers have unpublished data on another four million base pairs of Neanderthal DNA.In their Science paper, Edward Rubin at Lawrence Berkeley National Laboratory in Berkeley, Calif., with Pääbo and their colleagues sequenced 65,250 base pairs of Neanderthal DNA using metagenomics, in which DNA fragments are incorporated into plasmids, which are subsequently amplified by replication in bacteria. These DNA libraries are then amplified further enzymatically. "Pyrosequencing gives you a large amount of data, but it's untargeted. The metagenomics approach is really just as interesting as pyrosequencing in that it allows you to target specific genes of interest," Lambert said. He noted that Rubin and his colleagues recovered 29 out of 35 genes they targeted.The researchers published the two papers simultaneously because "it'd be silly to come out at different times, to compete to the finish line after collaborating for so long," Rubin told The Scientist.The papers estimate that human and Neanderthal genomes are at least 99.5 percent identical. "There's maybe a three-million base pair difference between Neanderthals and humans, compared to the 30- to 50-million base pair difference between chimpanzees and humans," Rubin said.The Nature paper estimates Neanderthal and human DNA diverged about 500,000 years ago, and the Science paper gives a similar estimate of about 370,000 years ago. The Nature data suggest Neanderthals were derived from a very small ancestral population of roughly 3,000 individuals, similar to the estimated ancestral population size of modern humans. This is consistent with "evidence of the 'out of Africa' idea of origins," Lambert said.One concern about the papers is that they estimate the level of modern human nuclear DNA contamination by looking at levels of modern human mitochondrial DNA contamination, Eske Willerslev at the University of Copenhagen, who did not participate in the studies, told The Scientist. Lahn agreed that the contamination estimates could be problematic. "For instance, their degradation rates might differ," he said. "Their estimates are probably pretty good, but I wouldn't be surprised if down the line they were found to be off."The researchers plan to finish a rough draft of the Neanderthal genome within two years and then to spend another six months analyzing it, Paabo said. The preliminary findings are being reported now "to encourage others into the ancient DNA field," Rubin added. "Darwin may have waited until the end, but we figured we reached enough insights for the world to know about."The papers do not resolve the question of whether modern humans and Neanderthals interbred in recent times. "We see no evidence of mixing between 30,000 and 400,000 years ago, but we don't exclude it," Rubin said.Future research could also shed light on which genes in the modern human lineage show signs of accelerated evolution after humans and Neanderthals split genetically, "which would be very interesting in understanding human evolution," Lahn said. For instance, investigations can look at whether Neanderthals had a human-like version of FoxP2, a gene linked to language and cognition, Philip Lieberman at Brown University in Providence, R.I., who did not participate in the studies, told The Scientist.Charles Q. Choi cchoi@the-scientist.comLinks within this article:R.E. Green et al. "Analysis of one million base pairs of Neanderthal DNA," Nature 444: 330-6, November 16, 2006. Noonan et al. "Sequencing and Analysis of Neanderthal Genomic DNA," Science 314: 1113-8, November 17, 2006. Hopkin, "Rebel with a Lab," The Scientist, Aug. 29, 2005 Pincock, "Comparing Relatives," The Scientist, April 5, 2004 Lambert Robinson, "Shadows Provide Illumination," The Scientist, Feb. 28, 2003 Willerslev Lieberman