Sunday, October 08, 2006

Rebuilding the Neaderthal genome

454 and Max Planck Institute to Sequence Neanderthal Genome

July 20, 2006 | At a press conference in Leipzig, Germany, today, 454 Life Sciences announced that it is embarking on a collaboration with the Max Planck Institute for Evolutionary Anthropology, in Leipzig, to sequence the Neanderthal genome.

The German team is led by institute director Svante Pääbo, the acclaimed evolutionary geneticist. In 1997, Pääbo's team published a landmark paper in the journal Cell in which it painstakingly purified and sequenced a small fragment of mitochondrial DNA from the original Neanderthal fossil, uncovered in a cave in Germany's Neander Vally 150 years ago. Based on the number of DNA mismatches with human mtDNA, Paabo's team concluded that Neanderthals were not ancestors of modern humans, but represented an extinct branch of the hominid evolutionary tree.

Pääbo described the partnership with 454 as "an ideal collaboration. The advent of 454 sequencing has enabled us to move forward with a project that was previously thought to be impossible." The project will take an estimated two years, with funding provided by the Max Planck Society. That decision was made after review of a sample sequence of 1 million bases of Neanderthal DNA produced by 454 recently from a 45,000-year-old Croatian Neanderthal fossil.

"We are excited to collaborate with the Max Planck Institute to sequence the Neanderthal genome, as it promises to yield more insight into human biology than the sequencing of any individual human," said Christopher McLeod, CEO of 454 Life Sciences. "This ambitious project is further validation of 454's sequencing technology and demonstrates that we can sequence any genome, even one from highly degraded samples."

The robust composite skeleton
of a Neandertal (left) is
unmistakably different from
that of a modern human (right).

The 454 single-molecule sequencing method assembles complex genome structures from millions of small DNA reads. These reads are about 100-200 bases in length, similar to the optimal fragment lengths that can be extracted from fossil DNA. In addition, contamination from bacteria and other microbes is a major problem.

Pääbo's goal is to marry his own group's expertise in extracting and sequencing ancient DNA with 454's high-throughput technology and produce a draft sequence of the Neanderthal genome, which was likely the same size as the human genome. Neanderthals are thought to have disappeared in Europe about 30,000 years ago as Homo sapiens thrived. 454's Genome Sequencer 20 System allows some 250,000 single DNA strands from small amounts of bone to be sequenced in only about five hours by a single machine.

A key issue in the project's success is that of contamination. "We'll extract [Neanderthal] DNA and prepare for sequencing, then it will be shipped to [454] directly from our clean room, since we're so afraid of contamination," said Pääbo. "Then it will be in [their] hands." The actual DNA analysis will probably be performed on several 454 machines, though in theory it could be done on a single instrument.

Scientists believe that of the 1 percent difference between human genomic DNA and chimpanzees, Neanderthals share 96 percent of it with Homo sapiens, and 4 percent with the chimpanzee. "The analysis of the estimated 4 percent of genome variation that Neanderthal shares with the chimpanzee will help us to understand the evolution of characteristics specific to the Homo sapiens and perhaps even aspects of cognitive function," Pääbo said. "This next leap in Neanderthal research will also identify those genetic changes that enabled modern humans to leave Africa and rapidly spread around the world."

"Sequencing of the Neanderthal [genome] will certainly be a major milestone, both for the insight it gives us into the origins of Homo sapiens as a species, as well as into what makes humans special," said Jonathan Rothberg, founder and chairman of 454 Life Sciences.

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