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With Draft Neandertal Sequence Complete, Researchers Aim for 'Finished Quality Genome'


By Monica Heger

This article was originally published on May 6

An international team of researchers led by Svante Pääbo that published a draft sequence of the Neandertal genome last week in Science plans to continue its effort so that it is of comparable quality to that of other sequenced genomes.

The group, which announced that it had completed the draft at last year's Biology of Genome's meeting at Cold Spring Harbor Laboratory, (IS 5/12/2009), wants to generate a "finished quality genome," Ed Green, lead author of the study and assistant professor of biomolecular engineering at the University of California, Santa Cruz, told In Sequence.

In order to do this, Green said he and his colleagues will need to increase their coverage from about 1-fold to 20- to 30-fold and increase the portion of the genome they are able to sequence from 60 percent to 100 percent.

To improve the quality of the genome, Green said they are evaluating different enrichment strategies, including an array-based hybridization method that a team from Cold Spring Harbor used to do targeted resequencing of the Neandertal genome, which was also published in Science last week (see related story, same issue).

That group used hybridization capture on a glass slide microarray using Agilent reagents. "This works pretty well for medium-sized projects of a few megabases," said Green, but he noted that it doesn't scale up easily for larger projects because it requires designing hundreds of different arrays. Green declined to comment on the other methods he and his colleagues are looking at because he said so far none of them have been published.

A full, high-quality Neandertal genome would not only enable researchers to study the differences between modern humans and Neandertals, but would allow them to study evolution and variation among Neandertals, said Green. "With a finished quality genome, we can really start to understand Neandertal-specific substitutions and how Neandertals were particularly adapted for life in the Pleistocene era."

For the Neandertal sequencing project published this week, the group originally began the project using Roche's 454 GS FLX, but later switched to the Illumina Genome Analyzer, and in subsequent analyses that they published in the current paper, only used Illumina-generated data.

Green said the advantage of 454 is its long read lengths. When working with ancient DNA, however, the samples are already so fragmented that they are frequently shorter than 454's read lengths, so it didn't make sense to continue to use 454, he said. The high throughput that Illlumina provides was much more important for this particular project, he added.

Also, since they initially reported the draft sequence of the Neandertal genome at the Biology of Genomes meeting last year, the authors have sequenced five modern human genomes to 4- to 6-fold coverage on Illumina, including a South African genome, a Yoruban from West Africa, a Papau New Guinean, a Han Chinese, and a French genome.

In a comparison of the Neandertal genome to the five modern humans and to the reference genome, they found that Neandertals shared more variants with humans from Eurasia than with humans in sub-Saharan Africa, suggesting that the Neandertals intermixed with non-African ancestors before the two groups diverged. This does not hold with the commonly held view that all humans trace their ancestry back to an African population, and did not mix with Neandertals.

"The data suggest that between 1 and 4 percent of the genomes of people in Eurasia are derived from Neandertals," the authors wrote, and it "presents a challenge to the simplest version of an 'out-of-Africa' model for modern human origins."