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Neandertal Draft Genome Sequence, Targeted Sequences Shine Light on Human Evolution

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COLD SPRING HARBOR, NY— A team of researchers led by Svante Pääbo at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, has generated a draft assembly of the Neandertal genome, based on sequencing data from both the Illumina and the Roche/454 platforms, and is planning to increase the coverage to between 15- and 20-fold within the next few years.

In addition, the scientists have been using two genome enrichment techniques to sequence additional mitochondrial genomes as well as selected regions of the nuclear genome for comparative studies.

Almost three years ago, the Max Planck Institute and 454 Life Sciences said they planned to generate a draft sequence of the Neandertal genome within two years (see GenomeWeb Daily News 7/20/2006), with financial support from the Max Planck Society.

Last summer, they published their first results, an analysis of the hominid's mitochondrial genome, (see In Sequence 8/12/2008), based on data produced by 454 Life Sciences under contract.

At the Biology of Genomes meeting at Cold Spring Harbor Laboratory last week, Pääbo said that the researchers have now completed a draft of the Neandertal genome sequence with about 1.5-fold coverage, based on more than a billion fragment reads from the Illumina Genome Analyzer and about 200 million fragment reads from the 454 platform. Most of the Illumina data, he told In Sequence, was produced at the Max Planck Institute. The main reason the scientists chose to bring in the Illumina platform was the abundance of reads it produces per run, he said.

Being able to produce large amounts of data is important for the project because the overwhelming number of sequence reads — more than 99 percent in some cases — derives from microbes that have infiltrated the Neandertal fossil bones.

The samples for the project came from sites in Croatia, Germany, and Spain that harbored fossils on the order of 40,000 years old; and from Southern Russia, which held fossil bones estimated to be 60,000 to 70,000 years old. The majority of the sequence data derived from the Vindija, Croatia, sample.

The researchers estimated the degree of contamination with modern human DNA to be small, based on differences in their mitochondrial and Y-chromosomal DNA.

To analyze the sequence data, they developed a short-read mapping assembler that is optimized for ancient DNA, taking into account typical base damage occurring in this type of DNA.

Based on the results, the scientists believe that Neandertals and modern humans diverged about 830,000 years ago. Based on simulations, the two populations diverged on the order of 300,000 years ago, although there is significant uncertainty associated with that number.

Pääbo and his colleagues are now also sequencing targeted regions of the Neandertal genome using two enrichment methods, he said.

A method called Primer Extension Capture has allowed them to enrich Neandertal DNA libraries up to 80,000-fold for mitochondrial DNA and to generate sequences for five additional Neandertal mitochondrial genomes.

Another capture method, developed by researchers at Cold Spring Harbor Laboratory, uses Agilent microarrays and has enabled the researchers to sequence regions of the Neandertal genome where about 14,000 amino acid substitutions have occurred on the human lineage, allowing them to reconstruct the ancestral proteome of modern humans and Neandertals.

Within the next few years, Pääbo said, his team plans to increase the coverage for the Neandertal genome to about 15- to 20-fold. He told In Sequence last week that the current plan is to use the Illumina Genome Analyzer for that work. However, he said this might change again if new sequencing technologies that are better suited for the project appear.

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