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International Team Sequences Ancient Human Genome

By Andrea Anderson

NEW YORK (GenomeWeb News) – An international research team reported online today in Nature that they have sequenced an ancient human genome using DNA isolated from preserved hair samples found in Greenland's permafrost.

The researchers used Illumina technology to sequence the nuclear genome of a 4,000-year-old man dubbed "Inuk" from western Greenland. They generated sequence covering nearly 80 percent of the diploid genome to an average depth of 20 times.

"I would say it's comparable to a modern human genome in terms of quality," senior author Eske Willerslev, director of University of Copenhagen's center for ancient genetics and researcher with BGI-Shenzhen's Sino-Danish Genomics Center, said during a telephone briefing with reporters this week.

Using SNPs found in the genome, the team gained clues into everything from the man's appearance to human migration history, demonstrating that the first inhabitants of Greenland were more closely related to individuals in present day Siberia than to Inuit or Native American populations.

The samples used in the study were excavated from a site in western Greenland in the mid-1980s, Willerslev explained. At that time, researchers uncovered four chunks of hair and four bone fragments that had been preserved in permafrost.

Based on the age and location of his remains, along with other archeological evidence, the researchers determined that the man belonged to an early Greenland population called the Saqqaq Culture, which lived in the region about 2,500 to 4,750 years ago.

But isolating DNA from the bone samples proved difficult. It wasn't until researchers began focusing on the tufts of preserved hair that they started finding fodder for sequencing projects. In a 2008 paper, the team reported that they used DNA from these hair samples to sequence the first ancient human mitochondrial genome.

For the current paper, the researchers went even further, using the Illumina GAII to sequence a dozen ancient libraries created from DNA in the hair.

In the process, they generated sequence covering 79 percent of the diploid nuclear genome to an average depth of 20 times. They also resequenced the mitochondrial genome to an average depth of 3,802 times.

To minimize contamination with modern human DNA, the researchers decontaminated the samples and tagged DNA in the ancient library using indexing adaptors and primers. They estimated that the contamination rate from modern human DNA was around 0.8 percent.

Although they detected 2.2 million potential SNPs in the ancient human genome, co-lead author Morten Rasmussen, a researcher affiliated with the University of Copenhagen and BGI-Shenzhen, told reporters, the team focused on the 353,151 most reliable and high quality SNPs in subsequent analyses. Of these, 93.2 percent overlapped with SNPs found in the dbSNP database, while 6.8 percent have not been detected in humans before.

By comparing SNPs in the genome with those in modern human genomes, the team was able to make some inferences about what Inuk looked like. They say he likely had brown eyes, brownish skin, thick dark hair, shovel-graded front teeth, and a propensity for baldness. Because so much hair was identified at the site where his remains were found, Willerslev noted, he may have died fairly young.

They also reported that Inuk had an A+ blood type — a type that is particularly common amongst individuals from east Siberia to central China — as well as dry earwax. A dozen SNPs in metabolic and body mass index-related genes suggest he and others in the population were adapted to cold weather.

Next, the team used the Illumina Bead Array to genotype samples from a dozen northern Asian populations and four Native American populations, comparing SNPs in these samples to those in the Saqqaq genome.

Based on this comparison, the researchers concluded that Inuk and other members of the Saqqaq culture are not ancestors of Inuit or Native American populations in North America today. Rather, the Saqqaq seem to be most closely related to three present-day populations in eastern Siberia: the Nganasans, Koryaks, and Chukchis.

The team's phylogenetic analyses indicate that the Saqqaq diverged from the ancestors of the Chukchis about 5,400 years ago, just before migrating to North America.

But while populations related to the Saqqaq survived in other parts of the world, the Saqqaq Culture itself apparently disappeared. The reason for its demise is unclear, though researchers speculate that climate changes or competition from populations moving into the area later may have played a part.

"The exact reason for why they died out … the genetics would not be able to tell you," Willerslev explained. Still, he said, genetic studies may be useful for exploring whether there was intermixing between Greenland's earliest populations.

With one successful ancient human sequencing effort under their belt, researchers are optimistic about sequencing other archeological samples. For instance, Willerslev noted, samples from South America, Tasmania, and elsewhere may help answer questions about how genetic diversity shifted in indigenous populations after the arrival of Europeans. And, he added, sequencing may also offer insights into the history of genetic diseases that tend to cluster within specific modern-day populations.

"The next technical challenge will be to sequence an ancient human genome from material outside the permafrost regions," the researchers concluded. "Although undoubtedly challenging, it will, if successful, take the emerging field of palaeogenomics to yet another level."

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