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Improved Denisovan Genome Sequence Reveals New Details on Archaic Hominins

NEW YORK (GenomeWeb News) – In a study appearing online today in Science, researchers from the Max Planck Institute for Evolutionary Anthropology and elsewhere describe the information gained by analyzing a new and improved genome sequence for a female Denisovan individual — the lone representative of a group of archaic hominins most closely related to Neandertals.

Using a new DNA library preparation method developed to optimize the amount of information available from the types of fragmented DNA present in very old samples, the team managed to come up with a draft Denisovan genome that's comparable in quality to genome sequences that are routinely produced for living humans.

"Every position of this genome is sequenced, on average, 30 times over," senior author Svante Pääbo, director of the Max Planck Institute for Evolutionary Anthropology's evolutionary genetics department, said this week during a telephone briefing with reporters. "So we have very few errors in the sequences — even [fewer] errors that we often have when you sequence a person today."

When the Denisovan genome was first sequenced in 2010, researchers explained, the methods available allowed them to achieve around 1.9-fold coverage of the genome, on average, meaning each base was represented less than twice. And while that level of resolution offered insights into the archaic hominin's history and relationships to Neandertals and modern humans, the initial draft sequence contained quite a few errors.

Now, using a library preparation method that let them amplify each individual strand of ancient DNA separately prior to sequencing, the researchers have sequenced the Denisovan genome to an average of more than 30-fold coverage on the Illumina GAIIx.

At that coverage depth, the team explained, it's possible to move along chromosomes teasing apart which of the archaic individual's sequences came from her mother and which came from her father — an analysis that pointed to very low genetic diversity within the wider Denisovan population.

"The genetic diversity of Denisovans was apparently much, much lower as in modern humans," co-first author Matthias Meyer, a researcher in Pääbo's Max Planck group, said during this week's press briefing.

Moreover, Meyer added, additional analyses hint that this lackluster diversity likely stretched back hundreds of thousands of years, potentially spanning much of the time since Denisovans split from modern humans between 170,000 and 700,000 years ago.

Along with the improved Denisova genome, authors of the new study sequenced the genomes of 11 humans from modern-day populations in Africa, Europe, Asia, and South America to between 24 and 33 times average coverage for the study.

By comparing these sequences with the Denisova genome, they learned new details about the nature of mixing that occurred between the archaic group and the modern human ancestors of these present-day populations.

In particular, the team determined that Denisova sequences are mainly found in individuals from Papua New Guinea and in aboriginal populations in Australia and the Philippines. Contrary to studies published previously, the new analysis did not detect Denisovan gene flow into populations in mainland Eurasia or Southeast Asia.

Archaic ancestry was especially pronounced on autosomal chromosomes in New Guineans, researchers reported, which appeared to have more Denisovan sequences than the X chromosome. That discrepancy in the archaic sequence content of the X chromosome could either reflect mixing between male Denisovans and female humans or else past selection pressures that have removed archaic DNA from the X chromosome.

Sequencing the Denisovan genome to greater depth has provided new insights into inter-breeding events between modern humans and another archaic hominin, too, researchers explained.

Past work has shown existing populations outside of Africa all carry sequences stemming from inter-breeding between modern humans and Neandertals. But analyses incorporating the upgraded Denisovan genome sequence data indicate that Asian and Native American individuals typically have more Neandertal DNA in their genomes than individuals from Europe.

That puzzling pattern may be a consequence of multiple mixing events between Neandertals and humans, though study authors say there's also a chance that it is a simply due to dilution of Neandertal sequences in Europeans due to later mixing with other populations that lacked Neandertal ancestry.

Which of these scenarios is more likely is still a matter of debate, according to co-senior author David Reich, a researcher affiliated with Harvard Medical School and the Broad Institute, who noted that "the Neandertal question becomes more exciting and interesting now that we have variability in the proportion in Neandertal material throughout Eurasia."

Finally, through comparisons of variant profiles across human and Denisovan genomes, the team narrowed in on a set of genetic features that are conserved in Denisovans, Neandertals, and non-human primates but distinct in modern humans.

Of the 100,000 or so single base variants and 10,000 gains or losses identified in the human genome since the last known split from other hominins, just a few hundred are predicted to alter the function of the resulting protein.

Interesting, though, among the 23 of these sites that are most highly conserved in non-human primates, eight fall in genes implicated in nervous system development, brain connectivity, and/or autism, Pääbo noted.

He and his colleagues hope that such comparisons will make it possible to drill down into the genetic features that have contributed to human-specific traits since modern humans split from archaic forms, such as the Denisovans and Neandertals.

"By providing a comprehensive catalog of features that became fixed in modern humans after their separation from their closest archaic relatives," he and his co-authors noted, "this work will eventually lead to a better understanding of the biological differences that existed between the groups. This should ultimately aid in determining how it was that modern humans came to expand dramatically in population size as well as cultural complexity while archaic humans eventually dwindled in numbers and became physically extinct."

The group is also using its new single-stranded sequencing protocol to improve the Neandertal genome, which was originally sequenced to a depth of 1.3x in 2010.