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Denisovan Anatomy Reconstructed From DNA Methylation Maps

Female Denisovan Teen

NEW YORK – Using DNA methylation patterns as a guide, researchers in Israel and Spain have reconstructed what the anatomical features of ancient Denisovans might have been like.

The Denisovan genome was first sequenced in 2010 from a finger bone, and so far only that pinky bone, three teeth, and a lower jaw belonging to Denisovans have been unearthed, leaving it unclear what their anatomy might have been like.

By building DNA methylation maps, though, the researchers teased out what genes may have been expressed in Denisovans. They then compared the DNA methylation patterns to those of modern humans and Neanderthals to try to predict a number of Denisovan skeletal traits. According to this analysis, which was published today in Cell, Denisovans likely shared some traits with Neanderthals, such as a projecting face and a wide pelvis, but also had Denisovan-specific characteristics like an increased dental arch and lateral cranial expansion.

"We provide the first reconstruction of the skeletal anatomy of Denisovans," senior author Liran Carmel from the Hebrew University of Jerusalem said in a statement. "In many ways, Denisovans resembled Neanderthals, but in some traits, they resembled us, and in others, they were unique."

Using a previously developed approach that relies on damage patterns seen in ancient DNA, the researchers generated full DNA methylation maps for one Denisovan sample, two Neanderthals, and five anatomically modern humans who lived 45,000 to 7,500 years ago. At the same time, they generated methylomes for 55 present-day humans and five chimpanzees.

With these maps in hand, they teased out regions of the genome that were differentially methylated in these various hominins and used them to home in on genes that were differentially methylated, using that as a proxy for differences in gene expression.

They then linked these differentially methylated genes to potential differences in phenotype using the Human Phenotype Ontology (HPO) database, which houses gene-phenotype associations. For instance, they based their prediction of what a phenotype resulting from a down-regulated gene would be on known loss-of-function phenotypes.

Before applying this approach to their Denisovan methylation data, the researchers first tested it on Neanderthal and chimpanzee methylome data, as there is available skeletal and anatomical data on both groups. They were able to predict phenotypic profiles with a precision of about 87 percent and a sensitivity of about 73 percent.

When they then applied this method to Denisovans, the researchers found that they shared a number of skeletal feature traits with Neanderthals. In particular, the two ancient hominins both had robust jaws, low foreheads, a wide pelvis, and a large ribcage, among a number of other shared traits, according to this analysis.

But they also uncovered some 56 traits where Denisovans differed from both Neanderthals and modern humans, particularly those affecting the skull. Overall, they predicted the Denisovan skull to be wider than either that of Neanderthals or modern humans.

Though they can't confirm many of these predictions until more complete Denisovan skeletons are unearthed, the Denisovan jawbone that has been uncovered does provide some confidence in the researchers' approach. They predicted four features for the mandibular region — a high anterior mandible, a wide anterior mandible, a mandibular protrusion, and a long dental arch — that were largely correct. They had predicted the width of the anterior mandible to be similar to that of Neanderthals, but in reality, it was longer.

"Studying Denisovan anatomy can teach us about human adaptation, evolutionary constraints, development, gene-environment interactions, and disease dynamics," Carmel said. "At a more general level, this work is a step towards being able to infer an individual's anatomy based on their DNA."