Tracing the Denisovans

Israeli researchers use DNA to reveal the look of the ancient human ancestor.

By JUDITH SUDILOVSKY
A portrait of a female Denisovan teenager. (photo credit: Courtesy)
A portrait of a female Denisovan teenager.
(photo credit: Courtesy)
Using DNA from a small bit of a pinky finger bone of a young 13-year-old girl who lived tens of thousands of years ago and belonged to the ancient Denisovan – one of our prehistoric ancestors – Israeli researchers have provided a glimpse of what members of this mysterious group may have looked like, with the first reconstruction of the skeletal anatomy of Denisovans, who went extinct approximately 50,000 years ago.
“In many ways, Denisovans resembled Neanderthals but in some traits they resembled us and in others they were unique,” says lead author Professor Liran Carmel of the Department of Genetics at the Hebrew University’s Institute of Life Sciences, who presented a 3-D likeness of the girl’s face at a news conference in Jerusalem on September 19.
“This (study) is important on two different levels,” Carmel told The Jerusalem Report. “It sheds light on the big question of what makes us human. There were different groups of humans – the Neanderthals, ourselves, the Denisovans – but we were the only ones to survive. Yet we are so similar. What makes us unique? It is important to compare (ourselves to others) to try to understand what the difference means in term of biology.”
Because modern-day humans have Denisovan DNA in our genome, such research can help scientists understand how we have adapted to life on earth, Carmel says, adding that it is also a very powerful tool to gain information on certain genetic traits and can add information to gene activity and DNA sequencing.
“There is a lot of information buried in gene activity patterns,” he said. “If we take them into account we can develop more powerful tools to understand the traits of our organism. [We can see] how we became what we are and what has changed in ourselves from other humans.”
As recently reported in the scientific journal Cell, the team led by Carmel and Dr. David Gokhman – currently a post-doctoral student at Stanford University in California – produced the reconstruction of these long-lost relatives based on patterns of methylation, or chemical modifications that affect a gene’s activity but not its underlying DNA sequence, in their ancient DNA.
“We took the DNA extracted from the pinky bone, and from this DNA we were able to identify chemical modifications to the DNA known as DNA methylation,” Carmel said. “We were able to recover from the ancient sample how the DNA was methylated when the Denisovan were alive.”
Using the DNA patterns, Carmel and his team were able to identify from the young Denisovan – who came to be known as “Denise” in the lab – 56 anatomical features in which Denisovans differ from modern humans and Neanderthals, 34 of them in the skull.
Professors Eran Meshorer from the Hebrew University, Yoel Rak from Tel Aviv University, and Tomas Marques-Bonet from Barcelona’s Institute of Evolutionary Biology (UPF-CSIC) also contributed to the research.
Murray Cox, professor of computational biology at Massey University in New Zealand, who did not take part in the research, said the reconstruction is “a significant advance” in the study of the Denisovans.

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“We have essentially no remains that are firmly identified as Denisovan – a few finger bones, a few teeth, part of a skull cap – so we know little to nothing about what Denisovans looked like,” Cox told the Report in an email. “This study begins to fill in that very patchy picture.”
The only known remains found of the Denisovans – who were so named for the cave in Siberia’s Altai Mountains where “Denise’s” pinky fragment was found by Russian scientists who had been excavating the cave starting in the 1970s – were three teeth, the pinky bone, and a lower jaw that was found on the Tibetan Plateau in 1980 by a Buddhist monk in the Baishiya Karst cave.
The jawbone, quite powerful, is described by researchers as lacking a chin, like Neanderthals, and the two molar teeth are especially large.
In their Cell paper, Carmel and his colleagues predict many Denisovan traits that resemble those of Neanderthals, such as a sloping forehead, long face and large pelvis, and others that are unique among humans, for example, a large dental arch and very wide skull.
“I think people assumed that Denisovans mostly resembled Neanderthals, but this study suggests a number of body features that differ quite a lot,” noted Cox. “The Denisovan range was very large, stretching from the frozen north to the tropics. It will be interesting to see whether the novel body features identified in this study are characteristic of all Denisovans or just those in the north.”
The work took three years of intense study of DNA methylation maps. The researchers first compared DNA methylation patterns among the three human groups to find regions in the genome that were differentially methylated. Next, they looked for evidence about what those differences might mean for anatomical features, based on what’s known about human disorders in which those same genes lose their function.
To test their ground-breaking method, the researchers applied it to the Neanderthal and the chimpanzee, whose anatomy is known. They found that roughly 85% of their trait reconstructions were accurate in predicting what traits diverged and in which direction they diverged. Then they applied this method to the Denisovan, and were able to produce the first reconstructed anatomical profile of the enigmatic Denisovan.
The reconstruction model was created together with scientific illustrator Maayan Harel, who prepared a sculpture based on their findings. The long process began with the construction of the skull and skeleton. Harel worked from an excel file with a list of traits in comparison to modern humans and Neanderthals that had been compiled by the scientists through their research.
“The list was limited to specific features and everything else was unknown,” Harel told the Report in an email from California where she is now based. “To make a complete image you must make assumptions, you cannot skip over or not comment on what you do not know.”
In consultation with anatomist Rak from Tel Aviv University, they decided to assume that anything that was unknown would be like the Neanderthal trait, as they are the closest known relatives of the Denisovans.
“This gave us a jumping off point to work with,” Harel said, but “if we assume that what is unknown is like Neanderthal, what does that mean exactly? Neanderthals were a varied population, like modern humans. There are many remains, but each is an individual. So a lot of effort went into creating a Neanderthal profile that would be as general and quintessential as possible.”
This general profile was used to help create the general Denisovan profile that was included in the graphics that appear in the research paper. The general Denisovan profile was then adapted to a juvenile female.
The reconstruction process began first with just a graphic of the skull, then by creating the sculpted skull, and then next was including the soft tissues. Finally, the digitally painted image of “Denise” was created.
“The wide parietal and temporal bones of the head really enhanced the childlike appearance of the reconstruction, and that surprised me a bit,” Harel said. “This was such an exciting project to be a part of. Our species once shared the world with other types of ancient humans, and it is so important for us to view them with as much respect and knowledge as possible. My goal is to humanize our ancestors and help people today to engage with them.”
Nevertheless, she notes, any type of anatomical reconstruction will have inaccuracies because there is no way to be sure of the structure of the soft tissues.
“We as humans are particularly tuned in to facial features and expressions, so we are especially sensitive to this,” she said. “Ultimately the reconstruction is an extrapolation that is consistent with the results of the skeletal profile laid out in the research, but it cannot be accurate, as so much is unknown. Its purpose is to bring the Denisovan girl to life and spark interest and inspiration in exploring human origins.”
Indeed, says Carmel, it was very satisfying to finally see the likeness of this ancient ancestor.
“This kind of human has been very mysterious and many people are looking for more remains,” Carmel said. Everyone is eager to know what they looked like, and then here we have the first glimpse into the appearance of this human group. It is very, very satisfying. We had absolutely no idea what we were going to see, but that non-expectation was that they would resemble the Neanderthals in traits because they are more related to them than us. The most fascinating trait for us was where the Denisovans were unlike humans and unlike Neanderthals.”
For example, he says, the Denisovan dental arch is longer than those of either modern humans or Neanderthals, and they also found that their skull was much wider than the skull of either of the two as well.
The find, he says, is especially interesting because it may shed light on the origin of two cranial parts found in China dating back 100,000 years, which nobody has been able to identify to what humanoids they may have belonged.
“Speculations arose that maybe these were Denisovans, but nobody can tell. When we compared [them] to our [model, they] match in seven out of 10 traits,” Carmel said. “So we provide evidence to this notion that [the] genetic evidence [shows] these are possibly Denisovans.”
In May of this year, just as Carmel’s team had completed their work and their paper was under peer review, a group of international scientists including Chinese archaeologist Dongju Zhang from Lanzhou University – who had begun to study the long ignored Tibetan cave jawbone in 2010 – published a report in the international science journal Nature, revealing the finds of their own study which indicated jawbone Denisovan.
Carmel’s team quickly compared the bone’s structure to their own predictions of what the Denisovan jawbone would have looked like, and it “matched perfectly. Without even planning on it, we received independent confirmation of our ability to reconstruct whole anatomical profiles using DNA that we extracted from a single fingertip. It was very exciting.”
The geographical locations where the bone fossils were found indicates that the Denisovans lived through East and Southeast Asia
Today people in East Asia, Australia, the Pacific Islands and even the Americas have Denisovan DNA, with up to 6% of present-day Melanesians and Aboriginal Australians containing Denisovan DNA.
Another paper published in Cell in May by a group of researchers including Massey University’s Cox held that the Denisovans were also able to reach New Guinea and interbreed with modern humans there as well.
The genetic variant in Tibetans that comes from Denisovans, unrelated to Neanderthals, was discovered a few years ago, suggesting the Denisovans might have lived in this area. Now, the jawbone found in the Tibetan cave confirms that they indeed were there. This has also led scientists to believe that at least one branch of the Denisovans were able to live at extremely high altitude. They conjecture that through interbreeding with both Neanderthals and modern humans, this gene adaptation may have been passed onto modern-day Sherpas in the region allowing them to live at higher altitudes and also contributed to the Greenland Inuits’ ability to withstand freezing temperatures.
While in general Carmel’s study is interesting, says Dr. Benice Viola, assistant professor at the department of anthropology of the University of Toronto, he cautions against basing reconstructions on these results.
“We don’t even understand in detail the correlation between genetic data and morphology in present day humans, as many of the genetic effects…rely on the complex interaction of many genes,” Viola wrote in an email. “I do think that the big picture these methods paint can be useful, but I would not rely on any single trait.”
Facial reconstructions of fossils are hard to do, even when you have complete and well-preserved faces, Viola says, and different artists frequently create very different reconstructions from the same cranium.
“I think that a reconstruction without any actual bone to rely on is even more tenuous,” he said. “The main reason why I enjoyed looking at this reconstruction was because for me this individual became a bit dehumanized over time – I was focusing on the finger the whole time; it is a nice reminder that there was a whole human being attached to that little finger bone.”
But as in research, the announcement of Carmel’s study findings has not come without some skepticism on the part of some colleagues, and Dr. Eva-Maria Geigl, head of research at the Institut Jacques Monod, Epigenome & Paleogenome group in Paris noted in an email that the data only partly compares to the scarce morphological information available.
“For example, as the authors state themselves, the data do not predict the size of the molars,” says Geigl, and furthermore, she and a group of other researchers have just published the morphological analysis of the Denisovan phalanx that has yielded the genome and showed that it was gracile, or slender, just as in modern humans and not broad like in Neanderthal.
Carmel’s team was not aware of this when writing their paper, and predicted that the Denisovan finger phalanx would be more Neanderthal-like, she said.
“This gives the impression that the reconstruction is more a matter of coincidence and sometimes it will by chance prove right,” she says.
Geigl also noted that among other issues she has with the possible accuracy of the study, the researchers partially relied on data that has not been published yet but rather was posted two years ago on a bioRxiv site, an open access preprint site for the biological sciences hosted by Cold Spring Harbor Laboratory which does not peer-review the papers prior to posting to them.
The data on the bioRxiv site “were posted without any description of the experimental methods so that they cannot be validated by other scientists,” she said. “This is a problem for any scientific study.”
She would like to see Carmel and his team publish all the methods they have used to create their reconstruction model, she says.
Researchers believe that it is likely that many misidentified Denisovan remains are sitting in museums and archaeological collections, notes Cox.
“I expect this reconstruction will now be used to begin to place tentative identifications on some of those remains,” he said. “In many ways, it does not matter whether these new identifications are absolutely correct. The point is that we begin the iterative process of classifying archaic and modern human diversity in Asia. This study takes us another step toward that bigger goal.”
Still, notes Carmel, much remains unknown about our prehistoric ancestors.
Scientists have not even been able to yet determine the cause of the demise of the Neanderthal for which there are hundreds of skeletal remains, let alone understand the reason for the disappearance of the Denisovans, he says.
“It is not yet possible to answer the question of why,” he said. “Many questions are still unknown and I don’t see a good way to answer them.”
In the meantime, he will continue focusing on his research with the ancient DNA methylation.
“We think they are powerful not only for making anatomical profiles but also in understanding other traits not necessarily in the skeleton,” Carmel said. “I hope one day to be able to tell another interesting story.”