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Thriving in Thin Air Goes Back 160,000 Years to the Denisovans, New Study Finds

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Posted May 14, 2019

Fleshing out the details of ancient humanity has typically begun with fossil finds and then, years later, sequencing genes and genomes. That was the case for Neanderthals, but now the reverse has happened for the Denisovans.

A new paper in Nature describes a partial upper jawbone from a Denisovan who lived 160,000 years ago. It was discovered quite far from the known home of these archaic humans in Siberia, in Baishiya Karst Cave in Xiahe, China, on the Tibetan Plateau.

Views of the virtual reconstruction of the Xiahe mandible after digital removal of the adhering carbonate crust. The mandible is so well preserved that it allows for a virtual reconstruction of the two sides of the mandible. Mirrored parts are in grey. Credit: Jean-Jacques Hublin, MPI-EVA, Leipzig

Views of the virtual reconstruction of the Xiahe mandible after digital removal of the adhering carbonate crust. The mandible is so well preserved that it allows for a virtual reconstruction of the two sides of the mandible. Mirrored parts are in grey. Credit: Jean-Jacques Hublin, MPI-EVA, Leipzig

The partial jawbone is the oldest human fossil from the area. It’s existence indicates that ancestors of today’s Sherpa from 10,000 or so years ago weren’t the first to be able to survive at high-altitude, low-oxygen environments, as had been thought.

A Brief History of Neanderthal DNA

Quarry workers blasted out the first bones discovered from Neanderthals from a limestone cave in Neander Valley, Germany on a summer day in 1856, providing our initial impressions. It wasn’t until 2000 that researchers got their hands on Neanderthal DNA, from fragments of bone found near the entrance of El Sidrón cave in northwestern Spain.

The environment of this westernmost part of the Iberian peninsula had been mild enough to sustain the Neanderthals, but with caves cool enough to preserve their remains, including DNA. Excavation of the El Sidrón cave began in 2000, and by 2005, researchers had sequenced the first Neanderthal genes from mitochondrial DNA, which is more likely to survive harsh environmental conditions than DNA from cell nuclei.

DNA from a hip bone of a 38,000-year-old woman found in Vindija Cave in Croatia was used to reconstruct the first complete Neanderthal genome, published in 2010 from researchers at the Max Planck Institute for Evolutionary Anthropology (MPI-EVA) in Leipzig, Germany, led by guru Svante Pääbo. Using dental drills they painstakingly withdrew pulverized “dust” from bones from to preserve them intact for future studies, and sequenced the DNA in a “clean room” to keep out contaminating DNA.

Thanks to this work, I now know that I have more Neanderthal DNA than 83 percent of the folks who’ve sent in DNA to 23andMe.

Svante Paabo and a friend.

A Brief History of Denisovan DNA

Svante Pääbo and his team introduced the first Denisovan, named Denise, in 2010, based on a preliminary genome sequence from a finger bone, discovered in 2008 in the cave she’s named for in the Altai Mountains of southern Siberia.

Denise lived 32,000 to 50,000 years ago and had dark skin and brown eyes and hair. She had some Neanderthal DNA sequences, so mixing of genomes had been going on (see “The Cave Where It Happened: the Daughter of a Neanderthal Mom and a Denisovan Dad”). A few other Denisovans emerged from the 2,000 or so bone fragments found in the cave (see “The Denisovan Genome and Guys Banging Rocks”).

Neanderthals and Denisovans diverged into distinct lineages around 445,000–473,000 years ago. Modern human genomes replaced both by about 40,000 years ago, with some Neanderthal DNA remaining in today’s European genomes and Denisovan DNA in Northern Island Melanesians and in Papua New Guineans. Australian aborigine genomes harbor sequences from Neanderthals and Denisovans.

A Critical Adaptation to Life on the Tibetan Plateau

The Denisovan cave in Siberia is about half a mile above sea level; the Tibetan plateau cave that yielded the jawbone is about two miles above sea level.

A hint that Denisovans might have lived on the plateau came in 2014, when researchers described a Denisovan DNA sequence pattern surrounding the EPAS1 gene in Tibetans, but not in other populations, with a very low frequency among the Han Chinese who live in the lowlands. That pointed to breeding ages ago between Denisovans and Tibetans, and selection for the gene variant ever since. And the reason is clear: a variant of EPAS1 that is missing some DNA provides the ability to live in high-altitude, low-oxygen conditions. That’s why the gene variant has persisted through the millennia, carrying the surrounding DNA sequences with it. People with it have an advantage.

EPAS1 stands for “hypoxia inducible factor 2.” Denisovans not only have a small section missing from the gene, but also have five single-base markers (SNPs) in the surrounding area of the chromosome, making it possible to track. These individuals survive and thrive in an environment that makes others feel too sick to reproduce because they experience headache, dizziness, ringing in the ears, heart palpitations, breathlessness, fatigue, sleep disturbance, lack of appetite, and confusion.

If a person who doesn’t have the deletion and isn’t otherwise adapted to high altitudes ascends to great heights, the kidney hormone EPO sends extra red blood cells into the bloodstream to extract maximal oxygen from the thin air. That raises risk of heart attack and stroke.

The New Findings

Although the hints of Denisovan ancestry in DNA from modern people were found in 2014, the oldest fossil evidence of any humans living on the Tibetan Plateau were from 30,000–40,000 years ago. Until now.

A local monk discovered the jawbone piece in 1980 and it ended up at Lanzhou University. Fahu Chen and Dongju Zhang, from the Institute of Tibetan Plateau Research at the university, began investigating the area of the discovery in 2010 and collaborating with MPI-EVA in 2016.

Unable to extract any DNA from the fossil, the investigators instead scrutinized proteins from the dentin of a molar. Without DNA they couldn’t delve directly into the EPAS1 gene, so instead they compared the entire proteome (all the proteins encoded in a genome) to those of other apes, including modern humans and Neanderthals. The dentin proteome was distinctly Denisovan.

“The ancient proteins in the mandible are highly degraded and clearly distinguishable from modern proteins that may contaminate a sample. Our protein analysis shows that the Xiahe mandible belonged to a hominin population that was closely related to the Denisovans from Denisova Cave,” said co-author Frido Welker of the MPI-EVA and the University of Copenhagen.

The size of the jaw and molars were reminiscent of those of Neanderthals. A carbon-rich crust of crud on the jaw enabled the dating to 160,000 years ago. “This minimum age equals that of the oldest specimens from the Denisova Cave,“ said Chuan-Chou Shen, another co-author, from National Taiwan University.

And so people living on the Tibetan Plateau were adapted to life in thin air in the Middle Pleistocene, long before Homo sapiens arrived.

The Bigger Picture

A return to the Neanderthal story illustrates how little we know of our beginnings and side branches.

Recent advances in the study of ancient genomes now allow scientists to study parts of the epigenetic code in our ancient forbears and compare it to patterns in present-day humans. Image credit: NHGRI

Recent advances in the study of ancient genomes now allow scientists to study parts of the epigenetic code in our ancient forbears and compare it to patterns in present-day humans. Image credit: NHGRI

Early depictions of Neanderthals were of big brutes with jutting faces, thick brows, and giant jaws and teeth above small chins, tempered perhaps by the affable image of Fred Flintstone. Half a century after the discovery of the first fossils, bones from the “Old Man” of La Chapelle-aux-Saints in France led to viewing Neanderthals as primitive, slow-witted, and stooped.

Then excavation from 1957 through 1961 of 10 Neanderthals from Shanidar Cave in Iraq revealed tools and flowers that added cultural clues. One specimen, an old man in his forties named “Nandy,” had cooked starch in his dental plaque. In 2007 evidence that some Neanderthals had red hair emerged, but due to a different variant of the gene that provides red hair among humans today.

Now dental plaque has dated Denisovans, albeit through a lone individual, on the Tibetan plateau to 160,000 years ago, illustrating a classic example of positive natural selection: tolerance to high altitude conditions. I visited my daughter in Denver last week and thanks to my morning headaches, can attest that I may have Neanderthal gene variants, but apparently not EPAS1 from the Denisovans.

Source: PLOS EveryONE

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