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Neanderthal genetic landscape reveals key differences with humans

Methylation map from Neanderthal, Denisovan genomes found most differences from modern humans in regions associated with disease, particularly brain disease

A Neanderthal skeleton, left, compared with a modern human skeleton.  Research into the Neanderthral genome offers tantalizing new theories about the modern human brain. in particular psychological and neurological diseases.

American Museum of Natural History


When scientists first sequenced the genome of a Neanderthal, our extinct, heavy-browed human cousin, we learned a surprising amount about our own species too: many modern humans carry Neanderthal genes, proving we interbred with them long ago.

Now, researchers have offered the first glimpse of the Neanderthal epigenome, and once again their results offer tantalizing new theories about the modern human brain and skeleton.

While the findings are surprising, the fact that the Neanderthal epigenome holds important secrets should not be. In the past decade, scientists have discovered that epigenetics, the chemical signals that regulate how genes are expressed, are almost as important as genetics in understanding how organisms look and act.

By exploiting a trick of how ancient DNA degrades, an Israeli-led team of researchers has created a map of the Neanderthal epigenetic landscape and that of another extinct human species, the Denisovans. Their work, hailed as a “fantastically exciting” technical achievement, was published Thursday in the journal Science.

The most intriguing findings of the study are the clues that emerged when the researchers compared those archaic epigenetic maps to those of present-day humans.

More than 99 per cent of the ancient and modern maps were the same, which is what one would expect to find in closely-related human species that shared a common ancestor approximately 600,000 years ago.

But the maps were almost twice as likely to differ in regions associated with disease — and, in a third of those cases, in regions associated with psychological and neurological diseases.

Scientists are a long way from being able to understand what this means, stressed Liran Carmel, who led the study along with Eran Meshorer and David Gokhman, all of the Hebrew University of Jerusalem.

“But this raises the hypothesis that perhaps many genes in our brain have changed recently, specifically in our lineage, the lineage leading to Homo sapiens. And perhaps things like autism, schizophrenia and Alzheimer’s are side-effects of these very recent changes,” said Carmel.

“This is an interesting suggestion, that (brain disease) is a side-effect of us being Homo sapiens and having our unique cognitive capabilities.”

Other scientists expressed caution with that interpretation.

“It’s definitely fantastically exciting that we can get this data, but the big, big next step is: can we actually come from circumstantial evidence to proper, experimental evidence? That is very hard,” said Michael Hofreiter, an evolutionary geneticist at the University of Potsdam.

Carmel and his colleagues created the maps by analyzing already-sequenced ancient genomes. They were gleaned from a 50,000-year-old female Neanderthal’s pinky-finger bone and a 40,000-year-old female Denisovan’s toe bone. The researchers were looking for areas of methylated DNA, an important epigenetic process that occurs when methyl affixes itself to cytosine, one of the building blocks of DNA, silencing the gene.

Scientists had no way of examining this process in degraded, ancient DNA until Adrian Briggs, a researcher in the lab of pioneering paleogeneticist Svante Paabo, stumbled on the discovery that methylated DNA degrades differently than regular DNA.

Other scientists have used his method to examine other ancient specimens, but Thursday’s study “is, I think, the coolest, because it was the first that actually looked at that in a sample where there were interesting biological questions,” says Briggs, now a molecular biologist at the Boston-based biotech startup AbVitro.

Aside from the discovery that the methylated regions were statistically more likely to differ in disease- and brain-disease-associated regions, Carmel’s group also discovered differences in a region known as HOXD. The HOXD gene cluster regulates limb development, so this epigenetic process may be the reason Neanderthal limbs are shorter than Homo sapiens.

More than anything else, the study opens up new avenues of inquiry. Paleogenetics, itself a newfound discipline, may soon be joined by paleoepigenetics, says Carmel.

While there are only two ancient genomes sequenced in fine enough detail to undertake this type of analysis, many more from ancient humans and even ancient animals are expected to be published in the coming years.

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