It's not what you've got but how you use it. The first maps of gene expression in two of our extinct cousins flag up important differences between the activity of their genes and our own. The results suggest that brain disorders like schizophrenia and autism may be unique to us.
The genomes of Neanderthals and Denisovans are relatively similar to our own, although we know that Neanderthals had some distinctive features, including a barrel-shaped chest and proportionally shorter limbs. Perhaps that's because these features were sculpted primarily by differences in the activity of genes during development rather than by differences in the genetic code.
Now Liran Carmel and his colleagues at the Hebrew University of Jerusalem in Israel have begun to investigate this possibility. They have created the first maps of gene activity in these extinct people, and compared them with modern humans.
Chris Stringer at the Natural History Museum in London hails the work as a remarkable achievement. "This pioneering work promises many further breakthroughs in understanding the biology of pre-modern humans," he says.
The activity of a gene typically decreases if it gets tagged with a chemical containing a methyl group – a process known as methylation.
We already know that methylated DNA bases decay in a distinctive manner, so by working through the Neanderthal and Denisovan genomes – and genomes of modern humans – Carmel and his colleagues could identify about 2000 genes that had been methylated differently in the three lineages.
Their results show that methylation in modern humans is particularly likely to affect genes with known links to health and neurological disorders – suggesting that the activity of these genes is different in our lineage to how it was in Neanderthals and Denisovans.
"We see associations with diseases like schizophrenia, autism and Alzheimer's," says Carmel. "Could it be that recent changes in the activity of genes in our brain also led to psychiatric disorders?"
He stresses that answering this question is difficult using the new data, because it is hard to predict how the differing pattern of gene activity would manifest itself in the brain.
Bernard Crespi at Simon Fraser University in Burnaby, Canada, studies the evolution of human neurodevelopment. He says the current thinking does indeed suggest that these disorders may be uniquely human. "Autism and schizophrenia are commonly viewed as disorders involving human-specific traits such as language and complex social cognition," he says. "As such, they are expected to be human-specific at least to a considerable degree."
Short and stout
The new information also provides tantalising clues that might inform the search for more Denisovan fossils: although we have samples of their DNA, to date we know of just one Denisovan finger bone and two unusually large teeth. The new analysis shows that Neanderthals and Denisovans both had distinctive patterns of methylation in genes involved in limb development not seen in our species.
As far as Neanderthals go, these distinctive patterns might help to explain why their limbs were shorter and stouter than our own, says Carmel. It is possible, then, that Denisovans also had distinctive limbs – although Carmel says the pattern of methylation in the Denisovan DNA is sufficiently different from the pattern in Neanderthals to make it unclear exactly how the Denisovan limbs might have looked.
The study is not the first attempt to look at gene expression in prehistoric remains. In 2012, Alan Cooper at the University of Adelaide in Australia and Catherine Suter at the University of New South Wales in Sydney, Australia,looked at methylation patterns in 26,000-year-old bison DNA. Such methylation patterns can actually be inherited – a process known as epigenetic inheritance – and Cooper thinks this might have allowed animals to adapt to the rapidly changing climates of the ice age faster than traditional genetic inheritance could.
"We are trying to track the impacts of major climatic shifts on the epigenetic variation in vertebrate populations," says Cooper. "I'm convinced this is how many of the megafaunal groups, including humans, adapted to the major and repeated climate swings of the late Pleistocene."