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Editorial: 鈥�Gene breakthrough shows Neanderthals in new light鈥�

BONES. That is all the passing millennia have left us of the Neanderthals and the more elusive Denisovans. Until recently, the main insights gleaned from these bones have been physical: what our cousins might have looked like, for instance, and how they moved. But cutting-edge genetic science is changing that.

We can now see, for the first time, which genes are switched on in humans but were not in Neanderthals and Denisovans, and vice versa. The findings point to subtle differences between our brain structure and function, and theirs.

The research, presented last week at the , reveals that after our ancestors split from Neanderthals and Denisovans, they evolved differences in genes connected with cognitive abilities. Many of those genes are associated with mental disorders in modern humans.

Working out which genes are switched on or not involves looking at the epigenome, or the chemical 鈥渕ethyl鈥� tags attached to genes. Genomes, in contrast, show only the basic sequence of genes. Liran Carmel at the Hebrew University of Jerusalem, Svante P盲盲bo of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, and colleagues analysed the epigenomes of Neanderthals and Denisovans and compared them with those of modern humans (see 鈥�What鈥檚 good about decay鈥�).

Altered methylation patterns are frequently associated with disease, particularly cancer and mental disorders. So Carmel鈥檚 approach has the potential to give us unprecedented insight into the mental abilities and behaviour of extinct hominin species: if a gene causes a mental disorder in humans, then variations in its sequence or expression pattern in another species could tell us something about their mental abilities. 鈥淭his just puts us into a whole different realm,鈥� says at the University of Pennsylvania in Philadelphia, who was not involved in the study.

鈥淭he approach could offer unprecedented insight into the mental abilities of extinct hominin species鈥�

Carmel and colleagues found that about 99 per cent of the epigenome was identical across the three species. But zooming in on about 700 regions that varied threw up some intriguing patterns. In more than 200 of these, Neanderthals and Denisovans shared the same methylation pattern while humans had the opposite, suggesting these differences are key to our uniquely human traits.

Many of the genes in these regions play big roles in immunity, metabolism and, when they misfire, disease. Preliminary findings suggest that more than half of the disease-linked human genes identified are associated with psychiatric and neurological conditions.

The findings complement previous studies. In 2012, P盲盲bo鈥檚 team sequenced the Denisovan genome and found that humans have eight key gene variants not shared with Neanderthals or Denisovans that allow neurons to project further across the brain and connect with one another. They may have allowed our direct ancestors鈥� brains to become more complex.

Taken together, the studies suggest that changes both in genetic sequences and in pattern of activation of the genes were crucial in enabling our ancestors to develop larger, more complex brains.

That may have helped give us our cognitive edge. For instance, genes and gene-expression patterns that conferred greater abilities in communication and social interaction, or changes in cognition, would have been evolutionarily advantageous for humans, says Tishkoff.

But if the genes that power our supersmart brains misfire, they can lead to altered mental states: in humans, changes in the eight gene variants identified by P盲盲bo have been linked to autism.

That doesn鈥檛 necessarily mean Neanderthals and Denisovans had autism-like traits, says Tishkoff, as neurological conditions are complex and involve many genes. And after all, our extinct relatives fared well for tens of thousands of years.

But the findings do suggest that their brains were wired differently. We have very little information about the culture and cognitive abilities of Neanderthals, says Philipp Khaitovich of the Chinese Academy of Sciences in Shanghai, and this is where the epigenome might come in useful.

Archaeologist Richard Klein of Stanford University in California hopes that the Neanderthal and Denisovan epigenomes, along with their genome sequences, might start to tell us why humans outcompeted their cousins and spread around the world.

鈥淭he epigenome might start to tell us why humans outcompeted their Neanderthal cousins鈥�

An interesting next step might be to analyse the epigenome of a chimpanzee, says Soojin Yi of the Georgia Institute of Technology in Atlanta, who was not involved in the latest research. This could reveal some of the mental traits of the common ancestor of humans and Neanderthals. Yi鈥檚 lab has already found that the areas of the genome in which chimp and human methylation patterns in the brain tend to differ are also those associated with neurological disorders (see 鈥�Evolving away from chimps鈥�).

As revealing as this new technique is, it has significant limitations. Each tissue in the body has its own methylation pattern, so patterns in the bones 鈥� the source of the DNA in all three species 鈥� may well be different from those in the brain. Methylation patterns also differ between individuals, and there are very few ancient hominins with DNA available to sequence. The individuals in this study may not be representative of their species.

James Noonan of Yale University says that to prove that the methylation differences matter, the team needs to put the ancient hominin DNA into human cells and see how the cells change. Tishkoff suggests we may be able to 鈥渘eanderthalise鈥� a mouse by inserting genes with Neanderthal methylation patterns and compare their effect with a similarly 鈥渉umanised鈥� mouse.

This article appeared in print under the headline 鈥淚nside the brain of a Neanderthal鈥�