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Inside the brain of a Neanderthal

The first look at which genes were switched on and off in our extinct cousins is allowing us to peer into their minds

Sara Reardon, Chicago

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

The approach could offer unprecedented insight into the mental abilities of extinct hominin species
point to subtle differences between our brain structure and function, and theirs. The research, presented last week at the Society for Molecular Biology and Evolution meeting in Chicago, 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 methyl tags attached to genes. Genomes, in contrast, show only the basic sequence of genes. Liran Carmel at the Hebrew University of Jerusalem, Svante Pbo 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 Whats good about decay, top right). Altered methylation patterns are frequently associated with disease, particularly cancer and mental disorders. So Carmels approach has the potential to give Dem bones got something to say us unprecedented insight into the
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PA/AP Photo/Frank Franklin II

In this section n Levitation by sound, page 10 n Chimps have more experimental sex than us, page 12 n Which twin is the lawbreaker? page 18

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. This just puts us into a whole different realm, says Sarah Tishkoff at the University of Pennsylvania in Philadelphia, who was not involved in the study. 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, Pbos 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 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 Pbo have been linked to autism. That doesnt 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 Khaitovich, and this is where the epigenome might come in useful. Archaeologist Richard Klein of Stanford University in California

Whats good about decay

The decay of DNA is one of the toughest hurdles in sequencing ancient genomes. But it has turned out to be a boon for those studying ancient epigenomes, such as Liran Carmel and colleagues at the Hebrew University of Jerusalem (see main story). DNA and RNA have five building blocks: adenine, cytosine, thymine, guanine and uracil. Over thousands of years, cytosine with a methyl tag degrades into thymine, while unmethylated cytosine becomes uracil. In 2009, Adrian Briggs, then at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, and colleagues invented a method for ancientgenome sequencing that distinguishes original thymines in DNA from degraded cytosines, making it possible to indirectly study the epigenomes which genes were switched on and off as a result of methylation in the bones of Neanderthals (Nucleic Acids Research, doi.org/ffqscd). Comparing the epigenomes of extinct animals could give us insight into key changes in the first mammals, says Philipp Khaitovich of the Chinese Academy of Sciences in Shanghai, such as when female mammals began methylating an entire X chromosome to inactivate it, which prevents a gene overdose in her offspring.

evolving away from chimps

In an ideal world, we would be able to compare which genes are switched on in our brainswith those in the brains of Neanderthals and other species. But all we have left of our extinct cousins are bones. So Soojin Yi of the Georgia Institute of Technology in Atlanta and colleagues went further back in evolutionary time and instead compared the patterns of gene activation, or epigenome, in chimps and humans in the prefrontal cortex. This brain area is highly developed in humans and is the seat of our unique cognitive abilities. The idea was that this would give some insight into changes that happened after our ancestors split from those of chimps, several million years ago. In the epigenomic regions that differ between species, the human brain contains almost five times as many genes that are linked to

hopes that the Neanderthal and neurological disorders (see Denisovan epigenomes, along Evolving away from chimps, with their genome sequences, below left). might start to tell us why humans As revealing as this new outcompeted their cousins and technique is, it has significant spread around the world. limitations. Each tissue in the An interesting next step might body has its own methylation be to analyse the epigenome of a chimpanzee, says Soojin Yi of the The epigenome might startto tell us why Georgia Institute of Technology humans outcompeted in Atlanta, who was not involved their Neanderthal cousins in the latest research. This could reveal some of the mental traits of the common ancestor of humans pattern, so patterns in the bones and Neanderthals. Yis lab has the source of the DNA in all three already found that the areas of species may well be different the genome in which chimp and from those in the brain. human methylation patterns Methylation patterns also differ in the brain tend to differ are between individuals, and there are also those associated with very few ancient hominins with DNA available to sequence. The individuals in this study may not be representative of their species. cognitive function as would be James Noonan of Yale expected by chance, Yi says. Defects University says that to prove in them are connected with problems that the methylation differences in the early stages of brain matter, the team needs to development. Humans also have 3.5 put the ancient hominin DNA times as many autism-related genes. into human cells and see how So while our brains have become the cells change. Tishkoff bigger and more intelligent, it seems suggests we may be able to that evolutionary changes have also neanderthalise a mouse by made our brains more prone to inserting genes with Neanderthal develop neurological conditions, methylation patterns and such as autism and schizophrenia. compare their effect with a similarly humanised mouse. n
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