Extinct Neanderthals still control expression of human genes
Andy Coghlan
Pierre Andrieu/Getty
Neanderthals are still affecting what illnesses some people develop, how tall they are and how their immune systems work, despite being extinct for 40,000 years.
This is thanks to the Neanderthal DNA those of non-African descent inherited from ancestors who mated with our cousins some 50,000 years ago. A study has now revealed how this genetic legacy is still controlling how some people’s genes work, with possible consequences for their health.
Tellingly, the Neanderthal influence has waned fastest in parts of the body that evolved most rapidly around that time, especially the brain. It suggests that once our direct human ancestors had evolved the equipment for sophisticated language and problem-solving, mating with Neanderthals – and the DNA that came with it – rapidly fell out of fashion.
But Neanderthal control of human genes endures, some of it positive and some negative. Evidence comes from an in-depth analysis of DNA from 214 people in the US, focusing on individuals of European ancestry. By comparing their modern DNA with that from Neanderthals – whose genome was sequenced in 2008 – a team led by Joshua Akey at the University of Washington in Seattle was able to identify which Neanderthal gene fragments had survived and were still active in 52 different types of human tissue.
The team found that some people had one human and one Neanderthal copy of the same gene. When comparing these genes, Akey and his colleagues found that a quarter showed differences in activity between the modern and Neanderthal versions of the same gene. More importantly, the researchers could tell which variant had the upper hand.
Upper hand
In one example, it turns out that Neanderthals may still be protecting some people from developing schizophrenia, as well as making them taller. A gene called ADAMTSL3 is a known risk factor for schizophrenia. But the way the gene is controlled by surviving Neanderthal DNA reduces risk and increases height, the team found.
“Strikingly, we find that Neanderthal sequences present in living individuals are not silent remnants of hybridisation that occurred over 50,000 years ago, but have ongoing, widespread and measurable impacts on gene activity,” says Akey.
Most genes can generate a variety of different proteins that do different jobs in different tissues of the body, depending on how sub-units of the protein are assembled. Akey’s study shows that the key contemporary impact of the Neanderthal remnants is in dictating which variant of a protein gets produced today.
“The results add to increasing evidence that these effects are often the outcome of changes to the genetic switches,” says Tony Capra of Vanderbilt University in Nashville, Tennessee. His own results published last year revealed Neanderthal influences on a variety of human disorders, including depression and addiction.
“The implication is that these variants that came into the human gene pool around 50,000 years ago are still affecting human biology,” says Sriram Sankararaman at the University of California at Los Angeles. “This study makes important progress in understanding how Neanderthal genes many of us carry in our genomes affect diverse human traits by dictating how genes are regulated.”
Receding influence
Elsewhere, however, the influence of our long dead cousins is receding, nowhere more so than in the brain and – unexpectedly – the testes. “Changes in gene regulation between modern humans and Neanderthals were greatest for these tissues,” says Akey.
“The finding that these Neanderthal variants tend to have lower activity in brains and testes is intriguing, as it offers hints on which aspects of biology diverged most rapidly between Neanderthals and us,” says Sankararaman.
Neanderthal control waned most in the cerebellum and the basal ganglia, brain regions vital for fine motor control and perception, that evolved further in humans to encompass advanced thinking, including language processing and behaviour.
One gene with fading Neanderthal influence is NTRK2, key to neuron survival and the formation of brain connections. This illustrates the kinds of fine-tuning that may have allowed our ancestors to soar away intellectually.
The differences in the testes, meanwhile, throw new light on how a species may eventually split by becoming sexually incompatible. One of the testes genes over which Neanderthal DNA lost control affects the formation of a sperm’s tail and, subsequently, its ability to penetrate and fertilise an egg.
Akey and his colleagues speculate that once this control had been relinquished, neither Neanderthals nor Neanderthal-human hybrids could mate with humans any more. “Our results are consistent with reduced fitness of male hybrid offspring,” says Akey.
Journal reference: Cell, DOI: 10.1016/j.cell.207.01.038
