Modern humans originated in Africa, and started spreading around the world about 60,000 years ago. As they entered Asia and Europe, they encountered other groups of ancient humans that had already settled in these regions, such as Neanderthals. And sometimes, when these groups met, they had sex.
We know about these prehistoric liaisons because they left permanent marks on our genome. Even though Neanderthals are now extinct, every living person outside of Africa can trace between 1 and 5 percent of our DNA back to them. (I am 2.6 percent Neanderthal, if you were wondering, which pales in comparison to my colleague James Fallows at 5 percent.)
This lasting legacy was revealed in 2010 when the complete Neanderthal genome was published. Since then, researchers have been trying to figure out what, if anything, the Neanderthal sequences are doing in our own genome. Are they just passive hitchhikers, or did they bestow important adaptations on early humans? And are they affecting the health of modern ones?
Some teams showed that Neanderthal DNA made its way into specific genes of interest, particularly those involved in the immune system. Others looked across the whole genome and showed that Neanderthal sequences cluster around genes that affect skin, hair, fat metabolism, and the risk of type 2 diabetes, cirrhosis, Crohn’s disease, and—bizarrely—smoking addiction (more on that later).
In a study published today in Science, Corinne Simonti from Vanderbilt University and her colleagues decided to take a different tack: They simultaneously looked at Neanderthal DNA across the entire genome and looked for associations with more than 1,600 traits and diseases. It was an unprecedentedly broad and systematic approach, made possible through an unlikely source of information: electronic medical records.
Since 2007, Vanderbilt researchers have been coordinating an 12-institute initiative called eMERGE (short for Electronic Medical Records and Genomics), analyzing the DNA of 55,000 volunteers and comparing those sequences to the patients’ medical records. Those records are goldmines of untapped data about the participants’ phenotypes—the full collection of their traits, including things like height, weight, cholesterol levels, heart function, cancer risk, and depression symptoms. Rather than looking for genes that are related to specific traits or diseases, as many large genetics studies do, eMERGE allows researchers to look for genes related to, well, pretty much anything in those records.
“We realized that it would be relatively straightforward to identify Neanderthal DNA in all these patients and analyze their [records] for a large range of phenotypes, which could speak to all kinds of traits and effects,” says Tony Capra from Vanderbilt University, who led the new study.
And so they did. They started with 13,700 people from the eMERGE Network, and looked for associations between 135,000 Neanderthal genetic variants and 1,689 different traits. They then checked any links they found against a second group of 14,700 eMERGE volunteers. “It is an exciting study—the first systematic assessment of the phenotypic impact of Neanderthal ancestry,” says Sriram Sankararaman from Harvard Medical School, who led an earlier study on Neanderthal DNA.
Capra and his colleagues found significant associations between Neanderthal variants and a dozen phenotypes, including actinic kerastoses (patches of dry, scaly skin caused by sun exposure) and a hypercoagulable state (where blood clots form too readily in the body).
Neither of these connections were particularly surprising: “Neanderthals had been living in central Asia and Europe for several hundreds of thousands of years before modern humans, so they were better adapted to the local climate, pathogens, and diets,” Capra says. “Perhaps interbreeding gave them a heads-up on adaptations to these challenges.” For example, Neanderthal variants could have shaped the skin cells of our ancestors, allowing them to cope with varying levels of ultraviolet radiation in new parts of the world; perhaps that is why such variants affect the risk of actinic kerastoses today. Similarly, blood clots close wounds and physically trap invading microbes; by influencing clotting, Neanderthal variants could have helped early humans to cope with new diseases.
More surprisingly, though, Capra’s team also found that Neanderthal DNA affects the risk of psychiatric disorders, including mood disorders and depression (which are new and unexpected). And 29 specific Neanderthal variants seem to influence when and where genes are turned on in different parts of the brain.
Sun exposure influences depression risk, so the link between Neanderthal variants and mood disorders may again reflect their role in adapting modern humans to new climates. But that’s just a guess: “It seems Neanderthal DNA has an effect on systems that regulate our moods or behaviors,” says Capra, “but for now, I don’t feel comfortable saying more than that.”
Some headlines will inevitably claim that we can blame Neanderthals for depression, but that’s nonsense. For a start, the effect is subtle, explaining just 1 percent of a person’s depression risk. “We shouldn’t blame Neanderthals for any of these associations, which are complex traits with many things contributing to them,” says Capra. “And of course, depression is a very new concept of a disease. You can’t think of Neanderthals or our ancestors being depressed.”
Nicotine addiction—a previously known link that this latest study confirmed—“is an even more extreme case,” he adds. “There was not nicotine in those environments! It comes from New World plants.”
“The Neanderthal genes are not disease agents,” says John Hawks from the University of Wisconsin-Madison, who was not involved in the study. But they’re “there in the brain, doing things, and having some detectable effects on behavioral outcomes. That’s amazing.” He and Capra both note that working out the role of these genes might help us to understand the underlying biology behind depression and other disorders.
They might also provide insights into parts of our lives, beyond just our health. “A lot of people will misunderstand this as saying that the Neanderthal genes typically have bad medical outcomes,” says Hawks. But that’s largely because of the study’s source material: “When you’re looking at medical records, you’re only looking at the problem phenotypes. You’re not seeing anything beneficial.”
Janet Kelso from the Max Planck Institute for Evolutionary Anthropology also hopes that Capra’s approach can be extended to non-medical traits. That’s not to diminish the existing study, though: “A tremendous amount of work must have been put into ensuring that the data from all these medical records was stored in a way that made this kind of study possible,” she says. “That’s great evidence for the value of this kind of concerted data curation.”
Capra agrees. “Given some recent arguments, this study is an important illustration of why it’s so important to make data open and accessible to the broader community,” he says. “The eMERGE Network was interested in the genomics of disease. They never conceived that this resource they were creating would be a really powerful tool for answering evolutionary questions.”