For much of 2015, Luis Barreiro adopted the role typically associated with a mosquito, a sneeze, or sexual intercourse. Sitting in his lab at the University of Montreal in Canada, he was infecting human cells with a particular virus or bacteria and then seeing what happened next. Although isolated and exposed in a Petri dish, the particular cells he used were far from helpless. They were a type of white blood cell—known as macrophages—that allow such pathogens to enter their innards and then try to destroy them. As the intruder is detected by the cell’s surveillance systems, a cascade of molecular messengers are sent around the cell and, eventually, into the nucleus with a simple instruction: turn on the anti-viral or anti-bacterial genes, and quick. Once activated, these genes produce proteins that chop up the threat like the enzymes in your stomach digest food into ever-smaller pieces. This essentially is what happens every time a potentially harmful infective agent enters a person’s blood and meets the cellular sentinels of the immune system. Shaped by millions of years of evolution, it’s a tried, tested, and carefully choreographed reaction that is shared by every human on the planet. And yet we are not all the same. In late 2016, Barreiro demonstrated that immune cells taken from people of African descent had, on average, a much stronger reaction to infection than people of European descent, their genes providing an additional boost of proteins to neutralize the threat. Although difficult to prove, one explanation behind this result might be a more diverse and plentiful suite of pathogens in Africa compared to Europe, priming a person’s immune system into a more reactive state on that continent. Whatever the case may be, “these cells have some ‘memory’ that tells them that you are supposed to respond this way or that way, depending on your genetic ancestry,” Barreiro says. Like parts of the immune system itself, which remember if you’ve already had the chicken pox, for example, the genetic makeup of entire populations are built on their collective prior experiences. The past shapes the present. But the past is complex: Our family tree is more like a river delta than a tree, with each species merging their genes into each other’s flow. Neanderthals are extinct, yet some of their genes are still very much alive. After 400,000 years of living in the chill of Ice Age Europe, they then passed parts of their lives—both genetic and cultural—on to early humans migrating out of Africa. Indeed, in his sample of immune genes Barreiro found that many were of Neanderthal origin, each a genetic hand-me-down from our close cousin. With immune cells from people of European ancestry, he is providing a microscopic window into their legacy, a story written in DNA and expressed in protein. Along with other scientists, Barreiro’s work is revealing how an understanding of our ancient origins can guide the future of medicine.

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Filling in the Picture In 2007, when Barreiro started contemplating how ancestry impacts our health today, he certainly wasn’t thinking about Neanderthals. He had no reason to. It’s only in the last few years that we have grasped their intimate relationship with humans. “It’s turning out that hominin evolutionary history is incredibly complex,” says Janet Kelso, a geneticist from the Max Planck Institute in Leipzig who studies human evolution. “We thought we had a perfectly simplistic view of how things worked even ten, 15 years ago: Neanderthals were completely unrelated to us, we didn’t even know about Denisovans, a closely related species that lived in parts of Asia. And the more we found out, the more we realized that it wasn’t all that simple. It wasn’t that simple at all.” In 2010, Kelso, Svante Pääbo, and their colleagues at the Max Planck Institute in Leipzig, Germany, sequenced the first Neanderthal genome, revealing that 1–4% of European genomes came from Neanderthals. Once assumed to be our ancestors, then a close but distinct relative, genomic studies have shown that we are closer than anyone imagined. This small percentage of DNA tells a story that fossilized bones alone could not. Initially, many still doubted this conclusion. After all, it was only a draft genome, a rough sketch that was speckled with errors and missing regions. And, as Philipp Messer from the University of Seattle says, 1–4% is within the range of error in many statistical analyses. “Initially, when they came out with this result, there was a lot of debate,” he says. But the debate didn’t last long. In 2014, Pääbo and his colleagues sequenced the first high-quality Neanderthal genome from a toe bone found in the Altai Mountains of southern Siberia. Unlike the first attempt, each of the 4 billion or so letters of DNA—A, T, C, G— that made up this so-called “Altai sequence” was sequenced anew a total of 52 times, each one reducing the possibility of error. If their computers found that one letter was an “A” 51 times and a “G” once, it was almost certainly an “A.” Its precision opened a new way to look at the relationship between Neanderthals and humans, between the extinct and the living. “Before we had this Neanderthal genome, there was a lot of speculation. People suggested a lot of parts of modern humans might have come from Neanderthals,” Kelso says. “And it was only until we had the Altai sequence that we could look and say either yes, or actually—as it would be more often—no, that was wrong.” In 2014, by comparing the Altai sequence to the genomes from 1,004 people around the world, David Reich and his colleagues from Harvard Medical School in Boston were able to find where Neanderthal DNA was located in modern humans. Letter by letter, they walked through the human genomes, comparing them to the Altai sequence, and determined whether they came from Neanderthals or not. This wasn’t a range of percentages but a thorough and detailed map, a cartographical basis for comparison between our cousins and ourselves. Thankfully, many of the regions that came from Neanderthals already had known functions, they just weren’t considered to be of Neanderthal origin before. Since 2002, international scientific efforts like HapMap and the 1000 Genomes Project have providing researchers with a rich resource to compare the genomes of people from around the world and link their DNA with their lives. From traits such as hair type to color to from chronic diseases such as cancer, nuances of life can be linked to mutations in DNA. For those regions that were of Neanderthal origin, Reich and his colleagues found that the majority were associated with how Europeans respond to external environments—their metabolism, their skin color or hair type, and their immune system. “If we take all the genes associated with innate immunity—the first line of immune defense—on average, Europeans have a higher degree of Neanderthal ancestry than the remainder of the genome,” says Lluis Quintana-Murci, a population geneticist from the Pasteur Institute in Paris. This goes against the norm, he says: Most Neanderthal DNA was diluted over time. Over 30,000 years since they interbred with humans, their injection of DNA was selected against more often than not. Their genes were detrimental to modern humans. But when it comes to the immune system, large sections of Neanderthal DNA remain largely unchanged today. This makes sense: With a long history in Europe, Neanderthals had plentiful opportunity to prime their bodies to the local bacteria, viruses, and parasites. By interbreeding with them, humans inherited thousands of years of adaptation in an evolutionary blink of an eye.

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After Reich’s genetic map was released, a number of studies into Neanderthal immune systems were published, each one piquing Barreiro’s interest. With immune cells from Europeans already in his lab, he started thinking about Neanderthals. Modern Effects In Montreal, as he was comparing the immune responses of African and European people, Barreiro found that 147 genes in his European samples showed signs of Neanderthal ancestry. But one stood out: the OAS family of genes that fight a variety of viral and bacterial infections. Today, 41% of people of European descent have the Neanderthal version of this family of genes, while the rest have the more common European-specific version. To Barreiro, it was a natural setup for an experiment: By comparing the immune cells from these two groups, he could start to understand how Neanderthal DNA shapes immune responses today. His experiment started with a 500-milliliter bag of blood, a red and rich blend of oxygen-carrying and disease-fighting cells in gloopy plasma. Taken from 40 European donors, the blood was filtered and the immune cells—such as macrophages, the cells at the vanguard of the immune system—were cultured for a week. Then, in a Petri dish, they were infected with one of a variety of viruses—influenza, herpes simplex 1 and 2, and a molecule that mimics viruses similar to HIV—or bacteria, in this case the species that causes typhus ( Salmonella typhimurium ). By comparing these cells to others that aren’t infected, a so-called “steady state,” Barreiro could measure the amount of RNA they produced in response to infection, an accurate gauge of their gene activity or inactivity. The proteins produced by the genes are the same for everyone; it’s just the amount that differs. On a microscopic scale, this is what links infectious disease in the environment to a person’s life, whether they are sick or healthy, and, in extreme cases, whether they live or die. “More and more we are starting to realize that susceptibility to common diseases is primarily driven by mutations that are not changing the protein…but are altering the expression levels of the genes they regulate,” Barreiro says. “And you can only detect that if you do the type of whole cell experiments that we do.” Enterobacteriaceae bacteria Even with this simplified surrogate of an immune system—one type of immune cell and one family of genes—there were some significant patterns. Published in late 2016, Barreiro found that one Neanderthal gene called OAS1-3 was up to 27 times more active than the European version after just two hours of infection with influenza or herpes simplex 1 and 2, ramping up its production of enzymes that chop up the threat at its core. Inside the macrophages, the viruses were immobilized and the infection halted more quickly if a person carried the Neanderthal version of the gene. In other words, how some people in Europe respond to the flu or other viral infections can depend, in part, on Neanderthals. “It’s just astounding,” says Tony Capra from Vanderbilt University, who is using similar techniques with nerve cells to study how Neanderthal DNA is linked to complex traits such as addiction and depression. “Ten years ago I never would have imagined that we could evaluate, directly, the effects of events in the history of our species on us today.” Such work is seeing a very recent surge in activity. Also in late 2016, Quintana-Murci, the population geneticist in Paris, used the detailed genetic maps to focus on PNMA1, a gene that produces a protein that directly interacts with the flu virus. “It’s not only super enriched in Neanderthal ancestry, but it’s present in 33% of Europeans, which is huge for a Neanderthal gene,” he says. Experiments with the virus and immune cells are currently underway to reveal how this relates to active infection, adding another layer to the OAS work in Barreiro’s lab. Even when protein levels are measured, the finer details of this work are still unknown. Immunology is a multifaceted area of biology that is dependent on the interplay between the genes in our bodies and the environments we face; what works in the Petri dish might not be the best fit for every situation in the wider world. For instance, Barreiro found that, when confronted with typhus, one Neanderthal gene—OAS3—in macrophages was significantly less active than the European version. At first glance, this may seem detrimental, allowing infections to take hold. But it could also be beneficial. If a person is unlikely to come across that particular type of bacterium, then there is no need to have a highly reactive immune response. Without an invader to attack, the immune system might target benign elements such as dust (causing allergies) or parts of the body itself (in the case of autoimmune diseases). In short, we’re a long way from linking Neanderthal gene activity in the Petri dish to that in our bodies, but this gap is getting smaller. Both Barreiro and Quintana-Murci have now found that African immune cells are more responsive to infection than Europeans. This may, in part, explain why African Americans have higher rates of inflammation and autoimmune diseases. Outside of Africa, the pathogen load may be reduced but their immune systems are still primed for any attack. By understanding how ancestry—and recent interbreeding—impacts health, scientists like Barreiro and Quintana-Murci hope their work can be used for more precise medicine. It won’t be universally applicable, but by finding people who have a genetic predisposition to certain infections or disorders, doctors can tailor the treatment to their needs. If someone has an over-reactive immune response to a certain virus or bacterium, for instance, they might not need as large a dose of vaccine or antibiotics. “This may even save money and secondary treatments to public health systems,” Quintana-Murci says. This work goes beyond a person’s genetics. “We’re trying to quantify how other factors—sex, age, lifestyle habits such as smoking, latent infections like herpes virus—influence differences in immune response,” Quintana-Murci says. By creating a multi-layered map of a person’s environment, lifestyle, and genetics, he hopes to eventually use computer models to predict how individuals will react to bacteria and viruses before they are infected and tailor their vaccines or antibiotics accordingly. Of course, such insights go way beyond the reach of Neanderthal DNA, but with each small advance we will learn a little more about ourselves as a species, our diversity, and, sometimes, those relatives we lost along the way.

Photo credits: AquilaGib/Wikimedia Commons (CC BY-SA), CDC