How ancient farmers throttled their immune systems to survive


When early farmers of the Vinca culture first sowed barley and wheat 7700 years ago in the rich soil of the Danube River and its tributaries, they changed more than their diet: They introduced a new way of life to the region. They crowded together in mud huts, living cheek by rump with aurochs, cows, pigs, and goats—and their poop—in settlements that eventually swelled to thousands of people. Togetherness brought a surge in diseases such as influenza, tuberculosis, and other maladies spread from animals to people and through early farming communities.

Now a new study of ancient DNA shows how the immune systems of those early farmers responded to this new, pathogen-ridden environment. The Neolithic Revolution was a “turning point” in the evolution of immune responses to infectious disease, according to a paper published today in eLife. The study suggests that in Europeans, evolution favored genes that throttled back inflammatory reactions to pathogens like influenza, restraining the hyperalert inflammatory response that can be deadlier than the pathogen itself.

“This study does a great job of showing that our immune system has continued to evolve in response to pathogen pressure,” says population geneticist Joseph Lachance of the Georgia Institute of Technology. But he notes that the paper relies on an unproven method of predicting ancient immune responses. “I buy it, but it needs to be studied [more] when we have more ancient DNA.”

Researchers have long suspected that early farmers got sick more often than nomadic hunter-gatherers. Studies suggest farmers in large Neolithic sites such as Çatalhöyük in Turkey faced a flurry of new zoonotic diseases such as influenza and salmonella, as well as new animal-borne strains of diseases like malaria and tuberculosis. “If farmers got sick more, how did their immune systems change?” asked infectious disease specialist Mihai Netea of Radboud University Nijmegen Medical Centre, who led the study.

To approach that question, his team first studied genetically based variation in the immune responses of living people. They took blood samples from more than 500 people in the Human Functional Genomics Project (HFGP), a biobank based in Nijmegen, Netherlands, and challenged the samples with various pathogens. Then they measured levels of specific cytokines—immunoregulatory proteins such as interleukin and interferon that are secreted by immune cells—and looked for correlations between those levels and a suite of immune gene variants.

In the new study, the team used those results to come up with what’s called a polygenic risk score that predicts the strength of the inflammatory response in the face of specific diseases, based on an individual’s immune gene variants. The researchers then applied their technique to the past: From existing databases they downloaded ancient DNA sequences from 827 remains found across Europe, including Vinca farmers from today’s Romania. They calculated the cytokine levels ancient people would likely have produced and their polygenic risk scores for inflammation.

The remains dated from between 45,000 and 2000 years ago, enabling the team to look for changes over time. They found that when faced with infections, Europeans who lived after agriculture likely produced dramatically lower levels of systemic cytokines than earlier hunter-gatherers. Those lower levels were likely adaptive, Netea says. “When people first encountered new pathogens, some overreacted and died, like we see with COVID today,” he says. “The children of the people who survived didn’t produce as many cytokines, so the whole population becomes more resistant.”

The study also revealed a flip side: When infected with the fungus Candida and Staphylococcus bacteria—pathogens that tend to start as localized infections—farmers likely mounted more robust inflammatory responses than earlier hunter-gatherers. A strong inflammatory response can quell a localized infection before it spreads, but a robust systemic response, as sparked by the flu or malaria, can spiral out of control.

The study is exciting because it clearly shows that the population frequencies of genes regulating inflammation “change strongly from the beginning of the Neolithic,” says molecular anthropologist Ben Krause-Kyora of Kiel University.

But Lachance questions whether polygenic risk scores developed for modern people can predict inflammation for people in other places and times. Pathogens have evolved over time, he notes, and modern risk prediction might not apply to ancient disease strains. Population geneticist Luis Barreiro of the University of Chicago, agrees, saying the authors “don’t formally demonstrate the predictive value of these polygenic risk scores.”

More samples of ancient DNA from people and pathogens, especially on other continents, is needed to test whether evolution scaled back the production of inflammatory cytokines in farmers everywhere. But the study clearly demonstrates that somehow or other, European’s inflammatory responses to pathogens did change dramatically during the Neolithic, Lachance says. To Netea, the findings suggest the ancient burst of evolution may have an impact even today: If a coronavirus like SARS-CoV-2 had swept through Europe before agriculture, he says, “more people would have died than today because they produced more proinflammatory cytokines.”, 7 September 2021