Wednesday, September 8, 2021

Early Farmers Developed Muted Autoimmunity Responses

Uncontacted hunter-gatherers usually die of disease en masse, when encountering outsiders from the modern world. This is because they lack the immune system adaptation that were developed by the first farmers in the various Neolithic revolutions of the world. 

An ancient DNA study from the early Neolithic Vinca culture of the Balkans and other ancient European DNA samples documents those evolutionary adaptations. Specifically, evolution muted their global autoimmune responses were muted, while enhancing their localized inflammatory responses.

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. . . . 

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 paper and its abstract are as follows:

As our ancestors migrated throughout different continents, natural selection increased the presence of alleles advantageous in the new environments. Heritable variations that alter the susceptibility to diseases vary with the historical period, the virulence of the infections, and their geographical spread. In this study we built polygenic scores for heritable traits that influence the genetic adaptation in the production of cytokines and immune-mediated disorders, including infectious, inflammatory, and autoimmune diseases, and applied them to the genomes of several ancient European populations. We observed that the advent of the Neolithic was a turning point for immune-mediated traits in Europeans, favoring those alleles linked with the development of tolerance against intracellular pathogens and promoting inflammatory responses against extracellular microbes. These evolutionary patterns are also associated with an increased presence of traits related to inflammatory and auto-immune diseases.

Jorge Domínguez-Andrés, et al., "Evolution of cytokine production capacity in ancient and modern European populations" eLife 10:e64971 (September 7, 2021). DOI: 10.7554/eLife.64971

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