When people started farming thousands of years ago, they faced an increase in infectious diseases caused by close contact with animals and their feces. This triggered a natural selection of genes that led to an adapted immune system in response to the new threats.
Since the start of the COVID-19 pandemic, intensive livestock farming has often been blamed for the emergence of pathogenic viruses and their transmission to humans. However, humans have been farming livestock for thousands of years and their proximity to animals was sometimes much greater in the past. Over 7000 years ago, when the first Vinča farmers arrived in the Balkans, they lived in villages of hundreds or thousands of people, sharing their mud huts with oxen, cows, pigs, and geese – and their excrement. This proximity was particularly conducive to diseases such as influenza, tuberculosis, malaria, and other infectious diseases. The oldest human hepatitis B virus dates back 7000 years, while measles, which is derived from a related virus that infects cattle and sheep, is thought to have been transmitted to humans 2500 years ago.
Proximity to livestock and animal husbandry: an explosive cocktail for the spread of disease
It has been shown that people who farm livestock are more likely to contract diseases than their nomadic hunter-gatherer counterparts. However, it was the farmers that prevailed, and no disease wiped out the human species, even though it was much more fragile than it is today because there were no vaccines or treatments then. An international team of researchers has now published a study in the journal eLife showing how the immune systems of this innovative livestock adapted to respond to this new threat.
Of course, there are no 7000-year-old blood samples to analyze and understand the immune system of our ancestors. So the researchers used a creative two-step approach. To better understand the mechanism of adaptation, the team first looked at genetic variations in the immune response in living humans. They took 500 blood samples from the Human Functional Genomics Project (HFGP) biobank in Nijmegen, the Netherlands, and tested the samples against different pathogens. They then measured the levels of cytokines – inflammatory proteins released by immune cells in response to infection. They then checked the correlation between the levels of these cytokines and several genes to calculate a “polygenic risk score”, in other words, the strength of the inflammatory and therefore immune response produced by a particular gene.
When the first farmers were first exposed to new pathogens, some of them had an immune overreaction and died, as is the case today with COVID.
The researchers then applied their method to the past. They downloaded ancient DNA sequences from 827 human remains found in Europe, dating back 45000 to 2000 years. Based on the gene sequences, they calculated polygenic risk scores and found that Europeans who had switched to domestic animal husbandry had much lower polygenic risk scores than hunter-gatherers in earlier periods. A counter-intuitive result. Except that, as we saw in the COVID-19 case, an excessive inflammatory response can trigger a “cytokine storm” during which the immune system itself destroys the organism. “When the first farmers were first exposed to new pathogens, some of them overreacted and died, as we see today with Covid,” says Mihai Netea from Radboud University Medical Centre in Nijmegen, who led the study.
The Neolithic period – a period that changed our immune system
As a result, genes that caused a lower inflammatory response “survived” and were passed on to subsequent generations. However, the researchers noted some exceptions, such as infections with the fungus Candida albicans or Staphylococcus aureus, where the inflammatory response is stronger in the farmers’ ancestors. The researchers suggested that in these cases, strong local inflammation can stop the infection before it spreads to the rest of the body.
However, the study is based on rather uncertain hypotheses, such as whether the genes of the ancestors trigger the same inflammatory response as their current counterparts, or whether it has something to do with animal husbandry. What is certain is that inflammation levels in humans changed dramatically during the Neolithic, when humans became sedentary. “If the first nomadic humans were affected by today’s SARS-CoV-2, it is certain that their mortality rate would have been much higher than today,” Mihai Netea concludes.
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