Ancient DNA tests the notion that allergies are due to our dirtier past

Genes for immunity forged in a germ-filled past are often blamed for making our bodies overreact to harmless triggers such as pollen or food. But evolution may not be so one-sided.

Some infection-fighting gene variants that spread over the past 10,000 years appear to reduce the risk of asthma and other allergies, not increase it, researchers report April 14 in a preprint posted to bioRxiv.org.

The finding challenges a long-standing idea that modern allergies are simply the price we pay for immune systems tuned to a dirtier past. That idea is “too simplistic,” says evolutionary geneticist Will Barrie of the University of Cambridge in England, who was not involved in the research.

The hypothesis developed out of observations that many gene variants that help fight infection are also implicated in autoimmune diseases, in which the immune system goes off the rails and mistakenly attacks the body’s healthy tissues. But determining when those variants rose in frequency — and thus whether protection against past infections truly came at the cost of greater autoimmune risk today — has been difficult without ancient DNA datasets spanning major transitions in human history.

Recently, those datasets have grown large enough for researchers to confidently track genetic changes across the Stone Age, the rise of agriculture and later periods. For example, a recent analysis of human genomes from 15,836 individuals who lived between 18,000 and 200 years ago identified hundreds of genetic variants shaped by natural selection after the shift to agriculture transformed people’s diets, environments and lifestyles.

Many of those changes were linked to immune function, reinforcing the idea that pathogens became dominant evolutionary forces as people moved into denser societies, researchers report April 15 in Nature. But that study stopped short of showing how those ancient immune adaptations shape disease risk today, leaving the hypothesis about past germs and modern allergies or asthma largely untested.

To probe the hypothesis, Harvard geneticist Javier Maravall López and colleagues integrated the Nature study’s ancient DNA datasets with modern genetic studies of disease risk. A clear pattern in the data showed humans retained and passed on gene variants that helped protect them from tuberculosis, influenza and intestinal pathogens, and, as expected, these same variants also tended to increase people’s risk for developing immune-mediated conditions such as inflammatory bowel disease.

But rather than simply making the immune system more reactive overall, evolution appears to have fine-tuned different parts of it in different ways.

As the researchers found, many genetic changes that rose in frequency after the advent of agriculture appear to have strengthened the body’s first lines of defense — especially in tissues that come into direct contact with microbes, such as the lungs and gut — helping block or clear infections more effectively. At the same time, some changes reduced the activity of signaling molecules closely linked to allergic inflammation, helping to curb overreactions to harmless substances.

Together, the authors contend, these shifts could help explain how, even in a world teeming with microbes, natural selection favored genes that conferred protection against infection while also lowering the risk of asthma and other allergic diseases. But that conclusion, and the research upon which it is based, have yet to be peer reviewed. And Barrie offers another way to interpret the findings.

It’s possible, he says, that in ancient hunter-gatherer populations, evolution rewarded fast, aggressive immune responses to survive constant infections, even if those responses also increased the risk of harmful inflammation. Only later, as lifestyles and disease exposures changed with the rise of agriculture, may other adaptations have tempered some of those responses back.

More ancient DNA from prehistoric times could help pin down when these changes occurred and whether they unfolded in distinct phases. But if Barrie’s intuition is correct, the new results may not show that evolution solved infection and allergy at once. Instead, they could reflect successive rounds of trade-offs, layered over time as environments changed, leaving today’s immune system a patchwork shaped by different eras.

From that perspective, Barrie says, “it’s hardly surprising that our immune system hasn’t got the right balance in the modern environment.”