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The arrival of agriculture coincided with a sharp rise in a gene variant that protected against the virus that causes winter vomiting, researchers from Karolinska Institutet and Linköping University report after analyzing DNA from over 4,300 prehistoric individuals and cultivating "mini guts."

Winter vomiting disease is caused by the norovirus, which is most virulent during the colder half of the year. The infection clears up after a couple of days, but the protection it provides is short-lived, meaning that the same person can repeatedly fall sick in a short space of time. But some people cannot succumb to the virus, thanks to a particular gene variant.

"We wanted to trace the historical spread of the gene variant," says Hugo Zeberg, senior lecturer in genetics at the Department of ÌÇÐÄÊÓƵiology and Pharmacology, Karolinska Institutet, and researcher at the Max Planck Institute for Evolutionary Anthropology in Leipzig.

Defective gene protects against virus

The FUT2 gene is the target of an enzyme found in the intestinal mucosa. One of its roles is to place sugar molecules on the surface of the intestinal cells, and it is through these molecules that the norovirus infects the gut. The protective gene variant is defective so that the enzyme fails to work—and without the sugar molecules, the virus is unable to enter the cells.

To trace the spread of the variant, the researchers analyzed the DNA of 4,343 prehistoric individuals from the past 10,000 years. The defective gene was brought to Europe in around 6,000 BCE by early farmers from what is now Turkey and then propagated throughout the population some 8,500 to 5,000 years ago.

In the early societies of the first farmers, the vomiting sickness virus spread much more quickly than when humans lived in small groups.

"Our results suggest that this type of disease environment drove up the frequency of the gene variant as it protects against winter vomiting disease and confers on the bearer the advantage of not falling sick," says Dr. Zeberg.

Finding confirmed with 'mini guts'

By studying questionnaires and genetic material from biobanks with 700,000 modern humans, the researchers observed that people with the gene variant rarely had vomiting sickness, especially if they had double copies—one from each parent.

To confirm their findings, the researchers cultivated human gut organoids (or miniature guts) from gut biopsies. In so doing, they found that individuals with two copies of the gene variant were fully protected against norovirus infection.

The study is published in Molecular Biology and Evolution and was conducted with researchers at Linköping University.

"Ascertaining why certain mutations arise and get selected allows us to better understand how they affect our health today," says the study's lead author Johan Nordgren, docent of medical microbiology at the Department of Biomedical and Clinical Sciences, Linköping University.

The downside—gallstones and stomach ulcers

But there is a price to this protection: modern biobanks show an elevated risk of stomach ulcers and gallstones in the gene variant bearers.

"These are usually linked to stress and a high intake of fat, which was probably less common during the neolithic period," says Dr. Zeberg.

As regards the clinical relevance of the study, Dr. Zeberg says that knowledge that the gene variant provides full protection can be of use in risk assessment. An estimated 20% of the Swedish population have double copies.

"But my chief interest is in evolutionary science," he says. "Prehistoric DNA is a time machine that allows us to replay evolution and see how genetic mutations can be tied to events in the human environment."