Natural Selection of a Virus-Protective FUT2 Variant Following the Transition to Agriculture

Abstract

Common enteric viruses rely on sugars mediated by the galactoside 2-alpha-L-fucosyltransferase 2 (FUT2) enzyme to infect host cells. Analyzing 4,343 ancient genomes, we map a premature stop codon in FUT2, which was introduced into Europe by migrating Anatolian farmers ∼6000 BC and provide evidence for positive selection. Using data from ∼700,000 present-day individuals, we confirm its protective effect against viral gastroenteritis. Experiments with intestinal organoids reveal that only homozygous carriers are protected against noroviruses and rotaviruses but not sapovirus. Our rotavirus findings resolve a long-standing contradiction between epidemiological data and experiments. Contrary to previous reports, we find no association between FUT2 loss of function and Helicobacter pylori infection. However, carriers exhibit an increased risk of gastric ulcers and gallbladder disease, associations replicated with an independent loss-of-function variant in East Asia. These findings suggest that the transition to agriculture and increased pathogen exposure drove positive selection of this allele.