Ancestral FUT2 genetic adaptation confers resistance to modern norovirus and rotavirus infections

Human genetic diversity plays a key role in modulating susceptibility to infectious diseases, reflecting a long history of host-pathogen co-evolution. While clinical outcomes were once attributed primarily to pathogen virulence, evidence today underscores the impact of host genes in infection susceptibility. Noroviruses and rotaviruses, leading causes of acute gastroenteritis, illustrate this dynamic interplay. Resistance to gastroenteritis infection in a subset of individuals is conferred by loss-of-function mutations in FUT2, which encodes α(1,2)-fucosyltransferase responsible for histo-blood group antigen (HBGA) synthesis on mucosal surfaces. Individuals homozygous for the FUT2 loss-of-function mutation rs601338-A, so-called nonsecretors, lack expression of specific HBGAs in the mucosa and exhibit strong resistance to common noro-and rotavirus genotypes. Analysis of more than 7000 ancient genomes revealed that this allele was introduced into Europe by Anatolian farmers around 6000 BCE and subsequently rose in frequency under positive selection. The transition to agricultural living, marked by higher population density and increased pathogen exposure, likely intensified selective pressures favoring the FUT2 loss-of-function variant. Today, genetics governing HBGA expression has a range of human health implications, from infection susceptibility, vaccination effect, population disease rates, and zoonotics. This case exemplifies how demographic transitions and ecological shifts during human evolution have shaped the landscape of genetic diversity and how it continues to influence health in modern populations today.