A TRADE-OFF BETWEEN RESISTANCE TO INFECTION AND REPRODUCTION IN PRIMATE EVOLUTION
Most mammals express a functional GGTA1 gene encoding the N-acetyllactosaminide -1,3-galactosyltransferase enzyme, which synthesizes Gal1-3Gal{beta}1-4GlcNAc (Gal) and are thus tolerant to this self-expressed glycan epitope. Old World primates including humans, however, carry GGTA1 loss-of-function mutations and lack Gal. Presumably, fixation of such mutations was propelled by natural selection, favoring the emergence of Gal-specific immunity, which conferred resistance to Gal-expressing pathogens. Here we show that loss of Ggta1 function in mice enhances resistance to bacterial sepsis, irrespectively of Gal-specific immunity. Rather, the absence of Gal from IgG-associated glycans increases IgG effector function, via a mechanism associated with enhanced IgG-Fc gamma receptor (Fc{gamma}R) binding. The ensuing survival advantage against sepsis comes alongside a cost of earlier onset of reproductive senescence. Mathematical modeling of this trade-off shows that under conditions of high exposure to virulent pathogens, selective pressure can fix GGTA1 loss-of-function mutations, as likely occurred during the evolution of primates towards humans.