Humans have been argued to be biologically adapted to a cooked diet, but this hypothesis has not been tested at the molecular level. Here, we combine controlled feeding experiments in mice with comparative primate genomics to show that consumption of a cooked diet influences gene expression and that affected genes bear signals of positive selection in the human lineage. Liver gene expression profiles in mice fed standardized diets of meat or tuber were affected by food type and cooking, but not by caloric intake or consumer energy balance. Genes affected by cooking were highly correlated with genes known to be differentially expressed in liver between humans and other primates, and more genes in this overlap set show signals of positive selection in humans than would be expected by chance. Sequence changes in the genes under selection appear before the split between modern humans and two archaic human groups, Neandertals and Denisovans, supporting the idea that human adaptation to a cooked diet had begun by at least 275,000 years ago.
