Many modern human diseases are attributed to incompatibility between our current environment and the environment for which our genome is adapted. It is unclear whether this model applies to alcoholism. We investigated this possibility by studying alcohol dehydrogenase class IV (ADH4), the first enzyme exposed to ethanol in the digestive tract that is capable of metabolizing ethanol. We resurrected ancestral ADH4 enzymes from various points in the ∼70 million y of primate evolution and identified a single mutation occurring ∼10 million y ago that endowed our ancestors with a markedly enhanced ability to metabolize ethanol. This change occurred approximately when our ancestors adopted a terrestrial lifestyle and may have been advantageous to primates living where highly fermented fruit is more likely.

Abstract

Paleogenetics is an emerging field that resurrects ancestral proteins from now-extinct organisms to test, in the laboratory, models of protein function based on natural history and Darwinian evolution. Here, we resurrect digestive alcohol dehydrogenases (ADH4) from our primate ancestors to explore the history of primate–ethanol interactions. The evolving catalytic properties of these resurrected enzymes show that our ape ancestors gained a digestive dehydrogenase enzyme capable of metabolizing ethanol near the time that they began using the forest floor, about 10 million y ago. The ADH4 enzyme in our more ancient and arboreal ancestors did not efficiently oxidize ethanol. This change suggests that exposure to dietary sources of ethanol increased in hominids during the early stages of our adaptation to a terrestrial lifestyle. Because fruit collected from the forest floor is expected to contain higher concentrations of fermenting yeast and ethanol than similar fruits hanging on trees, this transition may also be the first time our ancestors were exposed to (and adapted to) substantial amounts of dietary ethanol.