Ferment in the family tree.

In 1953, botanist Jonathan D. Sauer suggested that our initial motivation to cultivate cereals was not for flour or bread, but for beer (1). The implications of this idea— that a preference for dietary ethanol, or alcohol, sparked the Neolithic Revolution (2)—are profound. No stage of human evolution has left a larger global footprint than the domestication of plants, animals, and landscapes (3). However, there is scant evidence of directed fermentation before the onset of the Neolithic, approximately 10,000 B.C.E. (4). The earliest archaeological evidence of alcohol is associated with the cultivation (5) and initial domestication (6) of cereals during the early Neolithic (Fig. 1), which suggests that fermentation was the happy outcome, rather than the cause, of grain storage and consumption. Any gene involved in the alcohol metabolic pathway is therefore an exemplary candidate for testing the concept of gene-culture coevolution (7), a branch of theoretical population genetics that integrates Neolithic cultural shifts into models of genetic inheritance (8). This approach has been rewarding (9); however, the coevolutionary process is usually preceded with “cultural selection” (8), wherein cultural traits, such as dietary preference, impel the evolution of novel phenotypes. The reverse sequence is seldom considered, but a recent study in PNAS (10) raises new and alluring questions about the genetic adaptations that enabled our shift from foraging to producing societies. In PNAS, Carrigan et al. (10) report the protein sequences and corresponding kinetic activities of alcohol dehydrogenase class IV (ADH4), the first enzyme to encounter and metabolize dietary alcohol. The authors focused on 18 primate species and resurrected nine ancestral proteins to better understand the evolution and functional ecology of ADH4. This innovative approach revealed three key results. First, the ADH4 enzymes of most primates are essentially inactive against ethanol. Second, a single amino acid change (A294V) causes a dramatic 40-fold increase in ethanol-catalyzing activity. Third, this mutation arose independently in two distantly related primates, the aye-aye (Daubentonia madagascariensis) and the last common ancestor of African apes and humans. Ethanol with an Aye to Ecology In the hall of animal oddities, the aye-aye is an exemplar of dietary specialization. It is a peculiar lemur that uses percussive foraging to prey on the larvae of cerambycid (longhorn) beetles. Given that beetle larvae are an improbable source of alcohol, the A294V transition of aye-ayes is very likely a spurious mutation: except that aye-ayes appear to have an enduring mutualism with the traveler’s tree (Ravenala madagascariensis; Strelitziaceae) (11, 12). Aye-ayes probably pollinate R. madagascariensiswhen they probe the large (30-cm) inflorescences for nectar (Fig. 2A). Carrigan et al.’s (10) speculation that aye-ayes are ingesting fermented nectar invites immediate testing. A diet of fermented floral nectar is not unknown among primates (e.g., Nycticebus coucang) (13).