Genetics research sheds light on a long human relationship

A poison we adapted to tolerate

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Alcohol has been part of human existence for millennia. Alcoholic beverages are an integral part of human culture. Like the wines consumed in Jewish and Christian rituals, these drinks have ceremonial and religious uses. Until the nineteenth century, beer, brandy, rum or grog was the drink of choice for sailors in lieu of stagnant water during long voyages. Alcohol is a social lubricant, an anesthetic and an antiseptic. It is one of the most widely used drugs in the world and has been manufactured since the advent of agriculture nearly 9000 years ago. How is it that this drug an intoxicating poison has become such a part of human existence?

A new study finds that our forebears acquired the capacity to digest alcohol some 10 million years ago, among a common ancestor to humans, chimpanzees and gorillas, and certainly well before we learned to manufacture it. This suggests that alcohol became part of the human diet much earlier than previously thought, and in a manner that had significant implications for the survival of the human species.

Humans carry with them genetic signatures of their ancestral feeding habits. Genetic variants that make new food sources available can provide tremendous opportunities to those who possess them. The ability to consume milk, for example, is due to the lactase persistence variant of a gene which emerged around 7500 years ago among early Europeans. For those lacking the mutation, the lactose in milk is a mild poison, eliciting symptoms akin to those of dysentery. Similarly, the ability to digest alcohol may be a genetic signature of feeding pattern among human ancestors: this alcohol tolerance may have made it possible to eat over-ripe fruit that had fallen to the ground and begun to naturally ferment. Since few animals can tolerate alcohol, this would have provided our ancestors with an abundant food source for which there were few competitors. It may also have contributed to the move towards a terrestrial rather than arboreal existence.

The breakdown of alcohol after ingestion is a complex process that involves a number of different enzymes. Most of the alcohol that is ingested is broken down in the gut and liver. This study focused on the enzyme ADH4 because it is abundant in the gut and plays a major role in preventing ingested alcohol from entering the blood stream. ADH4 from human relatives as distant as the tree shrew were tested for their ability to digest alcohol. The form of ADH4 found in humans, gorillas and chimpanzees was found to be 40 fold more efficient at clearing alcohol than the form found in more primitive species. ADH4 also digests chemicals that plants produce in order to deter animals from feeding upon them. However, with the increase in ability to digest alcohol came a reduced ability to digest many of these other chemicals. This suggests that the food containing alcohol was more important.

While ADH4 is among the most important enzymes for the digestion of alcohol, it is not the only one. Another related enzyme, ADH3, also contributes to the breakdown of alcohol. Women typically have lower activity levels of this enzyme, leading them to have higher blood levels of alcohol then men after taking a high dose of alcohol. And ADH4 is not the only enzyme that may have helped humans adapt to the consumption of alcohol: a variant of a liver enzyme (ADH1B) with high activity in the breakdown of alcohol emerged among East Asian populations during the advent of rice cultivation, perhaps as an adaptation to rice fermentation. (Interestingly, other animals have adopted their own strategies: Using a different enzyme, a member of the tree shrew family is able to consume fermented nectar from palm tree flowers the equivalent of 10 -12 glasses of wine every day without obvious signs of intoxication.)

Because humans rely upon ADH4 as their primary means to digest alcohol, they are also susceptible to hangovers. ADH4 and similar enzymes digest alcohol by converting it into another chemical, acetaldehyde, which causes the skin flushing, headache and other symptoms of overindulgence. The modern consumption of alcohol has been characterized as an "evolutionary hangover," an adaptation to modest levels of alcohol in food sources which left humans prone to alcohol abuse once we learned how to manufacture it in highly concentrated forms. And, in fact, genetic variants of ADH4 have been linked to alcohol and drug dependence, although there are many other genes that may influence susceptibility to alcohol dependency. Regardless of the role ADH4 plays in alcohol addiction, its clear that our complex relationship with alcohol dates back millions of year, and began, in fact, before we were even human.

Robert Martone is a researcher working on neuro-oncology biomarker discovery and development. He lives and works in Memphis TN.

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Our Taste for Alcohol Goes Back Millions of Years