The role of thrifty genes in the origin of alcoholism: A narrative review and hypothesis

• Published in: Alcoholism, clinical and experimental research clinical and experimental research, 2021-08, Vol.45 (8), p.1519-1526
• Main Authors: Carn, David, Lanaspa, Miguel A., Benner, Steven A., Andrews, Peter, Dudley, Robert, Andres‐Hernando, Ana, Tolan, Dean R., Johnson, Richard J.
• Format: Article
• Language: English
• Subjects: Acid production; Adaptation, Biological - genetics; Alcohol dehydrogenase; Alcohol Dehydrogenase - genetics; alcohol dehydrogenase class IV; Alcohol use; Alcoholism; Alcoholism - genetics; Aldehyde reductase; Animals; Biological Evolution; Climate Change; Drug abuse; Ethanol; Ethanol - metabolism; Fructose; Fructose - metabolism; Fruits; Hominidae - genetics; Hominidae - metabolism; Humans; Hypotheses; Lipogenesis; Metabolism; Miocene; Mutation; Oxidation; Selection, Genetic; Starvation; Survival; thrifty genes; Urate oxidase; Urate Oxidase - genetics; Uric acid; uricase
• ISSN: 0145-6008; 1530-0277
• DOI: 10.1111/acer.14655

In this narrative review, we present the hypothesis that key mutations in two genes, occurring 15 and 10 million years ago (MYA), were individually and then collectively adaptive for ancestral humans during periods of starvation, but are maladaptive in modern civilization (i.e., “thrifty genes”), with the consequence that these genes not only increase our risk today for obesity, but also for alcoholism. Both mutations occurred when ancestral apes were experiencing loss of fruit availability during periods of profound climate change or environmental upheaval. The silencing of uricase (urate oxidase) activity 15 MYA enhanced survival by increasing the ability for fructose present in dwindling fruit to be stored as fat, a consequence of enhanced uric acid production during fructose metabolism that stimulated lipogenesis and blocked fatty acid oxidation. Likewise, a mutation in class IV alcohol dehydrogenase ~10 MYA resulted in a remarkable 40‐fold increase in the capacity to oxidize ethanol (EtOH), which allowed our ancestors to ingest fallen, fermenting fruit. In turn, the EtOH ingested could activate aldose reductase that stimulates the conversion of glucose to fructose, while uric acid produced during EtOH metabolism could further enhance fructose production and metabolism. By aiding survival, these mutations would have allowed our ancestors to generate more fat, primarily from fructose, to survive changing habitats due to the Middle Miocene disruption and also during the late‐Miocene aridification of East Africa. Unfortunately, the enhanced ability to metabolize and utilize EtOH may now be acting to increase our risk for alcoholism, which may be yet another consequence of once‐adaptive thrifty genes. We review mutations for uricase and class IV alcohol dehydrogenase and present the hypothesis that they were adaptive for survival during periods of starvation in our past—allowing ancestral humans to generate more fat, primarily from fructose—but are maladaptive in modern civilization (i.e., “thrifty genes”), with the consequence that these genes not only increase our risk today for obesity, but also for alcoholism. Thus, alcoholism may reflect yet another contemporary and adverse consequence of once‐adaptive selection on thrifty genes.