Do thrifty genes exist? Revisiting uricase

Abstract

Sixty years ago, the geneticist James Neel proposed that the epidemics of obesity and diabetes today may have evolutionary roots. Specifically, he suggested that our ancestors may have accumulated mutations during periods of famine that provided a survival advantage at that time. However, the presence of this "thrifty genotype" in today's world, where food is plentiful, would predispose us to obesity and diabetes. The "thrifty gene" hypothesis, attractive to some, has been challenged over the years. The authors have previously postulated that the loss of the uricase gene, resulting in a rise in serum and intracellular uric acid levels, satisfies the criteria of a thrifty genotype mutation. This paper reviews and brings up-to-date the evidence supporting the hypothesis and discusses the current arguments that challenge this hypothesis. Although further studies are needed to test the hypothesis, the evidence supporting a loss of uricase as a thrifty gene is substantial and supports a role for evolutionary biology in the pathogenesis of the current obesity and diabetes epidemics.

Figure 1.. Hypothesis for How the Uricase Mutation may have Aided Survival to Hominids Facing Seasonal Starvation.

According to the hypothesis, the loss of uricase would have amplified the uric acid response to fructose, and this would have led to a greater activation of the biologic switch in response to dwindling fruit supplies, leading to increased fat stores that would allow survival through the cooler seasons.

Figure 2.. Relationship of Serum Uric acid Levels with Obesity and Diabetes.

An analysis of 5707 adults from the NHANES population survey (2007 to 2008) demonstrated a strong relationship of serum uric acid levels with presence of obesity or diabetes(81). One can observed that the risk for obesity with uric acid levels < 4 mg/dl is relatively low, suggesting that the uricase mutation alone did not cause much obesity. It was the interaction of the uricase mutation with western diet that led to the dramatic rise in obesity and diabetes.