One of the most spectacular changes in human life history phenotypes is our increased life expectancy over the last 200 years {1}. While the average lifespan was about 45 years in 1840, it is now well over 80 for both genders. Obviously, this is a clear indication of our improved general health; we have however also witnessed an increase in non-communicable health problems such as cardiovascular disease, obesity, and type 2 diabetes.

This lifespan-transition happened in just about four generations and population genetic theory dictates that this phenotypic change cannot have been caused by a change in the genetic composition of human populations. However, this does not rule out that genetics plays a role here. Firstly, despite the increase in average life expectancy, the variation in lifespan is still there. Indeed, estimates from, among others, twin studies indicate that 25% of this variation is heritable. Secondly, genetics can contribute via an interaction with the environment (G-by-E). In fact, there is a clear “evolutionary mismatch” as the genes and genetic variants we carry in our genomes were selected in a starkly different environment compared to the one that they are expressed in today {2}.

James Neel was one of the first to notice this. The increase in type 2 diabetes that he observed in his daily medical practice led to his hypothesis of the existence of “thrifty genes”; genes that have helped us through periods of famine in the past, but are causing diseases now {3}. The paper by Guanlin Wang and John Speakman sets out to find evidence that such genes exist. They selected more than 100 single-nucleotide polymorphisms (SNPs) emerging from so-called genome-wide association studies (GWAS) for body mass index (BMI; as a proxy for obesity). The authors reason that if these BMI-related genes are somehow related to the thrift genes that Neel envisioned, they should carry population genetic signature of positive selection. To cut a longish story short, they did not find any indication that this was the case.

There are at least two issues that need to be taken into account when considering their conclusions. Firstly, do the selected genes represent thrifty genes Complex adaptations to such different nutritional conditions including famines are likely quantitative in nature, with potentially many genes contributing. Indeed, for a potentially complex and composite trait such as longevity with a significant heritable variation component, it has proven very hard, if not downright impossible, to find the causal SNPs using GWAS approaches {4}. Secondly, even if they would, the BMI SNPs are a (potentially biased) selection of the thrifty genes as GWAS can mainly pick up relatively common alleles with additive effects. It thus effectively ignores genetic variants with G-by-G and G-by-E interactions, while these are likely to contribute to adaptations for dealing with variable food conditions.

Attractive verbal hypotheses such as the one of thrifty genes are increasingly put to the test because of new insights and developments, including enhanced molecular and analytical techniques. And more often than not, things turn out to be more complicated and there is then a tendency to throw away the baby with the bath water. While the Wang and Speakman study indicates that there is likely not a set package of independent thrift genes, it does not refute the premise of evolutionary mismatches. It moreover forces us to think harder about studying these and what tools and experimental designs we need to facilitate that. This study should thus be applauded as it does just that.

☑️ Reference