For a long time, a fundamental question in genetics has been to determine how much of the phenotypic variation between individuals is due to genes and how much is due to the environment. However, these two factors are not mutually exclusive and it is generally acknowledged that genetic effects can vary between environments – this is known as Genotype-by-Environment interactions, or GxE.
How prevalent are GxE interactions? Which loci are sensitive to environmental variation? Which ones are not? Addressing these questions empirically has been particularly challenging, because it requires to map the genetic basis of a given trait across environments. Doing so involves large-scale experiments where genotypes and phenotypes need to be measured in thousands of individuals in multiple environments. It is only recently that high-throughput approaches have allowed such scale of data collection.
To explore the extent to which GxE interactions regulate phenotypic variation, the research performed by the HFSP Fellowship Awardee Luisa Pallares, from the Max Planck Friedrich Miescher Laboratory, and her research group, focused on lifespan variation in the fruit fly, Drosophila melanogaster, and set up to map its genetic basis in two dietary conditions, low and high sugar. The scientists chose to study lifespan for two reasons, first, high-sugar diets reduce lifespan in flies and other organisms. Therefore, it is clear that diet affects lifespan, but it is still not known whether such reduction has a genetic component. Second, identifying the genetic loci regulating lifespan can be done without measuring lifespan for each individual fly, which is slow, costly, and limits the available sample size (sample size is a critical factor to be able to statistically detect GxE interactions).
To avoid individual-fly lifespan measurements, the researchers developed an experimental approach that relies on population-level metrics. The idea behind this approach is that, if an allele regulates lifespan, its frequency in the population will change as the population ages. That is, individuals reaching old age will have the allele that increases lifespan, and therefore its frequency in the population will be higher in old flies compared to young ones. This simplifies the experiment because thousands of flies can be aged in population cages instead of individual vials (see Fig 1 – this can point to the cage picture).
To track allele frequency changes between old and young flies, scientists exposed ~100.000 flies in large population cages to low and high sugar diets over the course of their lifetime and genotyped ~10.000 individuals. The research group identified thousands of loci regulating lifespan in outbred Drosophila, and strikingly, they find that 30% of such loci show very strong genotype-by-environment interactions, with little to no effect on lifespan under low-sugar conditions, but playing a fundamental role when flies were exposed to high-sugar diet.
The results show that the environment modulates a large portion of the genetic effects that regulate complex traits, either by enhancing or silencing them, and therefore increasing or decreasing the importance of certain genes. These results represent one of the most comprehensive dissections of the context-dependency of the genetic effects that regulate lifespan.