Why and how to study genetic changes with context-dependent effects

The phenotypic impacts of a genetic change can depend on genetic background (e.g. epistasis), as well as other contexts including environment, developmental stage, cell type, disease state, and higher-order combinations thereof. Recent advances in high-throughput phenotyping are uncovering examples of context dependence faster than genotype-phenotype maps and other core concepts are changing to reflect the dynamic nature of biological systems. Here, we review several approaches to study context dependence and their findings. In our opinion, these findings encourage more studies that examine the spectrum of effects a genetic change may have, as opposed to studies that exclusively measure the impact of a genetic change in a particular context. Studies that elucidate the mechanisms that cause the effects of genetic change to vary with context are of special interest. Previous studies of the mechanisms underlying context dependence have improved predictions of phenotype from genotype and have provided insight about how biological systems function and evolve.