Janice L. Brissette

A primary goal of biomedical research is to elucidate molecular mechanisms, particularly those responsible for human traits, either normal or pathological. Yet achieving this goal is difficult if not impossible when the traits of interest lack tractable models and so cannot be dissected through time‐honoured approaches like forward genetics or reconstitution. Arguably, no biological problem has hindered scientific progress more than this: the inability to dissect a trait's mechanism without a tractable likeness of the trait. At root, forward genetics and reconstitution are powerful approaches because they assay for specific molecular functions. Here, we discuss an alternative way to uncover important mechanistic interactions, namely, to assay for positive natural selection. If an interaction has been selected for, then it must perform an important function, a function that significantly promotes reproductive success. Accordingly, selection is a consequence and indicator of function, and uncovering multimolecular selection will reveal important functional interactions. We propose a selection signature for interactions and review recent selection‐based approaches through which to dissect traits that are not inherently tractable. The review includes proof‐of‐principle studies in which important interactions were uncovered by screening for selection. In sum, screens for selection appear feasible when screens for specific functions are not. Selection screens thus constitute a novel tool through which to reveal the mechanisms that shape the fates of organisms.