Figure 2. Multiplex assays of variant effect (MAVEs) in context.

(A) MAVEs in cell lines can assay many variants for simple phenotypes like cell growth. Models like organoids and mice allow for measuring complex multicellular phenotypes like proportions of cell types but are currently limited to assaying only a few variants at a time. (B) Gene–gene interactions are examined in different models at different levels of phenotype complexity. Gene–gene interactions suggested for prioritization include compound heterozygotes, combinations of common and rare variants in a given locus in cis and trans, and experiments testing variants on different genetic backgrounds. (C) Gene–environment interactions are examined at different levels of phenotype complexity. Three broad categories are suggested to model the complexity of environmental context in the laboratory: abiotic stress, challenges to immunity, and metabolism.