Figure 3. Environmental context is key to trait interpretation.

(A) Adapted from Figure 1 of Ebrahim et al., 2010, age-, factory-, and occupation-adjusted percent prevalence (95% CI) of diabetes by type of migrant and sex, Indian migration study 2005–2007. Diabetes is prevalent in urban residents and residents who migrated to urban areas and resided there for more than 10 years. (B) Gene–environment interactions will affect an organismal trait at the level of genes, cells, tissues, and whole organisms. Extending the Mostafavi et al., 2022 model to incorporate environmental context captures more relevant biology, and hence facilitates variant effect interpretation. As shown, a variant (red allele) affects a gene’s function within a particular cellular context. Cells affected by the red allele function exist within the context of the organism, here a light-gray mouse as compared to a dark-gray mouse that does not carry the red allele. Mice with or without the red allele are exposed to environmental factors, symbolized by the cheese as a dietary factor challenging metabolism. Note that one of the mice carrying the red variant is not exposed to this environmental challenge (light gray, clipped ear). In the example shown, environmental context determines the trait value (obesity, big light-gray mouse) for mice carrying the red variant.