Gene dosage effects: nonlinearities, genetic interactions, and dosage compensation

•Mutations may or may not cause abnormal phenotypes depending on the genotype at other loci.•Nonlinear relations are responsible for dominance and genetic interactions.•We outline cellular mechanisms that compensate for the effects of mutations.

High-throughput genomic analyses have shown that many mutations, including loss-of-function (LOF) mutations, are present in diseased as well as in healthy individuals. Gene dosage effects due to deletions, duplications, and LOF mutations provide avenues to explore oligo- and multigenic inheritance. Here, we focus on several mechanisms that mediate gene dosage effects and analyze biochemical interactions among multiple gene products that are sources of nonlinear relations connecting genotypes and phenotypes. We also explore potential mechanisms that compensate for gene dosage effects. Understanding these issues is critical to understanding why an individual bearing a few damaging mutations can be severely diseased, whereas others harboring tens of potentially deleterious mutations can appear quite healthy.