Fig. 4

Mechanistic classes of suppression. A Distribution of suppression interactions across mechanistic classes for interactions identified in this study (left) or interactions described in the budding yeast using a similar literature curation approach (right) [8]. B Distribution of suppression interactions across mechanistic classes for interactions discovered in cultured human cells (left) or in patients (right). C Mechanisms of suppression between genes encoding proteins that function within the same biological process are illustrated. In a situation where the query (“Q”) activates a protein S2, which has an important biological function, suppression can take place in multiple ways. For example, the suppressor (S1) can be part of the same complex as the query, and gain-of-function mutations in S1 can restore the activation of S2. Alternatively, suppression can occur through gain-of-function mutations in S2, such that it no longer requires the query protein for its activation. The suppressor (S3) can also function in an alternative, but related, pathway. Specific alterations in this alternative pathway can restore the important function that was lacking in the absence of the query protein. D General mechanisms of suppression among pairs of genes that do not share a close functional relationship are illustrated. Often, general suppression is associated with partial loss-of-function query alleles that carry mutations that destabilize the protein or mRNA, leading to deleterious phenotypes due to reduced levels of the query protein. Partial loss-of-function query alleles can be suppressed by increasing protein expression, for instance via increased transcription of the query gene or through decreased degradation of the mutant mRNA via mutation of the nonsense-mediated mRNA decay (NMD) pathway. Partial loss-of-function mutations can also be suppressed by inactivation of a member of the protein degradation pathway, which may expand the pool of partially functional query protein. Finally, suppression may occur through inhibition of apoptosis. TF: transcription factor; AIF: apoptosis-inducing factor