Mechanisms of suppression: The wiring of genetic resilience

Abstract

Recent analysis of genome sequences has identified individuals that are healthy despite carrying severe disease-associated mutations. A possible explanation is that these individuals carry a second genomic perturbation that can compensate for the detrimental effects of the disease allele, a phenomenon referred to as suppression. In model organisms, suppression interactions are generally divided into two classes: genomic suppressors which are secondary mutations in the genome that bypass a mutant phenotype, and dosage suppression interactions in which overexpression of a suppressor gene rescues a mutant phenotype. Here, we describe the general properties of genomic and dosage suppression, with an emphasis on the budding yeast. We propose that suppression interactions between genetic variants are likely relevant for determining the penetrance of human traits. Consequently, an understanding of suppression mechanisms may guide the discovery of protective variants in healthy individuals that carry disease alleles, which could direct the rational design of new therapeutics.

Keywords: compensatory evolution; dosage suppression; epistasis; genetic interactions; protective alleles; suppression interactions; synthetic viability.

Figure 1

Genetic interaction classes. When two single mutants (x and y) have a relative fitness of 0.8 and 0.7, the expected fitness of the resultant double mutant (xy) based on a multiplicative model is 0.8 × 0.7 = 0.56. A negative genetic interaction, such as synthetic lethality, occurs when the observed double mutant fitness is lower than this expected fitness. A masking positive interaction occurs when the fitness of the double mutant is greater than expected, but lower or equal to that of the slowest growing single mutant. Suppression positive interactions occur when the double mutant fitness is greater than that of the slowest growing single mutant.

Figure 2

Mechanisms of suppression between functionally related genes. Three mechanisms of suppression between genes encoding proteins that function within the same biological process are illustrated using examples from budding yeast: suppression between members of the same complex, between members of the same pathway, or between members of alternative pathways. Query genes are colored yellow, while suppressor genes are magenta or cyan. Wild type alleles are represented as filled circles, partial or complete loss-of-function (LOF) alleles as open circles with a dashed border, and gain-of-function (GOF) alleles as filled squares. A: The query and suppressor genes encode members of the same complex. For example, either gain-of-function mutations in, or overexpression of, POL3 can restore polymerase activity in the presence of a partial loss-of-function allele of POL31. B,C: The suppressor and query are members of the same pathway. B: The genes can have opposite effects on the output of the pathway, or the suppressor can function downstream of the query protein. For instance, the growth defect caused by loss-of-function mutations in the Ras2-activating protein Cdc25 can be suppressed by mutation of Ira1, which inhibits Ras2. Suppression can also take place by increasing Ras2 activity, either by overexpression or by gain-of-function mutations in the RAS2 gene. C: The suppressor gene can function upstream of the query protein. For example, loss of Ade13 leads to a growth defect due to increased accumulation of a toxic metabolite SAICAR. This can be suppressed by loss of upstream pathway members, so that SAICAR does not get produced. D,E: The suppressor gene is part of an alternative, yet related, pathway, whose function can be slightly altered to restore the missing activity. D: The absence of the mitochondrial ribosomal protein Mrpl3 leads to a fitness defect due to a reduction in the mitochondrial membrane potential (Ψ_m). This can be restored by gain-of-function mutations in the ATP synthase subunit Atp1. E: An example of a dosage suppression interaction between members of alternative pathways. The fitness defect of nup116 mutants is the result of reduced nuclear protein import, which can be suppressed by overexpression of BRL1, a gene that changes the composition of the nuclear membrane.

Figure 3

General mechanisms of suppression. General suppression interactions 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 a fitness defect caused by reduced levels of the query protein (‘Q’). A: A suppressor mutation may occur in the translational machinery, such that the genetic code is changed, and the query mutation is reinterpreted. The example illustrates suppression caused by mutation of the anticodon of a tRNA to make it recognize a premature stop codon in the query allele, and introduce an amino acid in its place. B: Partial loss-of-function query alleles can also be suppressed by increasing protein expression, for instance through decreased degradation of the mutant mRNA via mutation of the nonsense-mediated mRNA decay (NMD) pathway, or via increased transcription or translation of the query gene or mRNA. TF: transcription factor. C: Partial loss-of-function mutations can be suppressed by loss of a member of the protein degradation pathway or by overexpressing a chaperone protein (‘Ch’). Both of these mechanisms may expand the pool of partially functional query protein.