Mapping a diversity of genetic interactions in yeast

Abstract

Genetic interactions occur when the combination of multiple mutations yields an unexpected phenotype, and they may confound our ability to fully understand the genetic mechanisms underlying complex diseases. Genetic interactions are challenging to study because there are millions of possible different variant combinations within a given genome. Consequently, they have primarily been systematically explored in unicellular model organisms, such as yeast, with a focus on pairwise genetic interactions between loss-of-function alleles. However, there are many different types of genetic interactions, such as those occurring between gain-of-function or heterozygous mutations. Here, we review recent advances made in the systematic analysis of such diverse genetic interactions in yeast, and briefly discuss how similar studies could be undertaken in human cells.

Keywords: complex haploinsufficiency; dosage interactions; epistasis; genetic interactions; higher-order interactions.

Figure 1.. Genetic interaction classes involving two genes.

In yeast, genetic interactions are frequently scored using a multiplicative model. When two single mutants (x and y) have a fitness of 0.8 and 0.7 relative to wild-type cells, the expected double mutant (xy) fitness is 0.8 × 0.7 = 0.56. Negative and positive interactions occur when the fitness defect of a double mutant is either more or less severe, respectively, than this expected fitness. A synthetic sick negative genetic interaction occurs when the observed double mutant fitness is lower than expected, but still viable. In a synthetic lethal negative genetic interaction, the combination of two viable single mutants results in an inviable double mutant. 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 genetic interactions.

Possible mechanisms of genetic interactions between different types of alleles are illustrated. Wild-type alleles are represented as filled circles, partial or complete loss-of-function alleles as open circles with a dashed border, and overexpression alleles as multiple filled circles. A) Genetic interactions between two loss-of-function alleles. Top: A negative genetic interaction can occur between loss-of-function alleles of genes (“A” and “B”) that function in parallel pathways. Bottom: A positive genetic interaction can occur between genes (“A” and “B”) that have opposite effects on the output of a pathway. B) Genetic interactions involving one loss-of-function allele and one overexpression allele. Top: Synthetic dosage lethality can also occur between genes (“A” and “B”) that have an opposite effect on the output of a pathway. Bottom: Dosage suppression can occur when a fitness defect caused by loss-of-function mutations in a gene (“A”) is compensated for by overexpressing a downstream component of the same pathway (“C”).

Figure 3.. Complex haploinsufficiency.

A) Haploinsufficiency occurs when a heterozygous mutation is sufficient to cause a phenotype. B) Complex haploinsufficiency occurs when the combination of two heterozygous mutations results in an unexpected phenotype.