Integrating genetic and protein-protein interaction networks maps a functional wiring diagram of a cell

Abstract

Systematic experimental approaches have led to construction of comprehensive genetic and protein-protein interaction networks for the budding yeast, Saccharomyces cerevisiae. Genetic interactions capture functional relationships between genes using phenotypic readouts, while protein-protein interactions identify physical connections between gene products. These complementary, and largely non-overlapping, networks provide a global view of the functional architecture of a cell, revealing general organizing principles, many of which appear to be evolutionarily conserved. Here, we focus on insights derived from the integration of large-scale genetic and protein-protein interaction networks, highlighting principles that apply to both unicellular and more complex systems, including human cells. Network integration reveals fundamental connections involving key functional modules of eukaryotic cells, defining a core network of cellular function, which could be elaborated to explore cell-type specificity in metazoans.

Figure 1.. Global yeast genetic interaction profiles similarity network.

(A) A global genetic profile similarity network encompassing all nonessential and essential genes was constructed by computing Pearson correlation coefficients (PCCs) for genetic interaction profiles of all pairs of genes (nodes). Gene pairs whose profile similarity exceeded a PCC > 0.2 were connected and graphed using a spring-embedded layout algorithm. Genes sharing similar genetic interactions profiles map proximal to each other, whereas genes with less similar genetic interaction profiles are positioned further apart. (B) Network regions enriched for specific GO biological process terms are colored. Adapted from [18].

Figure 2.. Quantitative definition of a genetic interaction

Under a multiplicative model, the expected fitness of a double mutant (relative to wild-type) is the product of the fitness of each single mutant. If the observe fitness of the double mutant falls below this expectation, genes X and Y share a negative GI (blue), while if double mutant fitness exceeds expectation, the interaction is positive GI (yellow). (A) Negative GIs include synthetic lethal or synthetic sick interactions. Positive GIs include masking or suppression GIs. (B) If the two single mutants (X and Y) exhibit the same defect in and the resultant double mutant shows the same fitness defect as the two single mutants, it is scored as a positive genetic interaction, which is often the case for nonessential genes in the same protein complex.

Figure 3.. A functional map of a yeast cell

The global yeast genetic interaction profile similarity network, in which genes are linked closely to one another if they share a highly similar genetic interaction profile is organized as a hierarchy of functional modules, enriched for specific cellular compartments, biological processes or protein complexes.

Figure 4.. Relationship between GIs and protein complexes

(A) Fold enrichment for physically interacting proteins (PPIs) among negative (blue) and positive (yellow) GIs connecting pairs of nonessential or essential genes. (B) (Left panel) The percentage of nonessential and essential complexes enriched for GIs within a complex. GIs are biased towards negative (blue) or positive (yellow) interactions. Black dashed lines indicate the background rate of coherent genetic interaction enrichment within individual complexes or between pairs of complexes. (Center panel). GI enrichment evaluated on complex-complex pairs. (Right panel) Schematic summary of GIs occurring within and between essential and nonessential protein complexes. Adapted from [18].

Figure 5.. Within- and Between-Pathway Models of GIs

(A) Within-pathway model (WPM). (i) A single mutation in a pathway (or complex) does not result in an extensive phenotype, but simultaneous mutation of two genes within the same pathway results in an extreme GI. Perturbation of any pair of genes within the same pathway results in e similar GI phenotype. (ii) Negative WPMs identify genes that belong to same essential pathway or complex while positive WPMs often identify nonessential pathways or complexes. (B) Between-pathway model (BPM). (i) Two biological pathways (or protein complexes) impinge on the same cellular function. Mutations in individual pathways do not result in a phenotype, but mutations in both pathways result in a GI. (ii) Any combination of mutations in both pathways will result in the same type of GI, either negative or positive. (C) Coherent WPM and BPM genetic interactions involving the 19S proteasome. (i) Protein complexes that show coherent negative or positive WPM or BPM GIs with the 19S proteasome are placed on a schematic representation of the global GI profile similarity network based on the average genetic interaction profile similarity of the complex and connected with negative (blue) or positive (yellow) edges, respectively. (ii) Genes belonging to a subset of protein complexes that showed coherent negative (blue) or positive (yellow) GIs with genes encoding the 19S proteasome. Adapted from [18].