Figure 2

Chemogenomic signatures of P. falciparum piggyBac mutants.

(a) Chemogenomic signatures of P. falciparum piggyBac mutants organized according to similarity in phenotypic profiles by 2-dimensional hierarchical clustering. Chemogenomic signatures for each piggyBac mutant consist of the RPR [GI_50pB over GI_50WT (GI_50pB/GI_50WT), where the GI₅₀ is based on growth curves, R² of >0.9] for a diverse collection of target-specific inhibitors (Table S8). The intensity of the blue color is proportional to the resistance of a mutant to an inhibitor and intensity of yellow indicates sensitivity. All data were log₂ transformed and relative phenotypic ratios (RPR) were used to construct correlations. (b) A drug-drug network based on chemogenomic profiling of the piggyBac mutants contained 47 nodes and 415 edges representing about 19% of the maximum possible pairwise interactions attainable. A drug pair was considered as interacting (blue lines) if its observed correlation coefficient was greater or equal to that observed in 1000 permutations of the same drug pair (Permutation test, P < 0.001). Edges between drug pairs acting in the same pathway demonstrate drug:drug relationships within the chemogenomic profiles. Color coding identifies common GO categories of biological pathways. (c) A piggyBac gene:gene interaction network created from chemogenomic response profiles of 71 piggyBac mutants (see also Table S7). The edges represent piggyBac mutants with highly correlated chemogenomic response profiles, where the correlation coefficients were greater than or equal to that observed in 1000 permutations (Permutation test, P < 0.001) of the chemogenomic profiles for each node pair). Solid edges indicate a cluster of highly interconnected nodes (as identified by MCODE in cytoscape³⁶) and dashed edges indicate non-cluster edges. The largest cluster has increased ART susceptibility, referred to as the K13 Kelch cluster with the addition of PF3D7_1001600 and PF3D7_1327100. Node size and color corresponds to DHA and QHS susceptibility, respectively, for each piggyBac mutant. Tightly interconnected regions of the network identified sets of genes with similar function within this gene-gene network^38,39.