Fig. 10.

A complex interaction model for pathogenicity of the 16p11.2 deletion. a Examples of interactions from quantitative phenotyping data observed with pairwise knockdown of genes. Blue lines indicate modulation of GeneB expression in wild-type flies, while orange lines indicate modulation of GeneA expression when GeneB is also knocked down. GeneA knockdowns that have the same phenotype with or without GeneB knockdown indicate no interaction between the two genes (left). Epistatic interactions between fly homologs occur when the change in effect for two-hit knockdown flies compared to GeneA knockdown is less severe (suppressor) or more severe (enhancer) than that for GeneB knockdown compared to control (center). When the effect of GeneB knockdown is the same in wild-type flies and flies with GeneA knockdown, the two genes show an additive interaction (right). b Summary table listing all validated interactions with 16p11.2 Drosophila homologs found using screening of eye phenotypes. For epistatic interactions between fly homologs, blue-colored genes represent suppressors while red-colored genes indicate enhancers of the one-hit phenotype. Epistatic interactions with available Flynotyper data were confirmed using two-way ANOVA tests (p < 0.05, df = 1, F > 4.5202; see Supplementary Data 8). Bold genes are annotated for cell proliferation/cell cycle GO terms. *indicates observed cell organization/proliferation defects in the developing eye, and ^†indicates observed axonal targeting defects. c A model of pathogenicity of 16p11.2 deletion inferred from fly studies. The knockdown of individual 16p11.2 homologs in Drosophila contributes towards various neuronal or developmental phenotypes. However, pairwise knockdown of 16p11.2 homologs, or knockdown of 16p11.2 homologs with other modifier genes, leads to enhancement, suppression, or rescue of these phenotypes, ultimately resulting in variable phenotypes dependent on the extent of modulation