HIGH-RESOLUTION PHENOTYPIC PROFILING BASED ON THE COMPLEX ARCHITECTURE OF THE C

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We profile the collection of C. elegans genes whose inhibition leads to sterility using high-resolution imaging of the syncytial gonad, a complex tissue whose architecture depends on a spectrum of interacting cellular processes. Analysis of 94 visible features in the gonad partitioned the 554 sterile genes into 102 phenotypic classes, predicting functions for 106 of the 116 uncharacterized genes in the collection while also revealing new functions for previously studied genes. We developed a theoretical framework to assess the significance of functional links between specific gene pairs. Using this framework, we integrated our analysis with a prior time-lapse screen in early embryos to generate a network of 819 essential C. elegans genes that can be viewed at multiple levels of functional resolution. Analysis of specific gene sets in the network indicates that multi-parametric phenotypic profiling in a complex tissue in a multi-cellular organism yields functional maps with a resolution equivalent to genetic interaction-based profiling in unicellular eukaryotes. Mass spectrometry was used to validate our prediction (based on phenotype) that an unknown gene (K10D2.4) associated with the APC/C.