Approaches for Mapping Unique Phenotype Screens To a Genetic Interaction Network

Abstract

Targeted and successful cellular therapies for disease treatment require an extensive mapping of the complex structure and dynamics of molecular mechanisms which determine the behaviour and function of cell. CELL-seq is a genome-wide screening procedure measuring specific and targeted protein quantities as phenotypic readouts and is employed by the Netherlands Cancer Institute to analyze which genes regulate the protein state of interest. This research aims to explore the current compendium of CELL-seq screens that investigate a range of phenotypes, to create a mapping of gene-gene associations that share similar phenotypic profiles and elucidate biology that is hard to uncover with more conventional screening techniques.

We perform exploratory research to investigate the ability of the screen compendium to show network structures that reflect known biological processes. We find that with stringent requirements on interactions the screen compendium shows enrichment for a wide range of biological processes and known protein-protein interactions. We further conclude that the experimental design biases network behaviour and needs to be accounted for when constructing networks. We recommended a mutual k-nearest neighbor network construction approach, which yielded networks with the most biological relevance.
We compare the CELL-seq screens using findings from the approaches to the DepMap dataset, a well-known collection of synthetic lethality CRISPR screens, and find that the behaviour of these datasets is in many ways mirrored. We conclude that this is both due to the biology they represent and the differences in the number of screens in each dataset. Finally, we compare the coverage of biological processes between the HAP1 compendium and DepMap, and show large overlap in their coverage. Nonetheless, the differences they do show leads us to bring forward two hypotheses for gene-gene interactions that score strongly uniquely in the CELL-seq networks which are biologically plausible but are not found in DepMap or curated literature, warranting future investigations.

All code pertaining to the methods and figures in this work are hosted on GitLab by the High Performance Computing Facility of the Netherlands Cancer Institute. As such the code can be viewed by supervisors, but further details could be shared upon request.