Prof. Dr. Manuel Kaulich, Vivlion GmbH, Frankfurt
Systematic mapping of genetic interactions provides a powerful route to uncover functional gene networks and actionable vulnerabilities. While single-gene CRISPR screens identify essential genes, they fail to resolve buffering relationships, paralog dependencies, and higher-order pathway organization. Combinatorial CRISPR screening overcomes these limitations by directly interrogating pairwise genetic perturbations at scale. In my presentation, I will outline experimental and computational strategies for extracting functional gene modules from combinatorial CRISPR datasets, with a particular focus on the ubiquitin-proteasome system (UPS). Using Vivlion’s optimised dual-guide RNA libraries and scalable screening platforms, we generate quantitative genetic interaction maps in human cells. These interaction profiles enable the identification of synthetic lethal and buffering relationships and reveal connectivity patterns characteristic of protein complexes. By integrating high-content phenotyping with network-based computational analysis, combinatorial interaction signatures can be leveraged to infer active UPS complexes and assign poorly characterized genes to defined functional modules. This approach further facilitates mechanistic studies of targeted protein degraders and supports target deconvolution and combination strategies in early drug discovery. Combinatorial genetics thus provides a systematic framework to move from perturbation data to functional complex-level insights, enabling the extraction of biologically and pharmacologically relevant modules that remain inaccessible to single-gene screening approaches.
