Abstract

Genome-scale fitness screens provide unparalleled insight into mammalian functional genomics, identify candidate tumor-specific genetic vulnerabilities, and enable the construction of coessentiality networks for inferring gene function. However, the “paralog gap” highlights a key blind spot of monogenic CRISPR screens: functional buffering by redundant genes is systematically missed in these assays. This seminar offers a systematic analysis of CRISPR multiplex platforms and describes advances in the Cas12a system for digenic and higher-order genetic interaction studies, with potential applications in the genetic modeling of polypharmacology and large-scale screens for synthetic lethality.