Probing gene-variant-context interactions with multiplexed base and prime editing

Genome sequencing in healthy and diseased individuals continues to identify a broad spectrum of genetic variants associated with predisposition, progression, and therapeutic outcomes for diseases like cancer. While insights derived from these efforts have potential to guide clinical diagnoses and treatment decisions, the relative importance and functional impact of most genetic variants remain unknown. The mutational processes driving these events are also not static; instead, they continue to operate throughout disease evolution and further diversify the genetic and phenotypic landscape of malignant cells. We and others have recently developed scalable base and prime editing methods to systematically engineer and measure the phenotypes produced by thousands of mutations in their native context. In this talk, I will present our ongoing efforts to probe gene-variant-context interactions using multiplexed base and prime editing in cells and mice, which have allowed us to construct a rich compendium of functional interactions between genes, mutations, perturbations (e.g. drugs), and physiological contexts (e.g. tissues).