Saturation-seq integrates single-cell saturation genome editing and RNA-seq to quantify NFE2L2 (NRF2) variant effects

Interpreting the functional consequences of variants remains one of the central unsolved problems in genomics and clinical genetics. Compounding this, most existing approaches rely on reductive, one-dimensional proxies such as cell growth to score variant effects, which can be a poor substitute for the rich, multidimensional phenotyping that is ultimately needed to understand how variants alter biology. This is especially true for variants known to act through gain-of-function/neomorphic mechanisms. We developed Saturation-seq, a high-throughput platform that combines saturation genome editing with single-cell DNA and RNA profiling to systematically map variant effects. Using CRISPR-based ed