High-throughput phenotyping of single nucleotide variants by linking transcriptomes to genotypes in single cells

CRISPR screens with single-cell transcriptomic readouts are a valuable tool to understand the effect of genetic perturbations, but are currently limited because genotypes are inferred from the guide RNA identity. We have developed a technique that couples single-cell genotyping to transcriptomics of the same cells to enable screening for the effects of single nucleotide variants. Analysis of variants tiling across the JAK1 gene demonstrates the importance of determining the precise genetic perturbation and classifies missense variants into three functional categories.