Building a Genome-Wide Atlas of Cell Morphology
Authors:
James Neal* ([email protected], PI)
Institutions:
Broad Institute of Massachusetts Institute of Technology and Harvard University
Abstract
A key challenge of the modern genomics era is developing empirical data-driven representations of gene function. This study presents the first unbiased morphology- based genome-wide perturbation atlas in human cells, containing three genome-wide genotype-phenotype maps comprising CRISPR/Cas9-based knockouts of >20,000 genes in >30 million cells. The optical pooled cell profiling platform (PERISCOPE) combines a de-stainable high-dimensional phenotyping panel (based on cell painting) with optical sequencing of molecular barcodes and a scalable open-source analysis pipeline to facilitate massively parallel screening of pooled perturbation libraries. This perturbation atlas comprises high-dimensional phenotypic profiles of individual cells with sufficient resolution to cluster thousands of human genes, reconstruct known pathways and protein-protein interaction networks, interrogate subcellular processes, and identify culture media-specific responses. Using this atlas, researchers identified the poorly characterized disease-associated TMEM251/LYSET as a Golgi-resident transmembrane protein essential for mannose-6-phosphate-dependent trafficking of lysosomal enzymes. In summary, this perturbation atlas and screening platform represents a rich and accessible resource for connecting genes to cellular functions at scale.