Models, Inference, Algorithms
September 28, 2022
Broad Institute of MIT and Harvard

Mapping informationrich genotypephenotype landscapes with genomescale Perturbseq
September 28, 2022
Reuben Saunders
University of California, San Francisco
A central goal of genetics is to define the relationships between genotypes and phenotypes. Highcontent phenotypic screens such as Perturbseq (CRISPRbased screens with singlecell RNAsequencing readouts) enable massively parallel functional genomic mapping but, to date, have been used at limited scales. Here, we perform genomescale Perturbseq targeting all expressed genes with CRISPR interference (CRISPRi) across greater than 2.5 million human cells. We use transcriptional phenotypes to predict the function of poorly characterized genes, uncovering new regulators of ribosome biogenesis (including CCDC86, ZNF236, and SPATA5L1), transcription (C7orf26), and mitochondrial respiration (TMEM242). In addition to assigning gene function, singlecell transcriptional phenotypes allow for indepth dissection of complex cellular phenomena—from RNA processing to differentiation. We leverage this ability to systematically identify genetic drivers and consequences of aneuploidy and to discover an unanticipated layer of stressspecific regulation of the mitochondrial genome. Our informationrich genotypephenotype map reveals a multidimensional portrait of gene and cellular function.

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