Mapping information-rich genotype-phenotype landscapes with genome-scale Perturb-seq Journal Article


Authors: Replogle, J. M.; Saunders, R. A.; Pogson, A. N.; Hussmann, J. A.; Lenail, A.; Guna, A.; Mascibroda, L.; Wagner, E. J.; Adelman, K.; Lithwick-Yanai, G.; Iremadze, N.; Oberstrass, F.; Lipson, D.; Bonnar, J. L.; Jost, M.; Norman, T. M.; Weissman, J. S.
Article Title: Mapping information-rich genotype-phenotype landscapes with genome-scale Perturb-seq
Abstract: A central goal of genetics is to define the relationships between genotypes and phenotypes. High-content phenotypic screens such as Perturb-seq (CRISPR-based screens with single-cell RNA-sequencing readouts) enable massively parallel functional genomic mapping but, to date, have been used at limited scales. Here, we perform genome-scale Perturb-seq targeting all expressed genes with CRISPR interference (CRISPRi) across >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, single-cell transcriptional phenotypes allow for in-depth 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 stress-specific regulation of the mitochondrial genome. Our information-rich genotype-phenotype map reveals a multidimensional portrait of gene and cellular function. © 2022 The Authors
Keywords: genetics; phenotype; genotype; genomics; chromosomal instability; chromosome mapping; cell biology; single cell analysis; single-cell analysis; procedures; genetic screens; integrator complex; crispr; crispr cas system; crispr-cas systems; chromosomal mapping; single-cell rna sequencing; genotype-phenotype map; mitochondrial genome stress response; perturb-seq
Journal Title: Cell
Volume: 185
Issue: 14
ISSN: 0092-8674
Publisher: Cell Press  
Date Published: 2022-07-07
Start Page: 2559
End Page: 2575.e28
Language: English
DOI: 10.1016/j.cell.2022.05.013
PUBMED: 35688146
PROVIDER: scopus
PMCID: PMC9380471
DOI/URL:
Notes: Article -- Export Date: 1 August 2022 -- Source: Scopus
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  1. Thomas Maxwell Norman
    6 Norman