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Mapping information-rich genotype-phenotype landscapes with genome-scale Perturb-seq.
Replogle, Joseph M; Saunders, Reuben A; Pogson, Angela N; Hussmann, Jeffrey A; Lenail, Alexander; Guna, Alina; Mascibroda, Lauren; Wagner, Eric J; Adelman, Karen; Lithwick-Yanai, Gila; Iremadze, Nika; Oberstrass, Florian; Lipson, Doron; Bonnar, Jessica L; Jost, Marco; Norman, Thomas M; Weissman, Jonathan S.
Affiliation
  • Replogle JM; Medical Scientist Training Program, University of California, San Francisco, San Francisco, CA 94158, USA; Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San F
  • Saunders RA; Tetrad Graduate Program, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge,
  • Pogson AN; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technolo
  • Hussmann JA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technolo
  • Lenail A; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • Guna A; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • Mascibroda L; Department of Biochemistry & Molecular Biology, The University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA.
  • Wagner EJ; Department of Biochemistry & Molecular Biology, The University of Texas Medical Branch at Galveston, Galveston, TX 77555, USA; Department of Biochemistry & Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
  • Adelman K; Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
  • Lithwick-Yanai G; Ultima Genomics, Newark, CA 94560, USA.
  • Iremadze N; Ultima Genomics, Newark, CA 94560, USA.
  • Oberstrass F; Ultima Genomics, Newark, CA 94560, USA.
  • Lipson D; Ultima Genomics, Newark, CA 94560, USA.
  • Bonnar JL; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technolo
  • Jost M; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA.
  • Norman TM; Program for Computational and Systems Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: normantm@mskcc.org.
  • Weissman JS; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02142, USA; Whitehead Institute for Biomedical Research, Massachusetts Institute of Technolo
Cell ; 185(14): 2559-2575.e28, 2022 07 07.
Article in En | MEDLINE | ID: mdl-35688146
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Genomics / Single-Cell Analysis Language: En Journal: Cell Year: 2022 Document type: Article Country of publication: Estados Unidos
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Genomics / Single-Cell Analysis Language: En Journal: Cell Year: 2022 Document type: Article Country of publication: Estados Unidos