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Cell. 2018 Aug 9;174(4):953-967.e22. doi: 10.1016/j.cell.2018.06.010. Epub 2018 Jul 19.

Mapping the Genetic Landscape of Human Cells.

Author information

1
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA; California Institute for Quantitative Biomedical Research, University of California, San Francisco, San Francisco, CA 94158, USA.
2
Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA 94305, USA.
3
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA.
4
Innovative Genomics Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
5
Center for Advanced Technology, Department of Biophysics and Biochemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
6
Institute for Neurodegenerative Diseases and Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, CA 94158, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
7
Department of Internal Medicine, Division of Bone and Mineral Diseases, and Department of Genetics, Institute for Public Health, Washington University School of Medicine, 425 S. Euclid Ave., St. Louis, MO 63110, USA.
8
Gladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA.
9
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA; California Institute for Quantitative Biomedical Research, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: jonathan.weissman@ucsf.edu.
10
Department of Urology, University of California, San Francisco, San Francisco, CA 94158, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: luke.gilbert@ucsf.edu.

Abstract

Seminal yeast studies have established the value of comprehensively mapping genetic interactions (GIs) for inferring gene function. Efforts in human cells using focused gene sets underscore the utility of this approach, but the feasibility of generating large-scale, diverse human GI maps remains unresolved. We developed a CRISPR interference platform for large-scale quantitative mapping of human GIs. We systematically perturbed 222,784 gene pairs in two cancer cell lines. The resultant maps cluster functionally related genes, assigning function to poorly characterized genes, including TMEM261, a new electron transport chain component. Individual GIs pinpoint unexpected relationships between pathways, exemplified by a specific cholesterol biosynthesis intermediate whose accumulation induces deoxynucleotide depletion, causing replicative DNA damage and a synthetic-lethal interaction with the ATR/9-1-1 DNA repair pathway. Our map provides a broad resource, establishes GI maps as a high-resolution tool for dissecting gene function, and serves as a blueprint for mapping the genetic landscape of human cells.

KEYWORDS:

CRISPR; CRISPRi; epistasis; functional genomics; genetic interactions

PMID:
30033366
PMCID:
PMC6426455
DOI:
10.1016/j.cell.2018.06.010
[Indexed for MEDLINE]
Free PMC Article

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