High-Resolution CRISPR Screens Reveal Fitness Genes and Genotype-Specific Cancer Liabilities.

Cell 2015 Dec 25;163(6):1515-26. Epub 2015 Nov 25.

Donnelly Centre, 160 College Street, Toronto, ON M5S3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A1, Canada; Canadian Institute for Advanced Research, Toronto, ON M5G1Z8, Canada. Electronic address:

The ability to perturb genes in human cells is crucial for elucidating gene function and holds great potential for finding therapeutic targets for diseases such as cancer. To extend the catalog of human core and context-dependent fitness genes, we have developed a high-complexity second-generation genome-scale CRISPR-Cas9 gRNA library and applied it to fitness screens in five human cell lines. Using an improved Bayesian analytical approach, we consistently discover 5-fold more fitness genes than were previously observed. We present a list of 1,580 human core fitness genes and describe their general properties. Moreover, we demonstrate that context-dependent fitness genes accurately recapitulate pathway-specific genetic vulnerabilities induced by known oncogenes and reveal cell-type-specific dependencies for specific receptor tyrosine kinases, even in oncogenic KRAS backgrounds. Thus, rigorous identification of human cell line fitness genes using a high-complexity CRISPR-Cas9 library affords a high-resolution view of the genetic vulnerabilities of a cell.

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http://www.cell.com/cell/pdf/S0092-8674(15)01495-6.pdf
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http://www.cell.com/cms/attachment/2042476803/2055463631/mmc
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http://linkinghub.elsevier.com/retrieve/pii/S009286741501495
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http://dx.doi.org/10.1016/j.cell.2015.11.015DOI Listing
December 2015
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