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Computational correction of copy number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells.

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Date
2017-12
Authors
Meyers, Robin M
Bryan, Jordan G
McFarland, James M
Weir, Barbara A
Sizemore, Ann E
Xu, Han
Dharia, Neekesh V
Montgomery, Phillip G
Cowley, Glenn S
Pantel, Sasha
Goodale, Amy
Lee, Yenarae
Ali, Levi D
Jiang, Guozhi
Lubonja, Rakela
Harrington, William F
Strickland, Matthew
Wu, Ting
Hawes, Derek C
Zhivich, Victor A
Wyatt, Meghan R
Kalani, Zohra
Chang, Jaime J
Okamoto, Michael
Stegmaier, Kimberly
Golub, Todd R
Boehm, Jesse S
Vazquez, Francisca
Root, David E
Hahn, William C
Tsherniak, Aviad
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(31 total)
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Abstract
The CRISPR-Cas9 system has revolutionized gene editing both at single genes and in multiplexed loss-of-function screens, thus enabling precise genome-scale identification of genes essential for proliferation and survival of cancer cells. However, previous studies have reported that a gene-independent antiproliferative effect of Cas9-mediated DNA cleavage confounds such measurement of genetic dependency, thereby leading to false-positive results in copy number-amplified regions. We developed CERES, a computational method to estimate gene-dependency levels from CRISPR-Cas9 essentiality screens while accounting for the copy number-specific effect. In our efforts to define a cancer dependency map, we performed genome-scale CRISPR-Cas9 essentiality screens across 342 cancer cell lines and applied CERES to this data set. We found that CERES decreased false-positive results and estimated sgRNA activity for both this data set and previously published screens performed with different sgRNA libraries. We further demonstrate the utility of this collection of screens, after CERES correction, for identifying cancer-type-specific vulnerabilities.
Type
Journal article
Subject
Cell Line, Tumor
Humans
Neoplasms
Genetic Predisposition to Disease
Sensitivity and Specificity
Reproducibility of Results
Computational Biology
Gene Dosage
Algorithms
Models, Genetic
DNA Copy Number Variations
CRISPR-Cas Systems
Permalink
https://hdl.handle.net/10161/22386
Published Version (Please cite this version)
10.1038/ng.3984
Publication Info
Meyers, Robin M; Bryan, Jordan G; McFarland, James M; Weir, Barbara A; Sizemore, Ann E; Xu, Han; ... Tsherniak, Aviad (2017). Computational correction of copy number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells. Nature genetics, 49(12). pp. 1779-1784. 10.1038/ng.3984. Retrieved from https://hdl.handle.net/10161/22386.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Bryan

Jordan Bryan

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