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

View ORCID ProfileRobin M. Meyers, Jordan G. Bryan, View ORCID ProfileJames M. McFarland, Barbara A. Weir, Ann E. Sizemore, Han Xu, Neekesh V. Dharia, Phillip G. Montgomery, Glenn S. Cowley, Sasha Pantel, Amy Goodale, Yenarae Lee, Levi D. Ali, Guozhi Jiang, Rakela Lubonja, William F. Harrington, Matthew Strickland, Ting Wu, Derek C. Hawes, Victor A. Zhivich, Meghan R. Wyatt, Zohra Kalani, Jaime J. Chang, Michael Okamoto, Todd R. Golub, Jesse S. Boehm, Francisca Vazquez, David E. Root, William C. Hahn, View ORCID ProfileAviad Tsherniak
doi: https://doi.org/10.1101/160861
Robin M. Meyers
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
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Jordan G. Bryan
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
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James M. McFarland
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
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Barbara A. Weir
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
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Ann E. Sizemore
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
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Han Xu
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
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Neekesh V. Dharia
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
2Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215 USA
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Phillip G. Montgomery
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
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Glenn S. Cowley
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
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Sasha Pantel
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
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Amy Goodale
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
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Yenarae Lee
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
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Levi D. Ali
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
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Guozhi Jiang
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
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Rakela Lubonja
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
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William F. Harrington
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
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Matthew Strickland
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
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Ting Wu
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
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Derek C. Hawes
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
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Victor A. Zhivich
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
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Meghan R. Wyatt
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
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Zohra Kalani
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
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Jaime J. Chang
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
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Michael Okamoto
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
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Todd R. Golub
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
2Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215 USA
3Harvard Medical School, 25 Shattuck Street, Boston, MA 02115 USA
4Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815 USA
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Jesse S. Boehm
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
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Francisca Vazquez
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
2Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215 USA
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David E. Root
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
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William C. Hahn
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
2Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215 USA
3Harvard Medical School, 25 Shattuck Street, Boston, MA 02115 USA
5Department of Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115
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  • For correspondence: aviad@broadinstitute.org william_hahn@dfci.harvard.edu
Aviad Tsherniak
1Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142 USA
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  • ORCID record for Aviad Tsherniak
  • For correspondence: aviad@broadinstitute.org william_hahn@dfci.harvard.edu
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Abstract

The CRISPR-Cas9 system has revolutionized gene editing both on single genes and in multiplexed loss-of-function screens, enabling precise genome-scale identification of genes essential to proliferation and survival of cancer cells. However, previous studies reported that an anti-proliferative effect of Cas9-mediated DNA cleavage confounds such measurement of genetic dependency, particularly in the setting of copy number gain1-4. We performed genome-scale CRISPR-Cas9 essentiality screens on 342 cancer cell lines and found that this effect is common to all lines, leading to false positive results when targeting genes 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, as well as variable sgRNA activity. We applied CERES to sets of screens performed with different sgRNA libraries and found that it reduces false positive results and provides meaningful estimates of sgRNA activity. As a result, the application of CERES improves confidence in the interpretation of genetic dependency data from CRISPR-Cas9 essentiality screens of cancer cell lines.

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Posted July 10, 2017.
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Computational correction of copy-number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells
Robin M. Meyers, Jordan G. Bryan, James M. McFarland, Barbara A. Weir, Ann E. Sizemore, Han Xu, Neekesh V. Dharia, Phillip G. Montgomery, Glenn S. Cowley, Sasha Pantel, Amy Goodale, Yenarae Lee, Levi D. Ali, Guozhi Jiang, Rakela Lubonja, William F. Harrington, Matthew Strickland, Ting Wu, Derek C. Hawes, Victor A. Zhivich, Meghan R. Wyatt, Zohra Kalani, Jaime J. Chang, Michael Okamoto, Todd R. Golub, Jesse S. Boehm, Francisca Vazquez, David E. Root, William C. Hahn, Aviad Tsherniak
bioRxiv 160861; doi: https://doi.org/10.1101/160861
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Computational correction of copy-number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells
Robin M. Meyers, Jordan G. Bryan, James M. McFarland, Barbara A. Weir, Ann E. Sizemore, Han Xu, Neekesh V. Dharia, Phillip G. Montgomery, Glenn S. Cowley, Sasha Pantel, Amy Goodale, Yenarae Lee, Levi D. Ali, Guozhi Jiang, Rakela Lubonja, William F. Harrington, Matthew Strickland, Ting Wu, Derek C. Hawes, Victor A. Zhivich, Meghan R. Wyatt, Zohra Kalani, Jaime J. Chang, Michael Okamoto, Todd R. Golub, Jesse S. Boehm, Francisca Vazquez, David E. Root, William C. Hahn, Aviad Tsherniak
bioRxiv 160861; doi: https://doi.org/10.1101/160861

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