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

Nature Genetics 49, 1779 (2017). doi:10.1038/ng.3984 Authors: 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, Kimberly Stegmaier, Todd R Golub, Jesse S Boehm, Francisca Vazquez, David E Root, William C Hahn & Aviad Tsherniak 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 activi...
Source: Nature Genetics - Category: Genetics & Stem Cells Authors: Tags: Letter Source Type: research