TY - JOUR T1 - Decoding directional genetic dependencies through orthogonal CRISPR/Cas screens JF - bioRxiv DO - 10.1101/120170 SP - 120170 AU - Michael Boettcher AU - Ruilin Tian AU - James Blau AU - Evan Markegard AU - David Wu AU - Anne Biton AU - Noah Zaitlen AU - Frank McCormick AU - Martin Kampmann AU - Michael T. McManus Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/03/25/120170.abstract N2 - Genetic interaction studies are a powerful approach to identify functional interactions between genes. This approach can reveal networks of regulatory hubs and connect uncharacterised genes to well-studied pathways. However, this approach has previously been limited to simple gene inactivation studies. Here, we present an orthogonal CRISPR/Cas-mediated genetic interaction approach that allows the systematic activation of one gene while simultaneously knocking out a second gene in the same cell. We have developed this concept into a quantitative and scalable combinatorial screening platform that allows the parallel interrogation of hundreds of thousands of genetic interactions. We demonstrate that the established platform works robustly to uncover genetic interactions in human cancer cells and to interpret the direction of the flow of genetic information. ER -