Online Program Home
My Program

Abstract Details

Activity Number: 180 - Statistical Methods for Functional Genomic and Epigenomic Data
Type: Contributed
Date/Time: Monday, July 29, 2019 : 10:30 AM to 12:20 PM
Sponsor: Section on Statistics in Genomics and Genetics
Abstract #304860
Title: Multiple-Gene Targeting and Mismatch Tolerance Can Confound Analysis of Genome-Wide Pooled CRISPR Screens
Author(s): Jean-Philippe Fortin* and Jenille Tan and Karen Gascoigne and Peter Haverty and William Forrest and Michael Costa and Scott Martin
Companies: Genentech and Genentech and Genentech and Genentech and Genentech, Inc and Genentech and Genentech
Keywords: CRISPR knockout screen; Functional genomics; Cancer vulnerabilities; CRISPR off-targets; CRISPR/Cas9

Genome-wide loss-of-function screens using the CRISPR/Cas9 system allow the efficient discovery of cancer cell vulnerabilities. While several studies have focused on correcting knockout effects for copy number alterations, the effects of sgRNAs co-targeting multiple genomic loci in CRISPR screens have not been discussed. We analyzed CRISPR essentiality screen data from 391 cancer cell lines to characterize biases induced by multi-target sgRNAs. We investigated two types of multi-targets: on-targets predicted through perfect sequence complementarity and off-targets predicted through sequence complementarity with up to two nucleotide mismatches. We found that the number of on-targets and off-targets both increase sgRNA activity and that existing additive models of gene knockout effects fail at capturing genetic interactions that may occur between co-targeted genes. We further found that single-mismatch tolerant sgRNAs can confound the analysis of gene essentiality and lead to incorrect co-essentiality functional networks. Lastly, we characterized the effects of single nucleotide polymorphisms on on-target activity as a result of mismatch tolerance.

Authors who are presenting talks have a * after their name.

Back to the full JSM 2019 program