Improved analysis of CRISPR fitness screens and reduced off-target effects with the BAGEL2 gene essentiality classifier

Abstract

Identifying essential genes in genome-wide loss of function screens is a critical step in functional genomics and cancer target finding. We previously described the Bayesian Analysis of Gene Essentiality (BAGEL) algorithm for accurate classification of gene essentiality from short hairpin RNA and CRISPR/Cas9 genome wide genetic screens. Here, we introduce an updated version, BAGEL2, which employs an improved model that offers greater dynamic range of Bayes Factors, enabling detection of tumor suppressor genes, and a multi-target correction that reduces false positives from off-target CRISPR guide RNA. We also suggest a metric for screen quality at the replicate level and demonstrate how different algorithms handle lower-quality data in substantially different ways. BAGEL2 is written in Python 3 and source code, along with all supporting files, are available on github (https://github.com/hart-lab/bagel).