Extended Data Fig. 1: Single-gene perturbation screens potentially miss dependencies of functionally paralogous genes.

(a) Stacked bar graph showing the percentage of non-essential or pan-essential human genes with or without paralogs. (b) Box and whisker plots for trametinib (BRD:BRD-K12343256-001-08-9) sensitivity from the Cancer Therapeutics Response Portal (CTRPv2.0_2015 dataset; https://portals.broadinstitute.org/ctrp/). Trametinib was dosed at 16 concentrations in duplicate. Percent-viability curves were fit and the area-under-concentration-response curve (AUC) was calculated. The AUCs of NRAS^MUT (n=31) and NRAS^WT (n=485) cells are shown (left). NRAS, MAP2K1, and MAP2K2 CERES dependence scores in NRAS^MUT (n=47) and NRAS^WT (n=692) cells from DepMap screen (right). The centerline, lower hinge, and upper hinge correspond to the 50th, 25th, and 75th percentiles, respectively. The upper and lower whiskers extend from the upper and lower hinges to the largest and smallest values no further than 1.5 * IQR (interquartile range). All observations beyond the whiskers are shown in black dots. Two-sided Wilcox P-values are shown. (c) Schematic of the dual sgRNA cloning strategy. (d) Library representation for pDNA from Digenic Paralog, Big Papi, CDKO and early time point gDNA from Shen-Mali (combined from 293T, A549, and HeLa) and Zhao-Mali (combined from A549 and Hela). (e) Mismatch reads were calculated as the percentage of reads with unintended pairs of sgRNAs from the pDNA and gDNA (at 21 days post library transduction).