Fig. 2: Top digenic and monogenic dependencies identified from combinatorial pgRNA CRISPR library analysis.

a, Calculation of the GI score to quantify synthetic lethality. The sum of the observed log₂(FC) for sgRNAs targeting gene A and gene B was calculated to determine the predicted log₂(FC) of that gene pair. The difference between the predicted and experimentally observed log₂(FC) was also calculated. b, Number of significantly depleted gene pairs across the cell lines screened. c, Dot plot depicting top synthetic lethal gene pairs from the combinatorial CRISPR screen that were common to at least 6 of the 10 screened cell lines, ranked (top to bottom) by descending mean GI score. Each dot represents the GI score of a given gene pair in a single cell line. All gene pairs had previously been screened across five independent CRISPR combinatorial screens and are colored by whether they were reported to be synthetic lethal in those studies^{19,20,21,22,23}. Any pair where one of the genes was defined as lethal on its own was removed. d, Dot plot depicting significantly depleted single genes (genes with an STG) that were defined by Ensembl to have a paralog and common to at least six of the ten screened cell lines, ranked (top to bottom) by descending mean normalized log₂(FC). log₂(FCs) are normalized so that the median of the STGs was 0 and the median of the reference essential guides was −1. Genes are labeled with their paralog in parentheses. Each dot represents a cell line. Color indicates the synthetic lethality across five previous combinatorial CRISPR screens^{19,20,21,22,23}. A nonhit (gray) denotes a gene not previously reported to have a synthetic lethal interaction with its partner. Significance was defined using an FDR < 0.05 (Methods). e, Correlation between INTS6L expression and INTS6 gene essentiality in 316 Project Score⁴⁷ cell lines, and the same for CDS1/CDS2. Low expressers (log₂(TPM + 1) < 1) versus high expressers (log₂(TPM + 1) ≥ 1) were defined using expression profiles from Cell Model Passports. Significance was determined by a t test (two-sided, equal variance). Box and whisker plots indicate median and 5th to 95th percentiles; points are outliers.