Combinatorial CRISPR Screen Identifies Fitness Effects of Gene Paralogues

Genetic redundancy has evolved as a way for human cells to survive the loss of genes that are single copy and essential in other organisms, but also allows tumours to survive despite having highly rearranged genomes. In this study we CRISPR screen 1191 gene pairs, including paralogues and known and predicted synthetic lethal interactions to identify 105 gene combinations whose co-disruption results in a loss of cellular fitness. 27 pairs influence fitness across multiple cell lines including the paralogues FAM50A/FAM50B, two genes of unknown function. Silencing of FAM50B occurs across a range of tumour types and in this context disruption of FAM50A reduces cellular fitness whilst promoting micronucleus formation and extensive perturbation of transcriptional programmes. Our studies reveal the fitness effects of FAM50A/FAM50B in cancer cells. Systematic screens for synthetic lethal gene pairs represent a powerful approach to define interactions that may be exploited in the clinic. Here, the authors use a dual-guide CRISPR screening approach to screen a curated selection of gene pairs across three cell lines and validate the Fam50a/Fam50b synthetic lethality was in isogenic cell models as well as in an in vivo setting.