RT Journal Article SR Electronic T1 Mapping in vivo genetic interactomics through Cpf1 crRNA array screening JF bioRxiv FD Cold Spring Harbor Laboratory SP 153486 DO 10.1101/153486 A1 Ryan D. Chow A1 Guangchuan Wang A1 Adan Codina A1 Lupeng Ye A1 Sidi Chen YR 2017 UL http://biorxiv.org/content/early/2017/06/21/153486.abstract AB Genetic interactions lay the foundation of biological networks in virtually all organisms. Due to the complexity of mammalian genomes and cellular architectures, unbiased mapping of genetic interactions in vivo is challenging. Cpf1 is a single effector RNA-guided nuclease that enables multiplexed genome editing using crRNA arrays. Here we designed a Cpf1 crRNA array library targeting all pairwise permutations of the most significantly mutated nononcogenes, and performed double knockout screens in mice using a model of malignant transformation as well as a model of metastasis. CrRNA array sequencing revealed a quantitative landscape of all single and double knockouts. Enrichment, synergy and clonal analyses identified many unpredicted drivers and co-drivers of transformation and metastasis, with epigenetic factors as hubs of these highly connected networks. Our study demonstrates a powerful yet simple approach for in vivo mapping of unbiased genetic interactomes in mammalian species at a phenotypic level.