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Genome-wide target specificities of CRISPR RNA-guided programmable deaminases - Nature Biotechnology
Base editors composed of Cas9 fused to a deaminase show high specificity in genome-wide analyses. 
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Fusing a cytidine deaminase to dCas9 allows for a forward genetic screen in mammalian cells that identifies mutations conferring drug resistance.
BigField GEG Tech's insight:
Here the scientists report the fusion of activation-induced cytidine deaminase (AID) with nuclease-inactive clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (dCas9) for efficient genetic diversification, which enabled high-throughput screening of functional variants. By targeting BCR-ABL with dCas9-AIDx, they efficiently identified known and new mutations conferring imatinib resistance in chronic myeloid leukemia cells. Thus, targeted AID-mediated mutagenesis (TAM) provides a forward genetic tool to screen for gain-of-function variants at base resolution.
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The off-target activity of CRISPR system is largely unknown. Here the scientists modify digested-genome sequencing (Digenome-seq) to assess the specificity of a programmable deaminase composed of a Cas9 nickase (nCas9) and the deaminase APOBEC1 in the human genome. Digenome-seq is sensitive enough to capture off-target sites with a substitution frequency of 0.1%. Notably, off-target sites of the base editors are often different from those of Cas9 alone, calling for independent assessment of their genome-wide specificities.