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While several Cas9-derived base editors have been developed to induce either C-to-T or A-to-G 1 mutation at target genomic sites, the possible genome editing space when using the current base editors 2 remains limited. Here, we present a novel base editor, Target-ACE, which integrates the abilities of both 3 of the previously developed C-to-T and A-to-G base editors by fusing an activation-induced cytidine 4 deaminase (AID) and an engineered tRNA adenosine deaminase (TadA) to a catalytically impaired 5Streptococcus pyogenes Cas9. In mammalian cells, Target-ACE enabled heterologous editing of multiple 6 bases in a small sequence window of target sites with increased efficiency compared with a mixture of 7 two relevant base editor enzymes, each of which may block the same target DNA molecule from the 8 other. Furthermore, by modeling editing patterns using deep sequencing data, the editing spectra of 9Target-ACE and other base editors were simulated across the human genome, demonstrating the 10

No abstract