Efficient base editing in G/C-rich regions to model androgen insensitivity syndrome

Dear Editor,

Most disease-associated genomic mutations are base substitutions and approximately half of pathogenic human single nucleotide polymorphisms (SNPs) are related to C-to-T substitutions in the ClinVar database.¹ Base editors (BEs), which combine Cas9-D10A nickase and APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) or AID (activation-induced deaminase) cytidine deaminase family members,² have been successfully applied to mediate C-to-T conversion in vitro and in vivo,³ providing a powerful tool to model or repair disease-related human SNPs. Yet, the editing scope of BE3 was limited by the low editing efficiency at GpC dinucleotides and/or in regions with high CpG methylation levels.² We recently replaced rA1 with human APOBEC3A (hA3A) and then engineered hA3A isoform to develop a series of hA3A-BEs, including hA3A-BE3-Y130F, which has an editing window similar to BE3.⁴ As hA3A can deaminate both C and methylated C in various sequence contexts efficiently,⁵ hA3A-BE3-Y130F mediated efficient C-to-T base editing in GpC context and CpG context in vitro.⁴

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