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Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage

Nature volume 551, pages 464471 (23 November 2017) | Download Citation


The spontaneous deamination of cytosine is a major source of transitions from C•G to T•A base pairs, which account for half of known pathogenic point mutations in humans. The ability to efficiently convert targeted A•T base pairs to G•C could therefore advance the study and treatment of genetic diseases. The deamination of adenine yields inosine, which is treated as guanine by polymerases, but no enzymes are known to deaminate adenine in DNA. Here we describe adenine base editors (ABEs) that mediate the conversion of A•T to G•C in genomic DNA. We evolved a transfer RNA adenosine deaminase to operate on DNA when fused to a catalytically impaired CRISPR–Cas9 mutant. Extensive directed evolution and protein engineering resulted in seventh-generation ABEs that convert targeted A•T base pairs efficiently to G•C (approximately 50% efficiency in human cells) with high product purity (typically at least 99.9%) and low rates of indels (typically no more than 0.1%). ABEs introduce point mutations more efficiently and cleanly, and with less off-target genome modification, than a current Cas9 nuclease-based method, and can install disease-correcting or disease-suppressing mutations in human cells. Together with previous base editors, ABEs enable the direct, programmable introduction of all four transition mutations without double-stranded DNA cleavage.

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Change history

  • Corrected online 02 May 2018

    Please see accompanying Publisher correction ( In this Article, owing to an error during the production process, in Fig. 1a, the dark blue and light blue wedges were incorrectly labelled as 'G•C  →  T•A' and 'G•C  → A•T', instead of 'C•G  → T•A' and 'C•G  → A•T', respectively. This error has been corrected online.


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This work was supported by DARPA HR0011-17-2-0049, US NIH RM1 HG009490, R01 EB022376, and R35 GM118062, and HHMI. A.C.K. and D.I.B. were Ruth L. Kirchstein National Research Service Awards Postdoctoral Fellows (F32 GM 112366 and F32 GM106621, respectively). M.S.P. was an NSF Graduate Research Fellow and was supported by training grant T32 GM008313. We thank Z. Niziolek for technical assistance. N.M.G. thanks A. E. Martin for his encouragement.

Author information

Author notes

    • Alexis C. Komor
    • , Michael S. Packer
    •  & David I. Bryson

    Present addresses: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093, USA (A.C.K.); Beam Therapeutics, 675 West Kendall Street, Cambridge, Massachusetts 02139, USA (M.S.P., D.I.B.).


  1. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA

    • Nicole M. Gaudelli
    • , Alexis C. Komor
    • , Holly A. Rees
    • , Michael S. Packer
    • , Ahmed H. Badran
    • , David I. Bryson
    •  & David R. Liu
  2. Howard Hughes Medical Institute, Harvard University, Cambridge, Massachusetts 02138, USA

    • Nicole M. Gaudelli
    • , Alexis C. Komor
    • , Holly A. Rees
    • , Michael S. Packer
    • , Ahmed H. Badran
    • , David I. Bryson
    •  & David R. Liu
  3. Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA

    • Nicole M. Gaudelli
    • , Alexis C. Komor
    • , Holly A. Rees
    • , Michael S. Packer
    • , Ahmed H. Badran
    • , David I. Bryson
    •  & David R. Liu


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N.M.G designed the research, performed all evolution experiments, conducted human cell experiments, analysed data, and wrote the manuscript. A.C.K assisted with experimental design and human cell experiments and analysed data. H.A.R. performed HDR and off-target experiments. M.S.P. performed computational data analyses and developed HTS processing scripts. A.H.B contributed to selection design and evolution strategy. D.I.B. assisted with cloning of late-stage ABEs. D.R.L designed and supervised the research and wrote the manuscript. All of the authors contributed to editing the manuscript.

Competing interests

N.M.G., A.C.K., and D.R.L. have filed patent applications on this work. D.R.L. is a consultant and co-founder of Editas Medicine, Beam Therapeutics, and Pairwise Plants, companies that use genome editing technologies.

Corresponding author

Correspondence to David R. Liu.

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