Nature, volume 576, issue 7785, pages 149-157

Search-and-replace genome editing without double-strand breaks or donor DNA

Anzalone Andrew V 1, 2, 3
Randolph Peyton B 1, 2, 3
Davis Jessie R 1, 2, 3
Sousa Alexander A 1, 2, 3
Koblan Luke W 1, 2, 3
Levy Jonathan M 1, 2, 3
Chen Peter J 1, 2, 3
Wilson Christopher 1, 2, 3
Newby Gregory A. 1, 2, 3
Raguram Aditya 1, 2, 3
Liu David R. 1, 2, 3
1
 
Department of chemistry and chemical biology, Harvard University, Cambridge, USA
3
 
Howard Hughes Medical Institute, Harvard University, Cambridge, USA
Publication typeJournal Article
Publication date2019-10-21
Journal: Nature
Quartile SCImago
Q1
Quartile WOS
Q1
Impact factor64.8
ISSN00280836, 14764687
Multidisciplinary
Abstract
Most genetic variants that contribute to disease1 are challenging to correct efficiently and without excess byproducts2–5. Here we describe prime editing, a versatile and precise genome editing method that directly writes new genetic information into a specified DNA site using a catalytically impaired Cas9 endonuclease fused to an engineered reverse transcriptase, programmed with a prime editing guide RNA (pegRNA) that both specifies the target site and encodes the desired edit. We performed more than 175 edits in human cells, including targeted insertions, deletions, and all 12 types of point mutation, without requiring double-strand breaks or donor DNA templates. We used prime editing in human cells to correct, efficiently and with few byproducts, the primary genetic causes of sickle cell disease (requiring a transversion in HBB) and Tay–Sachs disease (requiring a deletion in HEXA); to install a protective transversion in PRNP; and to insert various tags and epitopes precisely into target loci. Four human cell lines and primary post-mitotic mouse cortical neurons support prime editing with varying efficiencies. Prime editing shows higher or similar efficiency and fewer byproducts than homology-directed repair, has complementary strengths and weaknesses compared to base editing, and induces much lower off-target editing than Cas9 nuclease at known Cas9 off-target sites. Prime editing substantially expands the scope and capabilities of genome editing, and in principle could correct up to 89% of known genetic variants associated with human diseases. A new DNA-editing technique called prime editing offers improved versatility and efficiency with reduced byproducts compared with existing techniques, and shows potential for correcting disease-associated mutations.

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Anzalone A. V. et al. Search-and-replace genome editing without double-strand breaks or donor DNA // Nature. 2019. Vol. 576. No. 7785. pp. 149-157.
GOST all authors (up to 50) Copy
Anzalone A. V., Randolph P. B., Davis J. R., Sousa A. A., Koblan L. W., Levy J. M., Chen P. J., Wilson C., Newby G. A., Raguram A., Liu D. R. Search-and-replace genome editing without double-strand breaks or donor DNA // Nature. 2019. Vol. 576. No. 7785. pp. 149-157.
RIS |
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RIS Copy
TY - JOUR
DO - 10.1038/s41586-019-1711-4
UR - https://doi.org/10.1038%2Fs41586-019-1711-4
TI - Search-and-replace genome editing without double-strand breaks or donor DNA
T2 - Nature
AU - Anzalone, Andrew V
AU - Randolph, Peyton B
AU - Davis, Jessie R
AU - Sousa, Alexander A
AU - Koblan, Luke W
AU - Levy, Jonathan M
AU - Chen, Peter J
AU - Wilson, Christopher
AU - Newby, Gregory A.
AU - Raguram, Aditya
AU - Liu, David R.
PY - 2019
DA - 2019/10/21 00:00:00
PB - Springer Nature
SP - 149-157
IS - 7785
VL - 576
PMID - 31634902
SN - 0028-0836
SN - 1476-4687
ER -
BibTex |
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@article{2019_Anzalone
author = {Andrew V Anzalone and Peyton B Randolph and Jessie R Davis and Alexander A Sousa and Luke W Koblan and Jonathan M Levy and Peter J Chen and Christopher Wilson and Gregory A. Newby and Aditya Raguram and David R. Liu},
title = {Search-and-replace genome editing without double-strand breaks or donor DNA},
journal = {Nature},
year = {2019},
volume = {576},
publisher = {Springer Nature},
month = {oct},
url = {https://doi.org/10.1038%2Fs41586-019-1711-4},
number = {7785},
pages = {149--157},
doi = {10.1038/s41586-019-1711-4}
}
MLA
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Anzalone, Andrew V., et al. “Search-and-replace genome editing without double-strand breaks or donor DNA.” Nature, vol. 576, no. 7785, Oct. 2019, pp. 149-157. https://doi.org/10.1038%2Fs41586-019-1711-4.
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