Evidence map›Paper›PMID 34183861›Full record

ArticleNature biotechnology2021

Efficient C•G-to-G•C base editors developed using CRISPRi screens, target-library analysis, and machine learning.

Luke W Koblan, Mandana Arbab, Max W Shen, Jeffrey A Hussmann, Andrew V Anzalone, Jordan L Doman, Gregory A Newby, Dian Yang, Beverly Mok, Joseph M Replogle and 5 more

Erratum issuedOpen access · bronzeAbstract read
In one paragraph

Article in Nature biotechnology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 140 papers.

0numbers the graph read from it
0cells of the map it votes in
140citing papers in PubMed
12.9field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

140 citing papers in PubMed, 204 citations in OpenAlex.

  1. Base Editing: Mechanisms and Therapeutic Applications.Methods in molecular biology (Clifton, N.J.) · 2027
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80 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

15 authors at 4 institutions in 1 country.

Luke W Koblan *Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA, USA.ORCID http://orcid.org/0000-0003-2814-4412
Mandana Arbab *Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Max W Shen *Merkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-4226-1861
Jeffrey A HussmannDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.ORCID http://orcid.org/0000-0002-7778-9893
Andrew V AnzaloneMerkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Jordan L DomanMerkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-9887-0391
Gregory A NewbyMerkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA, USA.ORCID http://orcid.org/0000-0001-7869-2615
Dian YangDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.
Beverly MokMerkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Joseph M ReplogleDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.ORCID http://orcid.org/0000-0003-1832-919X
Albert XuDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA.ORCID http://orcid.org/0000-0001-5938-561X
Tyler A SisleyDepartment of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-7711-6234
Jonathan S WeissmanDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA. weissman@wi.mit.edu.ORCID http://orcid.org/0000-0003-2445-670X
Britt AdamsonDepartment of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA. badamson@princeton.edu.ORCID http://orcid.org/0000-0002-9451-5819
David R LiuMerkin Institute of Transformative Technologies in Healthcare, Broad Institute of Harvard and MIT, Cambridge, MA, USA. drliu@fas.harvard.edu.ORCID http://orcid.org/0000-0002-9943-7557
Broad Institute · USHoward Hughes Medical Institute · USHarvard University · USUniversity of California, San Francisco · US

Funding

TRANSCRIPTIONAL PROFILINGP30CA072720 · NCI · UNIV OF MED/DENT NJ-R W JOHNSON MED SCH · PI Tracie Saunders · 1997 to 2026
$94.5M
Center for Genomic Editing and Recording: Development and Application of Next-Generation Genome and Epigenome Editing Methods to Advance the Study and Treatment of Human DiseaseRM1HG009490 · NHGRI · WHITEHEAD INSTITUTE FOR BIOMEDICAL RES · PI Brittany S. Adamson, Martin Joseph Ankrah Aryee · 2017 to 2026
$22.7M
Integrating Chemistry and Evolution to Illuminate Biology and Enable Novel TherapeuticsR35GM118062 · NIGMS · HARVARD UNIVERSITY · PI LIU, DAVID R · 2016 to 2025
$6.4M
Graduate Training in Computational and Systems BiologyT32GM087237 · NIGMS · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI BURGE, CHRISTOPHER B · 2009 to 2023
$4.6M
Mapping the DNA damage response in human cells with high-resolution functional genomicsR35GM138167 · NIGMS · PRINCETON UNIVERSITY · PI Brittany S. Adamson · 2020 to 2026
$2.4M
Delivery Technologies for In Vivo Genome EditingUG3AI150551 · NIAID · BETH ISRAEL DEACONESS MEDICAL CENTER · PI CHAIKOF, ELLIOT · 2019 to 2021
$2.3M
Expanding the Scope of Base EditingU01AI142756 · NIAID · BROAD INSTITUTE, INC. · PI LIU, DAVID R · 2018 to 2022
$2.1M
The role of TMA7 in mitochondrial dysfunctionF31NS115380 · NINDS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI REPLOGLE, JOSEPH · 2019 to 2020
$75k
Howard Hughes Medical InstituteNCI NIH HHS P30 CA072720NHGRI NIH HHS RM1 HG009490NIAID NIH HHS U01 AI142756NIAID NIH HHS UG3 AI150551NIGMS NIH HHS R35 GM118062NIGMS NIH HHS R35 GM138167NIGMS NIH HHS T32 GM087237NINDS NIH HHS F31 NS115380
6 · The paper itself

Abstract

Programmable C•G-to-G•C base editors (CGBEs) have broad scientific and therapeutic potential, but their editing outcomes have proved difficult to predict and their editing efficiency and product purity are often low. We describe a suite of engineered CGBEs paired with machine learning models to enable efficient, high-purity C•G-to-G•C base editing. We performed a CRISPR interference (CRISPRi) screen targeting DNA repair genes to identify factors that affect C•G-to-G•C editing outcomes and used these insights to develop CGBEs with diverse editing profiles. We characterized ten promising CGBEs on a library of 10,638 genomically integrated target sites in mammalian cells and trained machine learning models that accurately predict the purity and yield of editing outcomes (R = 0.90) using these data. These CGBEs enable correction to the wild-type coding sequence of 546 disease-related transversion single-nucleotide variants (SNVs) with >90% precision (mean 96%) and up to 70% efficiency (mean 14%). Computational prediction of optimal CGBE-single-guide RNA pairs enables high-purity transversion base editing at over fourfold more target sites than achieved using any single CGBE variant.

Indexed as

Clustered Regularly Interspaced Short Palindromic RepeatsGene EditingAnimalsCRISPR-Cas SystemsMachine LearningMammalsRNA, Guide, CRISPR-Cas SystemsRNA, Guide, CRISPR-Cas Systems

Identifiers

PMID34183861
PMCPMC8985520
OpenAlexW3174716159

What OpenQuestion holds

Textmetadata
LicenceTDM
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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.