Cited by 317CRISPR and Genetic EngineeringRNA regulation and diseaseGenomics and Rare Diseases

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Massively parallel assessment of human variants with base editor screens

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Hanna, Ruth E., Hegde, Mudra, Fagre, Christian R., DeWeirdt, Peter C., Sangree, Annabel K., Szegletes, Zsofia, Griffith, Audrey, Feeley, Marissa N., Sanson, Kendall R., Baidi, Yossef, Koblan, Luke W., Liu, David R., Neal, James T., Doench, John G.·2021·Cell

DOI 10.1016/j.cell.2021.01.012

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Abstract

Understanding the functional consequences of single-nucleotide variants is critical to uncovering the genetic underpinnings of diseases, but technologies to characterize variants are limiting. Here, we leverage CRISPR-Cas9 cytosine base editors in pooled screens to scalably assay variants at endogenous loci in mammalian cells. We benchmark the performance of base editors in positive and negative selection screens, identifying known loss-of-function mutations in BRCA1 and BRCA2 with high precision. To demonstrate the utility of base editor screens to probe small molecule-protein interactions, we screen against BH3 mimetics and PARP inhibitors, identifying point mutations that confer drug sensitivity or resistance. We also create a library of single guide RNAs (sgRNAs) predicted to generate 52,034 ClinVar variants in 3,584 genes and conduct screens in the presence of cellular stressors, identifying loss-of-function variants in numerous DNA damage repair genes. We anticipate that this screening approach will be broadly useful to readily and scalably functionalize genetic variants.

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Authors: Hanna, R. E., Hegde, M., Fagre, C. R., DeWeirdt, P. C., Sangree, A. K., Szegletes, Z., Griffith, A., Feeley, M. N., Sanson, K. R., Baidi, Y., Koblan, L. W., Liu, D. R., Neal, J. T., & Doench, J. G.
Affiliations: Broad Institute (US)
Corresponding author: Doench, John G.
ORCID: Hanna, Ruth E.
Hegde, Mudra
Fagre, Christian R.
DeWeirdt, Peter C.
Sangree, Annabel K.
Szegletes, Zsofia
Griffith, Audrey
Feeley, Marissa N.
Baidi, Yossef
Koblan, Luke W.
Liu, David R.
Neal, James T.
Doench, John G.
Venue: Cell
Publisher: Elsevier BV
Published: 2021-02
Volume: 184
Issue: 4
Pages: 1064-1080.e20
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2021.01.012
OpenAlex: W3132864675
Cited by: 316
References: 81
Citations by year: 2026: 41 · 2025: 65 · 2024: 57 · 2023: 62 · 2022: 57 · 2021: 29
FWCI: 16.24
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 382 d)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Cell (publishedVersion)
bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
PubMed (publishedVersion)
Funders: National Science Foundation
National Institutes of Health
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords: single nucleotide variants, loss-of-function mutations, BRCA1, BRCA2, BH3 mimetics, PARP inhibitors, drug resistance, drug sensitivity, DNA repair genes, cellular stress, single guide RNA library, ClinVar variants
MeSH terms: Gene Editing, Loss of Function Mutation, Alleles, Base Sequence, Humans, Poly(ADP-ribose) Polymerases, Selection, Genetic, Genetic Variation, Reproducibility of Results, Mutagenesis, Point Mutation, BRCA1 Protein, Catalytic Domain, BRCA2 Protein, Cell Line, Tumor, bcl-X Protein, High-Throughput Nucleotide Sequencing, Myeloid Cell Leukemia Sequence 1 Protein

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Massively parallel assessment of human variants with base editor screens

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