Evidence map›Paper›PMID 33606977›Full record

ArticleCell2021

Massively parallel assessment of human variants with base editor screens.

Ruth E Hanna, Mudra Hegde, Christian R Fagre, Peter C DeWeirdt, Annabel K Sangree, Zsofia Szegletes, Audrey Griffith, Marissa N Feeley, Kendall R Sanson, Yossef Baidi and 4 more

Open access · bronzeAbstract read
PubMed Publisher
In one paragraph

Article in Cell, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 235 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
235citing papers in PubMed, 1 pooled it
19.6field-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

235 citing papers in PubMed, 1 synthesis or guideline pooled it, 318 citations in OpenAlex.

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175 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

14 authors at 2 institutions in 1 country.

Ruth E HannaGenetic Perturbation Platform, Broad Institute, Cambridge, MA 02142, USA.
Mudra HegdeGenetic Perturbation Platform, Broad Institute, Cambridge, MA 02142, USA.
Christian R FagreCancer Program, Broad Institute, Cambridge, MA 02142, USA.
Peter C DeWeirdtGenetic Perturbation Platform, Broad Institute, Cambridge, MA 02142, USA.
Annabel K SangreeGenetic Perturbation Platform, Broad Institute, Cambridge, MA 02142, USA.
Zsofia SzegletesGenetic Perturbation Platform, Broad Institute, Cambridge, MA 02142, USA.
Audrey GriffithGenetic Perturbation Platform, Broad Institute, Cambridge, MA 02142, USA.
Marissa N FeeleyGenetic Perturbation Platform, Broad Institute, Cambridge, MA 02142, USA.
Kendall R SansonGenetic Perturbation Platform, Broad Institute, Cambridge, MA 02142, USA.
Yossef BaidiCancer Program, Broad Institute, Cambridge, MA 02142, USA.
Luke W KoblanMerkin Institute of Transformative Technologies in Healthcare, Broad Institute, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
David R LiuMerkin Institute of Transformative Technologies in Healthcare, Broad Institute, Cambridge, MA 02142, USA; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA; Howard Hughes Medical Institute, Harvard University, Cambridge, MA 02138, USA.
James T NealCancer Program, Broad Institute, Cambridge, MA 02142, USA.
John G DoenchGenetic Perturbation Platform, Broad Institute, Cambridge, MA 02142, USA. Electronic address: jdoench@broadinstitute.org.
Broad Institute · USHarvard University · US

Funding

Expanding the Scope of Base EditingU01AI142756 · NIAID · BROAD INSTITUTE, INC. · PI LIU, DAVID R · 2018 to 2022
$2.1M
NIAID NIH HHS U01 AI142756
6 · The paper itself

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.

Indexed as

Gene EditingGenetic VariationHigh-Throughput Nucleotide SequencingAllelesBase Sequencebcl-X ProteinBRCA1 ProteinBRCA2 ProteinCatalytic DomainCell Line, TumorHumansLoss of Function MutationMutagenesisMyeloid Cell Leukemia Sequence 1 ProteinPoint MutationPoly(ADP-ribose) PolymerasesBCL2L1 protein, humanbcl-X ProteinBRCA1 ProteinBRCA2 ProteinMCL1 protein, humanMyeloid Cell Leukemia Sequence 1 ProteinPoly(ADP-ribose) Polymerasesapoptosisbase editingClinVarCRISPRDNA damagegenetic screensPARPi

Identifiers

PMID33606977
OpenAlexW3132864675

What OpenQuestion holds

Textmetadata
Read underepoch 390

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.