Recovering false negatives in CRISPR fitness screens with JLOE.
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
28 02 2023
28 02 2023
Historique:
accepted:
16
01
2023
revised:
09
01
2023
received:
01
04
2022
pubmed:
3
2
2023
medline:
4
3
2023
entrez:
2
2
2023
Statut:
ppublish
Résumé
It is widely accepted that pooled library CRISPR knockout screens offer greater sensitivity and specificity than prior technologies in detecting genes whose disruption leads to fitness defects, a critical step in identifying candidate cancer targets. However, the assumption that CRISPR screens are saturating has been largely untested. Through integrated analysis of screen data in cancer cell lines generated by the Cancer Dependency Map, we show that a typical CRISPR screen has a ∼20% false negative rate, in addition to library-specific false negatives. Replicability falls sharply as gene expression decreases, while cancer subtype-specific genes within a tissue show distinct profiles compared to false negatives. Cumulative analyses across tissues improves our understanding of core essential genes and suggest only a small number of lineage-specific essential genes, enriched for transcription factors that define pathways of tissue differentiation. To recover false negatives, we introduce a method, Joint Log Odds of Essentiality (JLOE), which builds on our prior work with BAGEL to selectively rescue the false negatives without an increased false discovery rate.
Identifiants
pubmed: 36727483
pii: 7023819
doi: 10.1093/nar/gkad046
pmc: PMC9976895
doi:
Banques de données
figshare
['10.6084/m9.figshare.21865167.v1']
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1637-1651Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM130119
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016672
Pays : United States
Informations de copyright
© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.
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