A genome-wide almanac of co-essential modules assigns function to uncharacterized genes
Open accessPreprint — published as 10.1038/s41588-021-00840-z · Paper page
Abstract
SUMMARY: A central remaining question in the post-genomic era is how genes interact to form biological pathways. Measurements of gene dependency across hundreds of cell lines have been used to cluster genes into ‘co-essential’ pathways, but this approach has been limited by ubiquitous false positives. Here, we develop a statistical method that enables robust identification of gene co-essentiality and yields a genome-wide set of functional modules. This almanac recapitulates diverse pathways and protein complexes and predicts the functions of 102 uncharacterized genes. Validating top predictions, we show that TMEM189 encodes plasmanylethanolamine desaturase, the long-sought key enzyme for plasmalogen synthesis. We also show that C15orf57 binds the AP2 complex, localizes to clathrin-coated pits, and enables efficient transferrin uptake. Finally, we provide an interactive web tool for the community to explore the results (coessentiality.net). Our results establish co-essentiality profiling as a powerful resource for biological pathway identification and discovery of novel gene functions.
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Co-essential genes were determined from Wainberg et al., 2019, which scored co-essentiality across genome-wide CRISPR screens in 485 cancer cell lines.
“Co-essential genes were determined from Wainberg et al., 2019, which scored co-essentiality of genes across genome-wide CRISPR screens in 485 cancer cell lines (Meyers et al., 2017) using a generalized least-squares regression.”
From Multimodal Analysis of Composition and Spatial Architecture in Human Squamous Cell Carcinoma (2020) · cites this paper as Wainberg et al., 2019
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- Authors
- Wainberg, M., Kamber, R. A., Balsubramani, A., Meyers, R. M., Sinnott-Armstrong, N., Hornburg, D., Jiang, L., Chan, J., Jian, R., Gu, M., Shcherbina, A., Dubreuil, M. M., Spees, K., Snyder, M. P., Kundaje, A., & Bassik, M. C.
- Affiliations
- Stanford University (US)
- Corresponding author
- Kundaje, Anshul
- Bassik, Michael C.
- ORCID
- Venue
- Nature Genetics
- Publisher
- openRxiv
- Published
- 2019-11-01
- Volume
- 53
- Issue
- 5
- Pages
- 638-649
- ISSN
- 1061-4036 (ISSN-L)
- PMC
- PMC8763319
- OpenAlex
- W3155528889
- Cited by
- 204
- References
- 0
- Citations by year
- 2026: 27 · 2025: 47 · 2024: 47 · 2023: 27 · 2022: 38 · 2021: 10 · 2020: 7 · 2019: 1
- FWCI
- 9.58
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Nature Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1dp2hd084069-01)
- Stanford Bio-X
- National Human Genome Research Institute (UM1HG009436)
- National Cancer Institute (T32CA009302)
- National Institute of General Medical Sciences (DP2GM123485)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (DP2 HD084069)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene Regulatory Network Analysis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- gene dependency, functional modules, plasmalogen synthesis, AP-2, clathrin-coated pits, transferrin uptake, protein complexes, cell lines
- MeSH terms
- Clathrin, Endocytosis, Gene Expression Regulation, Genes, HeLa Cells, Humans, Neoplasms, Plasmalogens, Signal Transduction, Genome, Epigenesis, Genetic, Gene Regulatory Networks, Molecular Sequence Annotation
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