A Systematic Mammalian Genetic Interaction Map Reveals Pathways Underlying Ricin Susceptibility
Open accessAbstract
Genetic interaction (GI) maps, comprising pairwise measures of how strongly the function of one gene depends on the presence of a second, have enabled the systematic exploration of gene function in microorganisms. Here, we present a two-stage strategy to construct high-density GI maps in mammalian cells. First, we use ultracomplex pooled shRNA libraries (25 shRNAs/gene) to identify high-confidence hit genes for a given phenotype and effective shRNAs. We then construct double-shRNA libraries from these to systematically measure GIs between hits. A GI map focused on ricin susceptibility broadly recapitulates known pathways and provides many unexpected insights. These include a noncanonical role for COPI, a previously uncharacterized protein complex affecting toxin clearance, a specialized role for the ribosomal protein RPS25, and functionally distinct mammalian TRAPP complexes. The ability to rapidly generate mammalian GI maps provides a potentially transformative tool for defining gene function and designing combination therapies based on synergistic pairs.
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Human genetics has successfully identified genetic modifiers for neurodegeneration, such as RAB10 for APOE in Alzheimer's disease and TMEM106B for GRN in frontotemporal dementia.
“Genetic modifiers for neurodegeneration have been identified successfully through human genetics, such as RAB10 for APOE65 in Alzheimer’s Disease (variants in the RAB10 locus are linked to resilience in individuals carrying the high-risk APOE ε4 allele85), and TMEM106B for GRN66, 67 in frontotemporal dementia (SNPs affecting TMEM106B expression are protective in carriers of disease-associated GRN”
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Self-citation
- Authors
- Bassik, M. C., Kampmann, M., Lebbink, R. J., Wang, S., Hein, M. Y., Poser, I., Weibezahn, J., Horlbeck, M. A., Chen, S., Mann, M., Hyman, A. A., LeProust, E. M., McManus, M. T., & Weissman, J. S.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of California, San Francisco (US)
- Max Planck Institute of Biochemistry (DE)
- Max Planck Institute of Molecular Cell Biology and Genetics (DE)
- Agilent Technologies (United States) (US)
- Corresponding author
- Bassik, Michael C.
- Kampmann, Martin
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-02
- Volume
- 152
- Issue
- 4
- Pages
- 909-922
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3652613
- OpenAlex
- W2149843002
- Cited by
- 365
- References
- 67
- Citations by year
- 2026: 9 · 2025: 15 · 2024: 13 · 2023: 19 · 2022: 19 · 2021: 19 · 2020: 36 · 2019: 37 · 2018: 34 · 2017: 35 · 2016: 32 · 2015: 28 · 2014: 40 · 2013: 29
- FWCI
- 23.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Leukemia and Lymphoma Society
- European Commission (241548)
- University of California, San Francisco
- National Cancer Institute (U01CA168370)
- National Institute of General Medical Sciences (R01 GM80783, R01GM080783, T32GM007618)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK063720)
- National Institute of Biomedical Imaging and Bioengineering (T32EB009383)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Toxin Mechanisms and Immunotoxins
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Keywords
- genetic interaction mapping, shRNA library, COPI, TRAPP complex, gene function, combination therapy, mammalian cells
- MeSH terms
- Atorvastatin, Bromodomain Containing Proteins, Biological Transport, Carrier Proteins, Endoplasmic Reticulum, Epistasis, Genetic, Heptanoic Acids, Humans, Membrane Proteins, Proto-Oncogene Proteins, Pyrroles, Ribosomal Proteins, Ricin, Coat Protein Complex I, Vesicular Transport Proteins, RNA, Small Interfering, Cell Line, Tumor
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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