Systematic mapping of genetic interactions in Caenorhabditis elegans identifies common modifiers of diverse signaling pathways
Abstract
Most heritable traits, including disease susceptibility, are affected by interactions between multiple genes. However, we understand little about how genes interact because very few possible genetic interactions have been explored experimentally. We have used RNA interference in Caenorhabditis elegans to systematically test approximately 65,000 pairs of genes for their ability to interact genetically. We identify approximately 350 genetic interactions between genes functioning in signaling pathways that are mutated in human diseases, including components of the EGF/Ras, Notch and Wnt pathways. Most notably, we identify a class of highly connected 'hub' genes: inactivation of these genes can enhance the phenotypic consequences of mutation of many different genes. These hub genes all encode chromatin regulators, and their activity as genetic hubs seems to be conserved across animals. We propose that these genes function as general buffers of genetic variation and that these hub genes may act as modifier genes in multiple, mechanistically unrelated genetic diseases in humans.
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Synthetic genetic interaction screens in yeast show thousands of combinations of individually viable mutations can be jointly lethal, with similar examples in Drosophila and C. elegans.
“Synthetic genetic interaction screens in yeast123,124 have demonstrated that thousands of combinations of individually viable mutations can jointly be lethal, and similar examples have been documented in Drosophila melanogaster and Caenorhabditis elegans125,126.”
From Rare and common variants: twenty arguments (2012) · cites this paper as [126]
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- Authors
- Lehner, B., Crombie, C., Tischler, J., Fortunato, A., & Fraser, A. G.
- Affiliations
- University of Siena (IT)
- Wellcome Sanger Institute (GB)
- Corresponding author
- Fraser, Andrew G
- Venue
- Nature Genetics
- Published
- 2006-07-16
- Volume
- 38
- Issue
- 8
- Pages
- 896-903
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2052815101
- Cited by
- 502
- References
- 47
- Citations by year
- 2026: 3 · 2025: 14 · 2024: 13 · 2023: 14 · 2022: 12 · 2021: 14 · 2020: 16 · 2019: 24 · 2018: 22 · 2017: 31 · 2016: 21 · 2015: 27 · 2014: 20 · 2013: 36 · 2012: 40
- FWCI
- 15.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- IRIS eCampus Telematic University (Università degli Studi eCampus) (submittedVersion)
- Funders
- Wellcome Trust
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bioinformatics and Genomic Networks
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- genetic interactions, genetic modifiers, hub genes, chromatin regulators, signaling pathways, Notch signaling, Wnt signaling, RNAi screen, genetic buffering, disease susceptibility, Caenorhabditis elegans
- MeSH terms
- Animals, Chromosome Mapping, Enhancer Elements, Genetic, Epidermal Growth Factor, Female, Humans, Mutation, Phenotype, Vulva, Signal Transduction, Caenorhabditis elegans, Genes, Helminth, RNA Interference
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