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Cited by 140Evolution and Genetic DynamicsProtein Structure and DynamicsGenetic Associations and Epidemiology

The genetic landscape of a physical interaction

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Diss, Guillaume, Lehner, Ben·2018·eLife
DOI 10.7554/elife.32472PMC PMC5896888
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Abstract

A key question in human genetics and evolutionary biology is how mutations in different genes combine to alter phenotypes. Efforts to systematically map genetic interactions have mostly made use of gene deletions. However, most genetic variation consists of point mutations of diverse and difficult to predict effects. Here, by developing a new sequencing-based protein interaction assay – deepPCA – we quantified the effects of >120,000 pairs of point mutations on the formation of the AP-1 transcription factor complex between the products of the FOS and JUN proto-oncogenes. Genetic interactions are abundant both in cis (within one protein) and trans (between the two molecules) and consist of two classes – interactions driven by thermodynamics that can be predicted using a three-parameter global model, and structural interactions between proximally located residues. These results reveal how physical interactions generate quantitatively predictable genetic interactions.

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  • Yeast models have been used to screen human disease genes in complementation assays, where the human gene functionally replaces a homologous yeast gene essential for growth, as well as protein-protein and protein-DNA interactions.

    “Yeast models have also been used to screen human disease genes in complementation assays, where the human gene functionally replaces a homologous yeast gene essential for growth (47), as well as protein–protein and protein–DNA interactions (67, 68).”

    From Massively parallel functional genomic assays in endocrinology: from promise to delivery (2026) · cites this paper as [67]

    The Results (no page listed) describe a yeast assay that measures how mutations in human FOS and JUN affect their protein–protein interaction, supporting that part of the clause cited to this paper. The paper does not report screening protein–DNA interactions. The earlier claim about replacing an essential yeast gene is attached to citation 47, not this source; this paper’s complementation assay instead joins enzyme fragments when two proteins interact. (LLM, conf=0.88)

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Cited by

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Authors
Diss, G., & Lehner, B.
Affiliations
  • Universitat Pompeu Fabra (ES)
  • Institució Catalana de Recerca i Estudis Avançats (ES)
Corresponding author
Lehner, Ben
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2018-04-11
Volume
7
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.32472
PMC
PMC5896888
OpenAlex
W2797104734
Cited by
140
References
4
Citations by year
2026: 14 · 2025: 16 · 2024: 17 · 2023: 22 · 2022: 14 · 2021: 11 · 2020: 22 · 2019: 19 · 2018: 5
FWCI
8.61
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RECERCAT (Consorci de Serveis Universitaris de Catalunya) (publishedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion, cc-by)
Funders
  • European Research Council (616434)
  • AXA Research Fund (Professorship)
  • Ministerio de Economía y Competitividad (BFU2011-26206 and SEV-2012-0208)
  • Agència de Gestió d’Ajuts Universitaris i de Recerca (SGR-831)
  • Fondation Bettencourt Schueller (Bettencourt Prize)
  • European Commission (Marrie-Currie co-fund fellowship 608959)
  • EMBL-CRG (Systems Biology Program)
  • Generalitat de Catalunya (CERCA Program)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
genetic interactions, point mutations, protein-protein interaction, AP-1 transcription factor, FOS, c-Jun, thermodynamic interactions, structural interaction, protein complex formation, genotype-phenotype mapping
MeSH terms
Algorithms, Epistasis, Genetic, Biological Evolution, Humans, Models, Genetic, Mutation, Protein Conformation, Thermodynamics, Proto-Oncogene Proteins c-jun, Proto-Oncogene Proteins c-fos, Protein Interaction Maps

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