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Dosage suppression genetic interaction networks enhance functional wiring diagrams of the cell

Nature Biotechnology volume 29, pages 505511 (2011) | Download Citation

Abstract

Dosage suppression is a genetic interaction in which overproduction of one gene rescues a mutant phenotype of another gene. Although dosage suppression is known to map functional connections among genes, the extent to which it might illuminate global cellular functions is unclear. Here we analyze a network of interactions linking dosage suppressors to 437 essential genes in yeast. For 424 genes, we curated interactions from the literature. Analyses revealed that many dosage suppression interactions occur between functionally related genes and that the majority do not overlap with other types of genetic or physical interactions. To confirm the generality of these network properties, we experimentally identified dosage suppressors for 29 genes from pooled populations of temperature-sensitive mutant cells transformed with a high-copy molecular-barcoded open reading frame library, MoBY-ORF 2.0. We classified 87% of the 1,640 total interactions into four general types of suppression mechanisms, which provided insight into their relative frequencies. This work suggests that integrating the results of dosage suppression studies with other interaction networks could generate insights into the functional wiring diagram of a cell.

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Acknowledgements

We thank S. Dixon for critical comments on the manuscript, M. Gebbia for microarray technical support, and C. Myers and J. Bellay for advice and data analysis support. L.M. was supported by a Canadian Institutes of Health Research (CIHR) doctoral research award. A.M.S. was supported by a University of Toronto open fellowship. J.S.C. and M.A.B. were supported by the Intramural Research Program of the US National Cancer Institute, US National Institutes of Health. G.G. was supported by the Canadian Cancer Society and the CIHR (research agreements 020380 and MOP-81340, respectively). C.N. was supported by the CIHR (MOP-84305). C.B. and B.A. were supported by Genome Canada through the Ontario Genomics Institute (2004-OGI-3-01). C.B. was supported by the CIHR (MOP-57830) and the Natural Sciences and Engineering Research Council of Canada (RGPIN 204899-06).

Author information

Author notes

    • Leslie Magtanong

    Present address: Howard Hughes Medical Institute, Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.

    • Leslie Magtanong
    • , Cheuk Hei Ho
    •  & Sarah L Barker

    These authors contributed equally to this work.

Affiliations

  1. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.

    • Leslie Magtanong
    • , Cheuk Hei Ho
    • , Sarah L Barker
    • , Wei Jiao
    • , Anastasia Baryshnikova
    • , Sondra Bahr
    • , Andrew M Smith
    • , Elena Kuzmin
    • , Kerry Andrusiak
    • , Zhijian Li
    • , Michael Costanzo
    • , Guri Giaever
    • , Corey Nislow
    • , Brenda Andrews
    •  & Charles Boone
  2. Banting and Best Department of Medical Genetics, Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.

    • Leslie Magtanong
    • , Cheuk Hei Ho
    • , Sarah L Barker
    • , Wei Jiao
    • , Anastasia Baryshnikova
    • , Sondra Bahr
    • , Andrew M Smith
    • , Lawrence E Heisler
    • , Elena Kuzmin
    • , Kerry Andrusiak
    • , Anna Kobylianski
    • , Zhijian Li
    • , Michael Costanzo
    • , Guri Giaever
    • , Corey Nislow
    • , Brenda Andrews
    •  & Charles Boone
  3. Genetic Branch Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.

    • John S Choy
    •  & Munira A Basrai
  4. Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada.

    • Guri Giaever

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Contributions

L.M. was involved in MoBY-ORF construction, carried out experimental analysis and wrote the manuscript; C.H.H. was involved in MoBY-ORF construction, carried out experimental analysis and wrote the manuscript; S.L.B. was involved in MoBY-ORF construction and wrote the manuscript; W.J. and A.B. carried out computational analysis and wrote the manuscript; S.B. was involved in temperature-sensitive strain generation and carried out experimental analysis; A.M.S. and L.E.H. were involved in microarray data analysis; J.S.C. carried out the chromosome loss assays; E.K. and K.A. carried out experimental analysis and edited the manuscript; A.K. carried out experimental analysis; Z.L. was involved in temperature-sensitive strain generation; M.C. wrote the manuscript; M.A.B. edited the manuscript; G.G. and C.N. provided microarray data analysis and edited the manuscript; B.A. wrote the manuscript; C.B. conceived and planned the construction of the MoBY-ORF 2.0 library and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Brenda Andrews or Charles Boone.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–5

Excel files

  1. 1.

    Supplementary Table 1

    Dosage suppression interactions curated in the Saccharomyces Genome Database.

  2. 2.

    Supplementary Table 2

    Dosage suppression interactions identified in this study using the MoBY-ORF 2.0 library.

  3. 3.

    Supplementary Table 3

    Gene pairs from this study tested for reciprocal suppression interactions.

  4. 4.

    Supplementary Table 4

    Gene pairs annotated in the Saccharomyces Genome Database that show reciprocal suppression interactions.

  5. 5.

    Supplementary Table 5

    Significant enrichment of yeast two-hybrid interactions in the dosage suppression interaction network.

  6. 6.

    Supplementary Table 6

    Restriction digest fragments of MoBY-ORF 2.0 plasmids.

  7. 7.

    Supplementary Table 7

    Yeast strains used in this study.

  8. 8.

    Supplementary Table 8

    MoBY-ORF 2.0 plasmids used in this study.

Zip files

  1. 1.

    Supplementary Data

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DOI

https://doi.org/10.1038/nbt.1855

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