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

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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Figure 1: Dosage suppression genetic interaction network for S. cerevisiae.
Figure 2: Properties of the yeast dosage suppression network.
Figure 3: A genetic requirement for PKA signaling in kinetochore function.
Figure 4: Decision tree used to categorize dosage suppression interactions.
Figure 5: Mechanisms of dosage suppression in yeast.

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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).

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Authors and Affiliations

Authors

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.

Corresponding authors

Correspondence to Brenda Andrews or Charles Boone.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 (PDF 694 kb)

Supplementary Table 1

Dosage suppression interactions curated in the Saccharomyces Genome Database. (XLS 410 kb)

Supplementary Table 2

Dosage suppression interactions identified in this study using the MoBY-ORF 2.0 library. (XLS 122 kb)

Supplementary Table 3

Gene pairs from this study tested for reciprocal suppression interactions. (XLS 20 kb)

Supplementary Table 4

Gene pairs annotated in the Saccharomyces Genome Database that show reciprocal suppression interactions. (XLS 27 kb)

Supplementary Table 5

Significant enrichment of yeast two-hybrid interactions in the dosage suppression interaction network. (XLS 12 kb)

Supplementary Table 6

Restriction digest fragments of MoBY-ORF 2.0 plasmids. (XLS 574 kb)

Supplementary Table 7

Yeast strains used in this study. (XLS 338 kb)

Supplementary Table 8

MoBY-ORF 2.0 plasmids used in this study. (XLS 38 kb)

Supplementary Data (ZIP 58 kb)

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Magtanong, L., Ho, C., Barker, S. et al. Dosage suppression genetic interaction networks enhance functional wiring diagrams of the cell. Nat Biotechnol 29, 505–511 (2011). https://doi.org/10.1038/nbt.1855

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