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The synthetic genetic interaction spectrum of essential genes



The nature of synthetic genetic interactions involving essential genes (those required for viability) has not been previously examined in a broad and unbiased manner. We crossed yeast strains carrying promoter-replacement alleles for more than half of all essential yeast genes1 to a panel of 30 different mutants with defects in diverse cellular processes. The resulting genetic network is biased toward interactions between functionally related genes, enabling identification of a previously uncharacterized essential gene (PGA1) required for specific functions of the endoplasmic reticulum. But there are also many interactions between genes with dissimilar functions, suggesting that individual essential genes are required for buffering many cellular processes. The most notable feature of the essential synthetic genetic network is that it has an interaction density five times that of nonessential synthetic genetic networks2,3, indicating that most yeast genetic interactions involve at least one essential gene.

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  1. 1

    Mnaimneh, S. et al. Exploration of essential gene functions via titratable promoter alleles. Cell 118, 31–44 (2004).

  2. 2

    Tong, A.H. et al. Systematic genetic analysis with ordered arrays of yeast deletion mutants. Science 294, 2364–2368 (2001).

  3. 3

    Tong, A.H. et al. Global mapping of the yeast genetic interaction network. Science 303, 808–813 (2004).

  4. 4

    Giaever, G. et al. Functional profiling of the Saccharomyces cerevisiae genome. Nature 418, 387–391 (2002).

  5. 5

    Hartman, J.L., Garvik, B. & Hartwell, L. Principles for the buffering of genetic variation. Science 291, 1001–1004 (2001).

  6. 6

    Hartwell, L. Genetics. Robust interactions. Science 303, 774–775 (2004).

  7. 7

    Finger, F.P. & Novick, P. Synthetic interactions of the post-Golgi sec mutations of Saccharomyces cerevisiae. Genetics 156, 943–951 (2000).

  8. 8

    Breitkreutz, B.J., Stark, C. & Tyers, M. The GRID: the General Repository for Interaction Datasets. Genome Biol. 4, R23 (2003).

  9. 9

    Fien, K. & Stillman, B. Identification of replication factor C from Saccharomyces cerevisiae: a component of the leading-strand DNA replication complex. Mol. Cell. Biol. 12, 155–163 (1992).

  10. 10

    Kolodner, R.D. & Marsischky, G.T. Eukaryotic DNA mismatch repair. Curr. Opin. Genet. Dev. 9, 89–96 (1999).

  11. 11

    Mayer, M.L., Gygi, S.P., Aebersold, R. & Hieter, P. Identification of RFC(Ctf18p, Ctf8p, Dcc1p): an alternative RFC complex required for sister chromatid cohesion in S. cerevisiae. Mol. Cell 7, 959–970 (2001).

  12. 12

    Peng, W.T. et al. A panoramic view of yeast noncoding RNA processing. Cell 113, 919–933 (2003).

  13. 13

    Mitchell, P. et al. Rrp47p is an exosome-associated protein required for the 3′ processing of stable RNAs. Mol. Cell. Biol. 23, 6982–6992 (2003).

  14. 14

    Jung, U.S. & Levin, D.E. Genome-wide analysis of gene expression regulated by the yeast cell wall integrity signalling pathway. Mol. Microbiol. 34, 1049–1057 (1999).

  15. 15

    Christie, K.R. et al. Saccharomyces Genome Database (SGD) provides tools to identify and analyze sequences from Saccharomyces cerevisiae and related sequences from other organisms. Nucleic Acids Res. 32, D311–D314 (2004).

  16. 16

    Fujioka, Y., Kimata, Y., Nomaguchi, K., Watanabe, K. & Kohno, K. Identification of a novel non-structural maintenance of chromosomes (SMC) component of the SMC5–SMC6 complex involved in DNA repair. J. Biol. Chem. 277, 21585–21591 (2002).

  17. 17

    Hennessy, K.M., Lee, A., Chen, E. & Botstein, D. A group of interacting yeast DNA replication genes. Genes Dev. 5, 958–969 (1991).

  18. 18

    Desany, B.A., Alcasabas, A.A., Bachant, J.B. & Elledge, S.J. Recovery from DNA replicational stress is the essential function of the S-phase checkpoint pathway. Genes Dev. 12, 2956–2970 (1998).

  19. 19

    Huh, W.K. et al. Global analysis of protein localization in budding yeast. Nature 425, 686–691 (2003).

  20. 20

    Hazbun, T.R. et al. Assigning function to yeast proteins by integration of technologies. Mol. Cell 12, 1353–1365 (2003).

  21. 21

    Avaro, S., Belgareh-Touze, N., Sibella-Arguelles, C., Volland, C. & Haguenauer-Tsapis, R. Mutants defective in secretory/vacuolar pathways in the EUROFAN collection of yeast disruptants. Yeast 19, 351–371 (2002).

  22. 22

    Belgareh-Touze, N. et al. Yeast functional analysis: identification of two essential genes involved in ER to Golgi trafficking. Traffic 4, 607–617 (2003).

  23. 23

    Popolo, L. & Vai, M. The Gas1 glycoprotein, a putative wall polymer cross-linker. Biochim. Biophys. Acta 1426, 385–400 (1999).

  24. 24

    Cowles, C.R., Odorizzi, G., Payne, G.S. & Emr, S.D. The AP-3 adaptor complex is essential for cargo-selective transport to the yeast vacuole. Cell 91, 109–118 (1997).

  25. 25

    Stepp, J.D., Huang, K. & Lemmon, S.K. The yeast adaptor protein complex, AP-3, is essential for the efficient delivery of alkaline phosphatase by the alternate pathway to the vacuole. J. Cell Biol. 139, 1761–1774 (1997).

  26. 26

    Gavin, A.C. et al. Functional organization of the yeast proteome by systematic analysis of protein complexes. Nature 415, 141–147 (2002).

  27. 27

    Phillips, P.C. & Johnson, N.A. The population genetics of synthetic lethals. Genetics 150, 449–458 (1998).

  28. 28

    Kile, B.T. et al. Functional genetic analysis of mouse chromosome 11. Nature 425, 81–86 (2003).

  29. 29

    Goddijn, M. & Leschot, N.J. Genetic aspects of miscarriage. Baillieres Best Pract. Res. Clin. Obstet. Gynaecol. 14, 855–865 (2000).

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We thank G. Bader for assistance with the comparison of our genetic interactions to known genetic and protein-protein interactions; A. Tong for assistance in SGA query selection and experiments, critical evaluation of the manuscript and help with network visualization; H. Ding for assistance with data analysis; and O. Ryan, H. Lu, M. McCabe, O. Morozova and W. Siu for technical contributions. This work was funded by grants from Canadian Institutes of Health Research, Genome Canada and the Ontario Genomics Institute to T.R.H., C.B., B.J.A. and G.W.B. A.P.D. was funded by a C.H. Best Postdoctoral Fellowship and J.H. was funded by an Estate of Betty Irene West/Canadian Institutes of Health Research doctoral research award.

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Competing interests

The authors declare no competing financial interests.

Correspondence to Timothy R Hughes.

Supplementary information

  1. Supplementary Table 1

    Query strains used in this study. (PDF 56 kb)

  2. Supplementary Methods (PDF 97 kb)

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Figure 1: Matrix display of SGA data.
Figure 2: Allele specificity of essential gene interactions.
Figure 3: Network diagram summarizing 229 synthetic genetic interactions between nine different queries (sec1-1ts, sec7-1ts, sec15-1ts, sec18-1ts, exo84-102ts, rfc5-1ts, lrp1-Δ, rps17a-Δ and slt2-Δ) and 147 strains in the TetO7-promoter array.
Figure 4: Analysis of DNA replication in the rfc5-1 mutants.
Figure 5: PGA1 (also known as YNL158W) is required for normal protein processing of ALP and Gas1p.
Figure 6: Characteristics of the essential SGA network.