Functional overlap and regulatory links shape genetic interactions between signaling pathways

Research output: Contribution to journalResearch articleContributedpeer-review


  • Sake van Wageningen - , University Medical Center (UMC) Utrecht (Author)
  • Patrick Kemmeren - (Author)
  • Philip Lijnzaad - (Author)
  • Thanasis Margaritis - (Author)
  • Joris J Benschop - (Author)
  • Inês J de Castro - (Author)
  • Dik van Leenen - (Author)
  • Marian J A Groot Koerkamp - (Author)
  • Cheuk W Ko - (Author)
  • Antony J Miles - (Author)
  • Nathalie Brabers - (Author)
  • Mariel O Brok - (Author)
  • Tineke L Lenstra - (Author)
  • Dorothea Fiedler - (Author)
  • Like Fokkens - (Author)
  • Rodrigo Aldecoa - (Author)
  • Eva Apweiler - (Author)
  • Virginia Taliadouros - (Author)
  • Katrin Sameith - , University Medical Center (UMC) Utrecht (Author)
  • Loes A L van de Pasch - (Author)
  • Sander R van Hooff - (Author)
  • Linda V Bakker - (Author)
  • Nevan J Krogan - (Author)
  • Berend Snel - (Author)
  • Frank C P Holstege - (Author)


To understand relationships between phosphorylation-based signaling pathways, we analyzed 150 deletion mutants of protein kinases and phosphatases in S. cerevisiae using DNA microarrays. Downstream changes in gene expression were treated as a phenotypic readout. Double mutants with synthetic genetic interactions were included to investigate genetic buffering relationships such as redundancy. Three types of genetic buffering relationships are identified: mixed epistasis, complete redundancy, and quantitative redundancy. In mixed epistasis, the most common buffering relationship, different gene sets respond in different epistatic ways. Mixed epistasis arises from pairs of regulators that have only partial overlap in function and that are coupled by additional regulatory links such as repression of one by the other. Such regulatory modules confer the ability to control different combinations of processes depending on condition or context. These properties likely contribute to the evolutionary maintenance of paralogs and indicate a way in which signaling pathways connect for multiprocess control.


Original languageEnglish
Pages (from-to)991-1004
Number of pages14
Issue number6
Publication statusPublished - 10 Dec 2010
Externally publishedYes

External IDs

PubMedCentral PMC3073509
Scopus 78649938122
ORCID /0000-0003-4306-930X/work/141545239



  • Epistasis, Genetic, Gene Expression Profiling, Phosphoric Monoester Hydrolases/genetics, Phosphorylation, Phosphotransferases/genetics, Saccharomyces cerevisiae/genetics, Signal Transduction