Network hubs buffer environmental variation in Saccharomyces cerevisiae

Sasha F. Levy, Mark Siegal

Research output: Contribution to journalArticle

Abstract

Regulatory and developmental systems produce phenotypes that are robust to environmental and genetic variation. A gene product that normally contributes to this robustness is termed a phenotypic capacitor. When a phenotypic capacitor fails, for example when challenged by a harsh environment or mutation, the system becomes less robust and thus produces greater phenotypic variation. A functional phenotypic capacitor provides a mechanism by which hidden polymorphism can accumulate, whereas its failure provides a mechanism by which evolutionary change might be promoted. The primary example to date of a phenotypic capacitor is Hsp90, a molecular chaperone that targets a large set of signal transduction proteins. In both Drosophila and Arabidopsis, compromised Hsp90 function results in pleiotropic phenotypic effects dependent on the underlying genotype. For some traits, Hsp90 also appears to buffer stochastic variation, yet the relationship between environmental and genetic buffering remains an important unresolved question. We previously used simulations of knockout mutations in transcriptional networks to predict that many gene products would act as phenotypic capacitors. To test this prediction, we use high-throughput morphological phenotyping of individual yeast cells from single-gene deletion strains to identify gene products that buffer environmental variation in Saccharomyces cerevisiae. We find more than 300 gene products that, when absent, increase morphological variation. Overrepresented among these capacitors are gene products that control chromosome organization and DNA integrity, RNA elongation, protein modification, cell cycle, and response to stimuli such as stress. Capacitors have a high number of synthetic-lethal interactions but knockouts of these genes do not tend to cause severe decreases in growth rate. Each capacitor can be classified based on whether or not it is encoded by a gene with a paralog in the genome. Capacitors with a duplicate are highly connected in the protein-protein interaction network and show considerable divergence in expression from their paralogs. In contrast, capacitors encoded by singleton genes are part of highly interconnected protein clusters whose other members also tend to affect phenotypic variability or fitness. These results suggest that buffering and release of variation is a widespread phenomenon that is caused by incomplete functional redundancy at multiple levels in the genetic architecture.

Original languageEnglish (US)
Article numbere264
Pages (from-to)2588-2604
Number of pages17
JournalPLoS Biology
Volume6
Issue number11
DOIs
StatePublished - Nov 2008

Fingerprint

Yeast
Saccharomyces cerevisiae
Buffers
Capacitors
buffers
Genes
genes
Proteins
Protein Interaction Maps
phenotype
Cell Cycle Proteins
Gene Knockout Techniques
Mutation
molecular chaperones
Molecular Chaperones
knockout mutants
proteins
gene deletion
Gene Regulatory Networks
Gene Deletion

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)
  • Neuroscience(all)

Cite this

Network hubs buffer environmental variation in Saccharomyces cerevisiae. / Levy, Sasha F.; Siegal, Mark.

In: PLoS Biology, Vol. 6, No. 11, e264, 11.2008, p. 2588-2604.

Research output: Contribution to journalArticle

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