Harmonious genetic combinations rewire regulatory networks and flip gene essentiality

Nat Commun. 2019 Aug 14;10(1):3657. doi: 10.1038/s41467-019-11523-z.

Abstract

We lack an understanding of how the full range of genetic variants that occur in individuals can interact. To address this shortcoming, here we combine diverse mutations between genes in a model regulatory network, the galactose (GAL) switch of budding yeast. The effects of thousands of pairs of mutations fall into a limited number of phenotypic classes. While these effects are mostly predictable using simple rules that capture the 'stereotypical' genetic interactions of the network, some double mutants have unexpected outcomes including constituting alternative functional switches. Each of these 'harmonious' genetic combinations exhibits altered dependency on other regulatory genes. These cases illustrate how both pairwise and higher epistasis determines gene essentiality and how combinations of mutations rewire regulatory networks. Together, our results provide an overview of how broad spectra of mutations interact, how these interactions can be predicted, and how diverse genetic solutions can achieve 'wild-type' phenotypic behavior.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA-Binding Proteins / genetics*
  • Epistasis, Genetic
  • Galactokinase / genetics
  • Galactose / metabolism*
  • Gene Expression Regulation, Fungal
  • Gene Regulatory Networks
  • Monosaccharide Transport Proteins / genetics
  • Mutation
  • Repressor Proteins / genetics*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins / genetics*
  • Systems Biology
  • Trans-Activators / genetics
  • Transcription Factors / genetics*

Substances

  • DNA-Binding Proteins
  • GAL10 protein, S cerevisiae
  • GAL2 protein, S cerevisiae
  • GAL4 protein, S cerevisiae
  • GAL80 protein, S cerevisiae
  • Gal3 protein, S cerevisiae
  • Monosaccharide Transport Proteins
  • Repressor Proteins
  • Saccharomyces cerevisiae Proteins
  • Trans-Activators
  • Transcription Factors
  • GAL1 protein, S cerevisiae
  • Galactokinase
  • Galactose