The ability of transcription factors to differentially regulate gene expression is a crucial component of the mechanism underlying inversion, a frequently observed genetic interaction pattern

PLoS Comput Biol. 2019 May 13;15(5):e1007061. doi: 10.1371/journal.pcbi.1007061. eCollection 2019 May.

Abstract

Genetic interactions, a phenomenon whereby combinations of mutations lead to unexpected effects, reflect how cellular processes are wired and play an important role in complex genetic diseases. Understanding the molecular basis of genetic interactions is crucial for deciphering pathway organization as well as understanding the relationship between genetic variation and disease. Several hypothetical molecular mechanisms have been linked to different genetic interaction types. However, differences in genetic interaction patterns and their underlying mechanisms have not yet been compared systematically between different functional gene classes. Here, differences in the occurrence and types of genetic interactions are compared for two classes, gene-specific transcription factors (GSTFs) and signaling genes (kinases and phosphatases). Genome-wide gene expression data for 63 single and double deletion mutants in baker's yeast reveals that the two most common genetic interaction patterns are buffering and inversion. Buffering is typically associated with redundancy and is well understood. In inversion, genes show opposite behavior in the double mutant compared to the corresponding single mutants. The underlying mechanism is poorly understood. Although both classes show buffering and inversion patterns, the prevalence of inversion is much stronger in GSTFs. To decipher potential mechanisms, a Petri Net modeling approach was employed, where genes are represented as nodes and relationships between genes as edges. This allowed over 9 million possible three and four node models to be exhaustively enumerated. The models show that a quantitative difference in interaction strength is a strict requirement for obtaining inversion. In addition, this difference is frequently accompanied with a second gene that shows buffering. Taken together, these results provide a mechanistic explanation for inversion. Furthermore, the ability of transcription factors to differentially regulate expression of their targets provides a likely explanation why inversion is more prevalent for GSTFs compared to kinases and phosphatases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromosome Inversion
  • Computational Biology
  • Computer Simulation
  • Databases, Genetic
  • Epistasis, Genetic
  • Gene Expression Regulation*
  • Genes, Fungal
  • Genetic Association Studies
  • Models, Genetic*
  • Mutation
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / growth & development
  • Saccharomyces cerevisiae / metabolism
  • Signal Transduction / genetics
  • Transcription Factors / metabolism*

Substances

  • Transcription Factors

Grants and funding

PK acknowledges the financial support of the Netherlands Organisation for Scientific Research (NWO); grant number 864.11.010; https://www.nwo.nl/en. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.