A high-resolution gene expression atlas of epistasis between gene-specific transcription factors exposes potential mechanisms for genetic interactions.

Katrin Sameith,Philip Lijnzaad,Frank C P Holstege,Sake Van Wageningen,Saman Amini,Nathalie Brabers,Mariel Brok,Dik Van Leenen,Tineke L Lenstra,Berend Snel,Eva Apweiler,Marian J A Groot Koerkamp,Sander R Van Hooff,Patrick Kemmeren,Joris J Benschop

doi:10.1186/s12915-015-0222-5

Katrin Sameith, Philip Lijnzaad + Show 13 more

Open Access

https://doi.org/10.1186/s12915-015-0222-5

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Abstract

BackgroundGenetic interactions, or non-additive effects between genes, play a crucial role in many cellular processes and disease. Which mechanisms underlie these genetic interactions has hardly been characterized. Understanding the molecular basis of genetic interactions is crucial in deciphering pathway organization and understanding the relationship between genotype, phenotype and disease.ResultsTo investigate the nature of genetic interactions between gene-specific transcription factors (GSTFs) in Saccharomyces cerevisiae, we systematically analyzed 72 GSTF pairs by gene expression profiling double and single deletion mutants. These pairs were selected through previously published growth-based genetic interactions as well as through similarity in DNA binding properties. The result is a high-resolution atlas of gene expression-based genetic interactions that provides systems-level insight into GSTF epistasis. The atlas confirms known genetic interactions and exposes new ones. Importantly, the data can be used to investigate mechanisms that underlie individual genetic interactions. Two molecular mechanisms are proposed, “buffering by induced dependency” and “alleviation by derepression”.ConclusionsThese mechanisms indicate how negative genetic interactions can occur between seemingly unrelated parallel pathways and how positive genetic interactions can indirectly expose parallel rather than same-pathway relationships. The focus on GSTFs is important for understanding the transcription regulatory network of yeast as it uncovers details behind many redundancy relationships, some of which are completely new. In addition, the study provides general insight into the complex nature of epistasis and proposes mechanistic models for genetic interactions, the majority of which do not fall into easily recognizable within- or between-pathway relationships.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-015-0222-5) contains supplementary material, which is available to authorized users.

Highlights

Genetic interactions, or non-additive effects between genes, play a crucial role in many cellular processes and disease
To score the genetic interaction εgrowth,XY between two gene-specific transcription factor (GSTF) X and Y, fitness observed for the respective double mutant WxΔyΔ is compared to the fitness that is expected based on both single mutants WxΔ × WyΔ [13]
The resulting genetic interaction scores largely agree with the initial scores used for selecting GSTF pairs [27] (Additional file 2B; R = 0.63, P = 2.64 × 10−5), taking into account differences in the growth procedures and media used (synthetic complete (SC) versus yeast extract peptone dextrose (YEPD))

Summary

Introduction

Non-additive effects between genes, play a crucial role in many cellular processes and disease. Which mechanisms underlie these genetic interactions has hardly been characterized. Understanding the molecular basis of genetic interactions is crucial in deciphering pathway organization and understanding the relationship between genotype, phenotype and disease. Predicting the phenotype of an individual organism based on its genotype is a major challenge. A genetic interaction is negative if the fitness observed for a double mutant is worse than expected based on the fitness of the respective single mutants. Understanding genetic interactions and the mechanisms underlying them are of obvious importance for understanding genotype-phenotype relationships

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