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Inferring modulators of genetic interactions with epistatic nested effects models

Published version
Peer-reviewed

Type

Article

Change log

Authors

Pirkl, M 
Diekmann, M 
van der Wees, M 
Beerenwinkel, N 
Fröhlich, H 

Abstract

Maps of genetic interactions can dissect functional redundancies in cellular networks. Gene expression profiles as high-dimensional molecular readouts of combinatorial perturbations provide a detailed view of genetic interactions, but can be hard to interpret if different gene sets respond in different ways (called mixed epistasis). Here we test the hypothesis that mixed epistasis between a gene pair can be explained by the action of a third gene that modulates the interaction. We have extended the framework of Nested Effects Models (NEMs), a type of graphical model specifically tailored to analyze high-dimensional gene perturbation data, to incorporate logical functions that describe interactions between regulators on downstream genes and proteins. We benchmark our approach in the controlled setting of a simulation study and show high accuracy in inferring the correct model. In an application to data from deletion mutants of kinases and phosphatases in S. cerevisiae we show that epistatic NEMs can point to modulators of genetic interactions. Our approach is implemented in the R-package 'epiNEM' available from https://github.com/cbg-ethz/epiNEM and https://bioconductor.org/packages/epiNEM/.

Description

Keywords

Computational Biology, Epistasis, Genetic, Gene Regulatory Networks, Genes, Fungal, Models, Genetic, Saccharomyces cerevisiae

Journal Title

PLoS Computational Biology

Conference Name

Journal ISSN

1553-734X
1553-7358

Volume Title

13

Publisher

Public Library of Science (PLoS)
Sponsorship
Cancer Research UK (CB4320)