title: No Evidence That Protein Noise-Induced Epigenetic Epistasis Constrains Gene Expression Evolution.
abstract: Changes in gene expression can affect phenotypes and therefore both its level and stochastic variability are frequently under selection. It has recently been proposed that epistatic interactions influence gene expression evolution: gene pairs where simultaneous knockout is more deleterious than expected should evolve reduced expression noise to avoid concurrent low expression of both proteins. In apparent support, yeast genes with many epistatic partners have low expression variation both among isogenic individuals and between species. However, the specific predictions and basic assumptions of this verbal model remain untested. Using bioinformatics analysis, we first demonstrate that the model's predictions are unsupported by available large-scale data. Based on quantitative biochemical modeling, we then show that epistasis between expression reductions (epigenetic epistasis) is not expected to aggravate the fitness cost of stochastic expression, which is in sharp contrast to the verbal argument. This nonintuitive result can be readily explained by the typical diminishing return of fitness on gene activity and by the fact that expression noise not only decreases but also increases the abundance of proteins. Overall, we conclude that stochastic variation in epistatic partners is unlikely to drive noise minimization or constrain gene expression divergence on a genomic scale.
authors.affiliation: Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Szeged, Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Boross
authors.affiliation: Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Szeged, Hungary.
authors.forename: Balázs
authors.initials: B
authors.lastname: Papp
mesh_terms: D005075:Biological Evolution; D019295:Computational Biology / Q000379:methods; D044127:Epigenesis, Genetic; D015870:Gene Expression; D015966:Gene Expression Regulation, Fungal; D053263:Gene Regulatory Networks; D005800:Genes, Fungal; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics*
keywords:  haploinsufficiency; Saccharomyces cerevisiae; dosage sensitivity; gene expression noise; genetic interaction network; kinetic modeling