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Genetic networks are surprisingly robust to perturbations caused by new mutations. This robustness is conferred in part by compensation for loss of a gene’s activity by genes with overlapping functions, such as paralogs. Compensation occurs passively when the normal activity of one paralog can compensate for the loss of the other, or actively when a change in one paralog’s expression, localization, or activity is required to compensate for loss of the other. The mechanisms of active compensation remain poorly understood in most cases. Here we investigate active compensation for the loss or reduction in expression of theSaccharomyces cerevisiaegeneTDH3by its paralogTDH2.TDH2is upregulated in a dose-dependent manner in response to reductions inTDH3by a mechanism requiring the shared transcriptional regulators Gcr1p and Rap1p.TDH1, a second and more distantly related paralog ofTDH3, has diverged in its regulation and is upregulated by another mechanism. Other glycolytic genes regulated by Rap1p and Gcr1p show changes in expression similar toTDH2, suggesting that the active compensation byTDH3paralogs is part of a broader homeostatic response mediated by shared transcriptional regulators. 

Heritable variation in gene expression is common within and among species and contributes to phenotypic diversity. Mutations affecting eithercis- ortrans-regulatory sequences controlling gene expression give rise to variation in gene expression, and natural selection acting on this variation causes some regulatory variants to persist in a population for longer than others. To understand how mutation and selection interact to produce the patterns of regulatory variation we see within and among species, my colleagues and I have been systematically determining the effects of new mutations on expression of theTDH3gene inSaccharomyces cerevisiaeand comparing them to the effects of polymorphisms segregating within this species. We have also investigated the molecular mechanisms by which regulatory variants act. Over the past decade, this work has revealed properties ofcis- andtrans-regulatory mutations including their relative frequency, effects, dominance, pleiotropy and fitness consequences. Comparing these mutational effects to the effects of polymorphisms in natural populations, we have inferred selection acting on expression level, expression noise and phenotypic plasticity. Here, I summarize this body of work and synthesize its findings to make inferences not readily discernible from the individual studies alone. This article is part of the theme issue ‘Interdisciplinary approaches to predicting evolutionary biology’. 

Studies of regulatory variation in yeast -- at the level of new mutations, polymorphisms within a species, and divergence between species -- have provided great insight into the molecular and evolutionary processes responsible for the evolution of gene expression in eukaryotes. The increasing ease with which yeast genomes can be manipulated and expression quantified in a high-throughput manner has recently accelerated mechanistic studies of cis- and trans-regulatory variation at multiple evolutionary timescales. These studies have, for example, identified differences in the properties of cis- and trans-acting mutations that affect their evolutionary fate, experimentally characterized the molecular mechanisms through which cis- and trans-regulatory variants act, and illustrated how regulatory networks can diverge between species with or without changes in gene expression.