Abstract
Genetic noise together with genome duplication and volume changes during cell cycle are significant contributors to cell-to-cell heterogeneity. How can cells buffer the effects of these unavoidable epigenetic and genetic variations on phenotypes that are sensitive to such variations? Here we show that a simple network motif that is essential for network-dosage compensation can reduce the effects of extrinsic noise on the network output. Using natural and synthetic gene networks with and without the network motif, we measure gene network activity in single yeast cells and find that the activity of the compensated network is significantly lower in noise compared with the non-compensated network. A mathematical analysis provides intuitive insights into these results and a novel stochastic model tracking cell-volume and cell-cycle predicts the experimental results. Our work implies that noise is a selectable trait tunable by evolution.
Highlights
Genetic noise together with genome duplication and volume changes during cell cycle are significant contributors to cell-to-cell heterogeneity
Network-dosage compensation refers to the phenomenon in which the output of a gene network is invariant to changes in network dosage; this is different from gene dosage compensation[3], which is about changes in the copy number of individual genes rather than entire gene networks
The activity of the GAL1 promoter is a reliable representative of the network activity, as this promoter has GAL4 binding sites
Summary
Genetic noise together with genome duplication and volume changes during cell cycle are significant contributors to cell-to-cell heterogeneity. As many sources of extrinsic noise (for example, changes in cell volume, or variations in the abundance of ribosomes, general transcription factors or RNA polymerase) affect all genes in the network, noise from those sources may be thought of as effectively altering the dosage level of the gene network, though more fine-grained than actual changes in the network copy number. On the basis of a mathematical analysis (Supplementary Note 1), it is reasonable to expect that the activity of a dosage-compensated network would be less sensitive to such noise sources compared with non-compensated networks, reducing the effects of a significant contributor to overall noise level. We hypothesize that the activity of dosage compensated networks is less noisy compared with networks that are not compensated To test this hypothesis, we use the canonical galactose (GAL) network[4,12,13,14] as experimental model in the yeast Saccharomyces cerevisiae. Mediated by proteins that function as inducers and repressors in the network, key positive and negative feedback loops are embedded into the network[4,12,14]
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