CE12 - Génétique, génomique et ARN

Evolution of the regulation of gene expression – VORTEX

Submission summary

The regulation of gene expression in response to environmental changes, a property known as expression plasticity, is critical for the adaptation of living organisms to a dynamically changing world. While decades of research uncovered the molecular mechanisms underlying gene expression regulation in several species and environmental conditions, how such regulation evolves remains largely unknown. This project builds on recent genomic advances to determine how the evolution of gene expression plasticity depends on 1) mutational constraints – “what can happen?”, and 2) its impact on reproductive fitness in fluctuating environments – “who can survive?”. I propose to address these fundamental questions at the genome-wide scale through a combination of innovative experimental and computational approaches using a powerful model organism: the yeast Saccharomyces cerevisiae.

The way new mutations alter the response of living organisms to their environment is a major determinant of evolution and disease, but it has rarely been characterized empirically. In particular, very little is known about how random mutations shape the evolution of gene expression regulation. To fill this gap, we will profile the transcriptome of hundreds of yeast clones with random mutations under normal and stressful conditions. This will reveal for each gene the mutational input of expression plasticity: How frequently and in which direction do new mutations alter expression plasticity? With these data at hand, we will investigate what known properties of a gene make its expression plasticity more or less susceptible to be modified by mutations. By comparing the effects of new mutations to the natural variation of expression plasticity measured in wild isolates of S. cerevisiae, we will determine if the evolution of transcriptional regulation has been influenced by the mutational input in nature.

To understand how selection may influence regulatory evolution, I propose to measure the reproductive fitness of the mutant strains in constant and in fluctuating environments using pooled competition assays. Statistical associations between fitness and expression plasticity will tell us which genes are likely to contribute to adaptation in fluctuating stress conditions and whether selection acts more strongly on expression plasticity in fluctuating than in constant conditions.

To demonstrate the causal impact of expression plasticity on fitness, we will artificially force the temporal dynamics of gene expression and measure how it affects growth rate when cells are periodically exposed to stress. Population growth will be measured for diverse patterns of expression plasticity, providing empirical descriptions of the added value of gene expression dynamics in fluctuating environmental conditions. Finally, time-lapse microscopy of cells grown in microfluidic devices will be used to characterize precisely how gene expression dynamics control cellular proliferation.

The proposed work will bring innovations at the conceptual, mechanistic, and technological levels. By uncovering basic principles that govern the adaptation of a biological system confronted to dynamic environmental conditions, this project will have broad impact not only for evolutionary biology but also for biomedical research.

Project coordination

Fabien Duveau (LABORATOIRE DE BIOLOGIE ET MODELISATION DE LA CELLULE)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

CNRS LBMC LABORATOIRE DE BIOLOGIE ET MODELISATION DE LA CELLULE

Help of the ANR 293,132 euros
Beginning and duration of the scientific project: February 2021 - 48 Months

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