Description du sujet de thèse

Diploidy is characterized by the presence of two copies of each gene, one of paternal and one of maternal origin. While much theory has been devoted to understanding how the relative length of diploid versus haploid phases evolves in eukaryotes, less attention has been devoted to understanding how fair 1:1 diploid expression is maintained within the diploid phase. In particular, mutations in cis-regulators are expected to cause 'allele-specific expression' (ASE), where one allele is consistently over- or under-expressed when associated with strong or weak cis-regulator(s). ASE is widespread in eukaryotes (1–3). However, we lack a comprehensive theory to predict ASE levels, and the evolutionary consequences of cis-regulatory variation are only beginning to be incorporated into population genetic theory.

Several evolutionary processes may contribute to ASE. Some of this variation can be neutral, some can be deleterious (for example, when cis-regulatory variation causes a departure from optimal gene expression), and some can be beneficial (when an alternative level of gene expression is occasionally selected for a given gene). In addition to these direct effects, cis-regulatory runaway can generate substantial ASE (4). Indeed, in this runaway, stronger cis-regulators repeatedly fix in populations, generating strong ASE during a transient phase (i.e. when new, stronger cis-regulators reach intermediate frequencies and before they approach fixation). Finally, ASE levels may be globally attenuated by adaptations that enforce 1:1 diploid expression to some extent.

The first aim of this PhD project is to develop a comprehensive theory of ASE that combines the different processes mentioned above. This theory will consider multilocus models where cis-regulators evolve continuously for each gene, alongside a genome-level trait that coevolves to attenuate ASE resulting from cis-regulatory variation. It will also incorporate stabilizing selection on expression levels and the co-evolution of cis- and trans-regulators. This theory will predict how much ASE can be expected and the critical parameters that influence this distribution. In particular, it will be useful in determining the frequency distribution of cis-regulatory variants at steady state, the proportion of rare cis-regulatory variants (mostly reflecting variants maintained at mutation-selection equilibrium), and cis-regulatory variants that transiently reach intermediate frequencies (mostly reflecting runaway dynamics or possibly direct positive selection). Extensions of this theory are possible to explore how cis-regulator runaway might contribute to the evolution of the complexity of eukaryotic gene regulatory networks.

The second aim of this PhD project is to compare these predictions with actual ASE distribution data in eukaryotes. The approach will be to use the PopPhyl database (5), which contains 76 non-model species (in 31 families) spanning metazoan diversity. This database has the advantage of having been collected, sequenced and analyzed using standardized protocols. It also includes replicate individuals for each species and covers a wide diversity of species in terms of biology and ecology. This database will be expanded to include publicly available ASE data for a range of model species (e.g. Drosophila, yeast, mouse, Arabidopsis, maize) and in-house acquired data (on Silene, Daphnia and Artemia).

References:
1. J. C. Knight, Allele-specific gene expression uncovered. Trends in Genetics 20, 113–116 (2004).
2. M. S. Hill, P. Vande Zande, P. J. Wittkopp, Molecular and evolutionary processes generating variation in gene expression. Nature Reviews Genetics 22, 203–215 (2021).
3. P. J. Wittkopp, “Evolution of Gene Expression” in The Princeton Guide to Evolution, J. B. Losos, H. E. Hoekstra, Eds. (2013).
4. F. Fyon, A. Cailleau, T. Lenormand, Enhancer runaway and the evolution of diploid gene expression. PLoS genetics 11, e1005665 (2015).
5. https://kimura.univ-montp2.fr/popphyl/

Contexte de travail

The students will receive comprehensive training in state-of-the-art evolutionary genomics and theoretical population genetics. The students will spend most of their time in the Genetic and Evolutionary Ecology group (GEE) at the Centre d'Ecologie Fonctionnelle et Evolutive (CEFE), a large, ecology and evolution-focused research institute in Montpellier, Southern France, with possible visits of project partners elsewhere in France. Montpellier is a lively student town with a beautiful historic center, located about 10 km from the Mediterranean Sea. The PhD will be part of an advanced ERC project ('RegEvol', Thomas Lenormand), addressing novel ideas and theoretical predictions on the role of regulatory evolution for several important fundamental topics in evolutionary biology (sex chromosomes, maintenance of sex, complexity of gene networks, etc.). The students will join the team working on this project, including Aline Muyle, Denis Roze, Sylvain Glémin, Christoph Haag and Thomas Lenormand as well as other people recruited on the project. Sylvain Glémin and Thomas Lenormand will co-supervise the PhD.

Candidate requirements:
(1) Enthusiasm and genuine curiosity for evolutionary genetics, genomics, and evolutionary biology.
(2) An undergraduate degree in the subject area of evolutionary biology. Experience with genomics and/or population genetics and/or evolutionary theory is desirable.
(3) Strong quantitative skills. Experience with programming or bioinformatics is desirable.
(3) Strong oral and written communication skills in English (the work language for science at the CEFE is English).
(4) Ability to work both independently and in a highly collaborative environment.
(5) Well organized and highly motivated.

Contraintes et risques

There is no specific risk associated with this position