Description du sujet de thèse

Decanalization by the exposome and emergence of complex diseases: putting Rendel's legacy back in the (now) molecular game using the Drosophila peripheral nervous system as a model
The ability of development to produce a nearly constant phenotype despite genetic and environmental variation corresponds to the process of canalization described by Conrad Waddington [1]. It has been proposed that the emergence of certain complex diseases can be interpreted as cases of decanalization [2]. Decanalization can be caused by changes in the environment that uncover cryptic genetic variation with phenotypic impact, here with health consequences. The concept of decanalization is timely in view of the increasing impact of anthropogenic changes (pollution, global warming) that have adverse effects on human health but do not affect all individuals similarly. The goal of this PhD project is to test the hypothesis that environmental factors can lead to decanalization in the light of the largely forgotten legacy of James M. Rendel (1915-2001). Rendel proposed that the canalization of a developmental system can be represented by the particular form of a function ϕ linking the quantity of a certain substance (noted “M” for “Make”) to the phenotype produced by this system. In the absence of canalization, this function is linear: any variation in the quantity of M is reflected by a proportional variation in the phenotype produced. By contrast, when the system is canalized, it results in a double threshold framing a plateau: for this range of values in the parameter space, the phenotype remains constant. Rendel's model was based on a very substantial body of experimental research, notably involving variation in the number of bristles in Drosophila [3]. Such a conceptual framework is very appropriate to interpret modern data and conversely Rendel's data can be interpreted with the modern knowledge in developmental genetics [4]. Thus, this interdisciplinary project will allow her/him to navigate between the history of the concepts of canalization/decanalization and experimental work allowing to test it in a tractable organism. The PhD candidate will be co-supervised by Jean-Michel Gibert, developmental biologist, and Laurent Loison, historian of science.
In a preliminary phase of the research, the PhD candidate will aim to understand what Rendel was aiming for, and how he articulated theory and experimentation, in a context of virtual absence of molecular data. For this, the study of Rendel's published sources will be a significant task in the project. In parallel, the PhD candidate will test experimentally the concept of environmental decanalization using the alteration of Drosophila peripheral nervous system development by the environment as a model. The pattern of four dorsocentral (DC) mechanosensory bristles on the adult thorax of Drosophila melanogaster is canalized and shows almost no variation. However, exposure to low developmental temperature or to methotrexate (a drug used to treat certain cancers and auto-immune diseases and found as pollutant in waste waters) induces the development of ectopic DC bristles. The PhD candidate will use the alteration of DC bristle development by these factors as a model of disease to test the hypothesis of decanalization by the exposome. First, he/she will use the genetic tools available in Drosophila to analyse how cold and methotrexate affect DC bristle development. Second, he/she will use a panel of sequenced isogenic lines derived from a natural population of Drosophila [5], expose each line to different environmental conditions and quantify DC bristle phenotypes. This will allow him/her to conduct genome-wide association studies and to identify natural genetic variation that makes some genotypes more susceptible to environmental changes. The impact of these variants on DC bristle development will be validated functionally (CRISPR-Cas9 genome editing, mendelian randomization). The PhD candidate will analyse how this natural genetic variation modulates the impact of the environment on development. This will be done in Rendel's conceptual framework, where M can now be interpreted as a proneural gene product whose amount is modulated by natural genetic variation and/or the environment.

References:
1. Waddington CH. Canalization of Development and the Inheritance of Acquired Characters. Nature. 1942;150: 563–565. doi:10.1038/150563a0
2. Gibson G. Decanalization and the origin of complex disease. Nat Rev Genet. 2009;10: 134–40.
3. Rendel JM, Sheldon BL, Finlay DE. Canalisation of development of scutellar bristles in Drosophila by control of the scute locus. Genetics. 1965;52: 1137–1151. doi:10.1093/genetics/52.6.1137
4. Usui K, Goldstone C, Gibert JM, Simpson P. Redundant mechanisms mediate bristle patterning on the Drosophila thorax. Proc Natl Acad Sci U A. 2008;105: 20112–7. doi:10.1073/pnas.0804282105
5. Mackay TF, Richards S, Stone EA, Barbadilla A, Ayroles JF, Zhu D, et al. The Drosophila melanogaster Genetic Reference Panel. Nature. 2012;482: 173–8. doi:10.1038/nature10811

Contexte de travail

The PhD candidate will be affiliated to the doctoral school “Complexité du vivant” (ED515). He/she will perform the experimental work in the team “Heterochromatin, Cell fate and Exposome” in the unit “Development, Adaptation and Ageing” (Dev2A), in the Institut de Biologie Paris-Seine (IBPS, Paris) under the supervision of Jean-Michel Gibert. The PhD candidate will visit regularly Laurent Loison (team “History and Philosophy of Biology”, SPHERE, Paris), who will supervise him/her for the history of science part. Regular meetings with both supervisors will ensure that the project goes smoothly.

Contraintes et risques

The PhD candidate will manipulate Drosophila and perform immunostainings on dissected tissues. The functional validation of genetic variants identified in genome wide association studies will involve molecular biology experiments. The project will involve the manipulation of fly tubes with medium containing methotrexate. All required protection measures will be taken when necessary (gloves, work under a fume hood).

Informations complémentaires

Candidates should have a Master's degree or an engineer degree in biology. Previous experience with drosophila would be an advantage but is not essential. A strong interest in history of science is required. The position requires good oral and written communication skills (English necessary). We are looking for a young, curious and enthusiastic researcher who is able to work in a team on multidisciplinary projects. Applications should include a detailed CV, at least two references (people likely to be contacted), a one-page covering letter, a one-page summary of the Master's thesis and marks from Master's 1 and 2 or engineer school.