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Reference : UMR9198-ERIESP-002
Workplace : ORSAY
Date of publication : Thursday, June 10, 2021
Scientific Responsible name : Eric Espagne and Stéphanie Boisnard
Type of Contract : PhD Student contract / Thesis offer
Contract Period : 36 months
Start date of the thesis : 1 October 2021
Proportion of work : Full time
Remuneration : 2 135,00 € gross monthly
Description of the thesis topic
Shuffling of maternal and paternal alleles through meiotic recombination increases genetic diversity in the progeny and ensures the accurate segregation of homologous chromosomes during the first meiotic division. Errors in segregation lead to the formation of aneuploid gametes and/or sterility. However, the mechanisms responsible for both formation and regulation of crossing-overs (COs) remain largely unknown.
Meiotic recombination starts with the formation of programmed DNA double strand breaks (DSBs). The repair of DSBs preferentially uses the homologous chromosome as a template, generating COs and non-crossing-overs (NCOs). Their accurate repair is essential for both the pairing of homologous chromosomes and the establishment of the pairing structure called the synaptonemal complex. The formation of both DSBs and COs is tightly regulated. The choice between NCO and CO is crucial to ensure the presence of at least one CO per homologous pair (independently of the size of the chromosomes) to allow the required link essential for their proper segregation. In addition, the occurrence of a CO at one position disfavors the occurrence of a CO nearby, leading to evenly spaced COs along the chromosomes by the phenomenon called interference. As this phenomenon requires the propagation of an inhibition signal along the chromosome, the number of COs per bivalent depends, therefore, on both the length of the axis and the strength of the interference signal.
Although CO interference was first described in 1916, the actors of this essential regulatory process remain unknown. The only pathway known to play a role in interference modulation is the TopoII pathway, involved in the posttranslational modifications (SUMOylation and ubiquitination) of two axis components in Saccharomyces cerevisiae. Our preliminary results show that this pathway is conserved in our model system Sordaria macrospora. We showed, moreover, that in three null mutants of this pathway: (i) the number of COs is increased, (ii) their location along chromosomes is changed, (III) interference strength is decreased and (iv) chromosome axis lengths are changed when compared to wild type.
Based on these robust preliminary results, the overarching goal of this project will be to understand the mechanisms and players involved in CO interference of S. macrospora by combining genetics, molecular biology, genomics and cytological approaches. Three axes are proposed:
(1) Precise characterization and role of the three mutants (above) with modified CO interference using the high resolution of the single-cell imaging approaches available in this model organism,
(2) Search for new actors of the CO interference process (e.g. proteins involved in chromatin conformation or in post-translational modifications, or axis composition).
(3) Characterize the relationship between axis length and CO interference on the one hand, and between DSB localization and CO patterning on the other hand.
By shedding a new light on the molecular mechanisms that govern CO number and patterning along chromosomes, the project will deepen our understanding of the basic logic of CO patterning and of its molecular mechanisms, which constitute a critical knowledge for the scientific communities working either on human fertility or plant breeding.
This position, funded by a grant from the ANR (CO-PATT; 2021-2024), will be carried out in the I2BC, a very large joint CNRS, CEA and Paris-Saclay University research unit. The institute, located both on the Gif-sur-Yvette research campus and the Faculté d'Orsay campus, groups nearly 700 people divided between 65 research teams and 13 high-level technological platforms. The project will be developed in the "Recombination and Meiotic Pairing" team, composed of 5 researchers, a Research Engineer and a PhD student, under the supervision of E. Espagne and S. Boisnard. The laboratory is currently located in Orsay (building 400), a move to new buildings in Gif-sur-Yvette is planned for 2022.
The techniques and equipment required for the project are available in the team or in a nearby environment. The many technical platforms of the I2BC are an asset for the project.
Constraints and risks
Possible risks associated with laboratory work
The candidate will have obtained a Master's degree during which he/she will have done a research internship in cellular and/or molecular biology. He/she should have good knowledge and skills in genetics.
Please attach to your application, your CV, official Master's transcript and a cover letter explaining your motivation and research work as well as the contact details (email) of two referees. The doctoral student will be followed by an individual monitoring committee and a tutor will monitor the progress of the research.
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