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How does meiotic DNA replication shape sexual genetic recombination?

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  • Full or part time
    Dr A Lorenz
    Prof A Donaldson
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description

The mitotic cell cycle, a recurring cellular process consisting of DNA replication followed by cell division, produces two identical daughter cells from a single mother. Accurate execution of the cell cycle is of the utmost importance to maintain genome integrity and cell health. Importantly, cell cycle dysregulation is a hallmark of cancer.
DNA is replicated during S phase of the cell cycle, while division occurs during M phase. Generally, the duration of the cell cycle (and of S phase) is similar for cells of the same species. Intriguingly however, the cell cycle that initiates meiosis (the cell division producing gametes) proceeds much more slowly. Two meiotic cell cycle stages are especially elongated: meiotic S phase and meiotic Prophase I last three-times longer than their mitotic counterparts. Meiotic Prophase I requires more time due to the requirement for chromosome pairing, recombination, and synaptonemal complex formation. However, the reasons for, and mechanistic causes, of the long meiotic S phase remain unexplained.
This project will explore and elucidate the mechanism and regulation of the long meiotic S phase. Using as models the budding yeast Saccharomyces cerevisiae and the fission yeast Schizosaccharomyces pombe, we will address the following objectives:
1) Determining origin use and replication fork speed in meiotic S phase
The long meiotic S phase could be caused by firing of fewer replication origins, or by replication forks moving more slowly than in mitotic S phase. We will assess whether the same set of replication origins is used in meiotic S phase as in mitosis, and determine whether fork speed is similar.
Replication origin firing will be compared in mitotic and meiotic S phase cells using genome-wide replication profiling based on next-generation sequencing analysis. This will reveal whether the same origins are used in meiosis and mitosis, and whether they initiate replication in the same order.
Fork speed will be examined by multi-colour fibre labelling or by DNA fibre labelling combined with DNA combing and fluorescence in situ hybridization.
2) Characterizing Sz. pombe mutants with altered (meiotic) S phase
To elucidate how the special meiotic S phase is regulated, meiotic S phase will be examined in Sz. pombe mutants already known to affect mitotic replication or progression through meiosis. We will also test the effects of derailed meiotic replication on subsequent events including recombination and chromosome segregation.
3) Testing conservation by comparison with S. cerevisiae
To ascertain whether mechanisms controlling meiotic DNA replication progression are evolutionarily conserved, homologs of interesting candidate regulators identified in Sz. pombe will also be characterized in S. cerevisiae. Mechanisms that control meiotic DNA replication in both these distantly related yeasts are strong candidates for controlling meiosis in mammalian cells.
This project will employ a variety of state-of-the-art techniques including data-driven biology to elucidate how and why meiotic S phase is much longer than mitotic S phase. The successful candidate will be trained in a genetics, genomics, and molecular cell biology techniques and will exploit new ways of working to elucidate a fundamental cellular process crucial to cell health and fertility. The student will gain skills in data-driven biological research by generating a comparative database of origin usage of mitotic vs meiotic yeast cells via next-generation sequencing; additional training in DNA combing, fluorescence in situ hybridization, and comparative yeast genetics will be provided.

This project is advertised in relation to the research areas of MEDICAL SCIENCES. Formal applications can be completed online: You should apply for Degree of Doctor of Philosophy in Medical Sciences, to ensure that your application is passed to the correct person for processing.

NOTE CLEARLY THE NAME OF THE SUPERVISOR AND EXACT PROJECT TITLE ON THE APPLICATION FORM. Please apply for admission to the ’Degree of Doctor of Philosophy in Medical Sciences’ to ensure that your application is passed to the correct school for processing.

Candidates should contact the lead supervisor to discuss the project in advance of submitting an application, as supervisors will be expected to provide a letter of support for suitable applicants. Candidates will be informed after the application deadline if they have been shortlisted for interview. Interviews are expected to take place on 23rd or 24th July 2019.

Funding Notes

This project is part of a competition funded by the Institute of Medical Sciences. Full funding is available to UK/EU candidates only. Overseas candidates can apply for this studentship but will have to find additional funding to cover the difference between overseas and home fees (approximately £15,680 per annum).

Candidates should have (or expect to achieve) a minimum of a 2.1 Honours degree in a relevant subject. Applicants with a minimum of a 2.2 Honours degree may be considered provided they have a Merit/Commendation/Distinction at Masters level.

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