How meiotic checkpoints prevent mutations and aneuploidy in offspring

This 4-year PhD studentship is offered in Dr James Turner’s Group based at the Francis Crick Institute (the Crick).

A critical step in the development of mammalian sperm and eggs is meiosis, during which maternal and paternal homologues pair and exchange genetic information. Meiosis is inherently error-prone: the programmed double-strand breaks (DSBs) that permit genetic exchange are sometimes not repaired correctly, or they fail to mature into crossovers that are essential for accurate chromosome segregation. Because these meiotic errors are passed on in the gametes, they can cause mutations or aneuploidy in offspring (1).

To prevent these outcomes, mammals are equipped with meiotic checkpoints, which eliminate cells carrying unrepaired DSBs or unpaired homologues (1). Our lab has recently shown that the pro-apoptotic factors PUMA, NOXA and BAX are essential effectors of this pathway. When these genes are deleted, germ cells with persistent DNA damage or unpaired chromosomes are not eliminated, resulting in meiotic catastrophe. PUMA, NOXA and BAX all act at the end of the checkpoint pathway. However, the proteins that act at the beginning of the checkpoint, i.e. that first detect the meiotic errors, are unknown. Based on their established mitotic checkpoint functions (2), the DNA damage PI3-kinase-like-kinase (PI3KK) family ATM, ATR and PRKDC are good candidates to fulfil this role.

In this project, you will decipher the contributions of the PI3KK family in the meiotic pairing and DSB checkpoints. You will study how ATM, ATR and PRKDC, as well as their phosphor-targets, are activated in response to meiotic defects in mouse oocytes. Using already established conditional mouse mutants (3,4) and novel CRISPR-derived lines, you will investigate whether ATM, ATR and PRKDC deletion prevent oocyte arrest in response to these meiotic errors. Finally, you will examine the influence of ablating meiotic checkpoints on genome stability and aneuploidy in offspring. The project is designed to give you broad expertise in developmental biology and embryology, chromosome biology, genome editing, DNA metabolism and computational biology.

This is just one example of the sort of project that might be available in this research group. The precise project will be decided on in consultation with the supervisor.

Talented and motivated students passionate about doing research are invited to apply for this PhD position. The successful applicant will join the Crick PhD Programme in September 2019 and will register for their PhD at one of the Crick partner universities (Imperial College London, King’s College London or UCL).

Applicants should hold or expect to gain a first/upper second-class honours degree or equivalent in a relevant subject and have appropriate research experience as part of, or outside of, a university degree course and/or a Masters degree in a relevant subject.

APPLICATIONS MUST BE MADE ONLINE VIA OUR WEBSITE (ACCESSIBLE VIA THE ‘APPLY NOW’ LINK ABOVE) BY 12:00 (NOON) NOVEMBER 13 2018. APPLICATIONS WILL NOT BE ACCEPTED IN ANY OTHER FORMAT.