Sexual reproduction depends on the transmission of exactly one copy of each chromosome by the male and female gamete during fertilisation. Gametes become haploid during a specialised cell division known as meiosis. Female meiosis is error prone and this increases markedly as women get older. As a consequence, there is a sharp decline in fertility and an increased risk of miscarriage and birth defects from the age of ~35 years. Taken together with the increased tendency for women to delay starting a family, female reproductive ageing is one of the most pressing problem for human reproductive health.
Meiosis is a highly conserved process involving meiotic recombination between replicated parental homologues to from bivalent chromosomes, which are resolved to their four constituent chromatids during two successive meiotic divisions. This depends on stepwise removal of chromosomal cohesion: first from arms during meiosis I and then from centromeres during meiosis II. In females, meiosis occurs over an extraordinarily protracted period, commencing during fetal life and not completed until the mature egg is fertilised. Baby girls are born with their lifetime supply of primordial oocytes arrested in prophase of meiosis I. During the decades between being formed and recruited for growth and ovulation, primordial oocytes have the task of maintaining their nuclear and mitochondrial genomes in a pristine condition for transmission to the next generation. During this time bivalent chromosomes are stabilised by cohesin complexes containing the meiosis-specific subunit Rec8. We have previously found that female ageing is characterised by a marked reduction in oocyte chromosome-associated Rec8. Moreover, we found that this was associated with reduced recruitment of a protein known as Sgol2, which protects centromeric cohesin until the second meiotic division (Lister et al, 2010, Curr Biol). We also observed a marked age-related reduction in the level of kinetochore proteins recruited to oocyte centromeres. A primary goal of this project is to investigate the causes and consequences of age-related changes occurring at the centromere and to determine whether these are reset after the egg is fertilised. In addition, we will determine whether mitochondrial turnover reported to occur around the time of fertilisation also acts as a “resetting” mechanism to eliminate mtDNA mutations acquired during oogenesis. Experiments will be conducted in mouse and human oocytes.
Broader implications of the project: The findings of the project will advance our understanding of the underlying causes female age-related infertility. In addition, the work has the potential to provide novel insights on the cell biology of ageing and mechanisms of regeneration.
Experimental approach and training: Core techniques include super-resolution imaging of oocytes at all stages of development including after fertilisation. Making molecular tools for live cell imaging. Training will be provided in oocyte manipulation and micro-injection and 4D high resolution live cell imaging and advanced image analysis to study dynamic events in oocytes and early embryos. Next generation sequencing will be used for analysis of mitochondrial DNA.
Link to lab webpage: http://www.newcastle-mitochondria.com/prof-mary-herbert/
Benefits of being in the DiMeN DTP:
This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.
We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.
Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: http://www.dimen.org.uk/overview/student-profiles/flexible-supplement-awards
Further information on the programme can be found on our website: http://www.dimen.org.uk/
Studentships are fully funded by the Medical Research Council (MRC) for 3.5yrs
Stipend at national UKRI standard rate
Research training and support grant (RTSG)
Studentships commence: 1st October 2019.
To qualify, you must be a UK or EU citizen who has been resident in the UK/EU for 3 years prior to commencement. Applicants must have obtained, or be about to obtain, at least a 2.1 honours degree (or equivalent) in a relevant subject. All applications are scored blindly based on merit. Please read additional guidance here: View Website
Hyslop et al., (2016). Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease. Nature: 534, 383-386. PMID 27281217
Herbert et al., (2015). Meiosis and maternal ageing: Insights from aneuploid oocytes and trisomy births. Cold Spring Harbor Perspectives in Biology: 7(4):a017970. PMID 25833844
Lister et al., (2010). Age-related meiotic segregation errors in mammalian oocytes are preceded by depletion of cohesin and Sgo2. Current Biology: 14;20(17):1511-21. PMID: 20817533