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Elucidating mechanisms of chromosome mis-segregation and aneuploidy in mammalian eggs and embryos


Warwick Medical School

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Prof A McAinsh , Prof G Hartshorne No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

This project is available through the MIBTP programme on a competition basis. The successful applicant will join the MIBTP cohort and will take part in all of the training offered by the programme. For further details please visit the MIBTP website - https://warwick.ac.uk/fac/cross_fac/mibtp/

Fertilisation of an egg with a sperm produces a single-cell zygote that undergoes serial divisions to produce an embryo, and ultimately a human being. For development to proceed normally the zygote should contain 46 chromosomes (23 from the egg and 23 from the sperm). However, in humans this process often fails, resulting aneuploidy (the wrong number of chromosomes) which is associated with recurrent miscarriage and infertility. It is estimated that 15% of couples in the UK experience infertility, while 1% of women experience recurrent miscarriage. Furthermore, gains of a single chromosome (trisomy) is associated with lifelong developmental disorders such as Downs syndromes.

It is well established that human female fertility decreases with advancing maternal age (Gruhn et al, 2019), and this is attributed to increased chromosome segregation errors during the first meiotic division – which generate the haploid eggs (Zielinska et al, 2015, Holubcová et al, 2015). It is also known that human embryos can be mosaic (different cells with different chromosome numbers) and that this is likely due to chromosome segregation errors during the mitotic divisions of the embryo.

We have recently made ground-breaking observations by directly observing chromosomes for the first time in live human one and two cell embryos (Ford et al, 2020). This has provided new insight into the molecular origin of aneuploidies at the start of human life, which are surprisingly common and can be compatible with healthy foetal development. We discovered that mistakes are made frequently during the first division of the zygote, including segregation of the chromosomes into more than two masses! – see example movie in the figure above, in which a single-cell embryo can be seen dividing with errors (chromosomes visualised with a fluorescent DNA dye in the upper row; brightfield imaging of the same embryo in the lower row).

In this project you will build on these exciting findings using live cell imaging with light sheet and super-resolution microscopes to improve temporal and spatial resolution. This in itself will be transformative for our understanding of these processes. You will then work to label different cellular structures in bovine and human eggs/embryos and establish imaging protocols to follow these through meiosis and the first cleavage divisions of the embryo. With these new tools, and the use of small molecule inhibitors, we will be able to address key questions that will provide great insight into human infertility:

1. Do surveillance mechanisms function during mammalian meiotic and early mitotic divisions? The ability to visualise ‘checkpoint proteins’ in live eggs/embryos will provide great insight into the control of chromosome segregation during meiosis and early mitosis in mammals. We can then probe these functions through the use of small molecule inhibitors to elucidate molecular mechanisms and investigate the effects of maternal age.
2. What is the fate of cells that make errors during the first cleavage division in human embryos? Both our current data, and observations made in the clinic, suggest that the first mitotic division of the human embryo is highly error-prone, while the following divisions appear to be unremarkable. By imaging these processes in higher resolution and for longer durations we hope to be able to shed light on the fate of error-prone embryos, and investigate whether there are more errors in the later divisions.

In this project you will learn how to conduct live cell imaging of human eggs and embryos donated by volunteer patients at the Centre for Reproductive Medicine (CRM) at University Hospitals Coventry & Warwickshire (UHCW), alongside bovine oocytes matured in vitro. You will also use molecular biology and biochemical techniques to apply new approaches for visualising cellular structures within these highly unique cells. This project is particularly collaborative, and you will work together with NHS embryologists and research scientists at Warwick and Edinburgh Universities. Overall, you will be trained in a variety of standard and highly specialised techniques which will allow you to address important cell biological questions using innovative and challenging systems.

BBSRC Strategic Research Priority: Integrated Understanding of Health: Ageing

Techniques that will be undertaken during the project:
• Basic embryology techniques including microinjection
• Live cell imaging of eggs and embryos (Spinning disk confocal and light sheets)
• Molecular biology (PCR, cloning, mRNA expression)
• Biochemical methods (protein purification)
• Dissection of animal material
• In vitro maturation of oocytes

References

Gruhn, J., Zielinska, A., Shukla, V., Blanshard, R., Capalbo, D. et al (2019) Chromosome errors in human eggs shape natural fertility over reproductive lifespan, Science 365:1466-1469

Zielinska, A., Holubcová, Z., Blayney, M., Elder, K. and Schuh, M (2015) Sister kinetochore splitting and precocious disintegration of bivalents could explain the maternal age affect, eLife 4:1-19

Holubcová, Z., Blayney, M., Elder, K. and Schuh, M (2015) Error-prone chromosome-mediated spindle assembly favors chromosome segregation defects in human oocytes, Science 348: 1143-1147

Ford, E., Currie, C., Taylor, D., Erent, M., Marston, A., Hartshore, G. and McAinsh, A. (2020) The first mitotic division of the human embryo is highly error-prone, bioRXiv, doi: 10.1101/2020.07.17.208744
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