Origins of chromosomal abnormalities in human embryos

Division of Biomedical Sciences, Warwick Medical School, University of Warwick, and Biomedical Research Unit in Reproductive Health, University Hospitals Coventry and Warwickshire NHS Trust.

Project title: Origins of chromosomal abnormalities in human embryos

Project description Kinetochores attach chromosomes to the spindle during cell division. Their function is critical for normal distribution of chromosomes to daughter cells. Errors in this process, in human oocytes or early embryos, predispose to genetic disorders such as Trisomy 21 Down Syndrome, which is the commonest inherited cause of disability.

Human eggs and embryos have a very high risk of chromosomal abnormalities. The origin of this high degree of chromosomal disorder remains uncertain although many hypotheses have been proposed.

We have discovered an unusual age-related dissociation of the sister kinetochores in humans that differ from other species and may underlie the maternal age-related increase in chromosomal abnormalities (see: Patel et al, Biology Open, 5:178-84, 2015 and also the related work in Zielinska et al; eLife, e11389, 2015.)

The purpose of this project is to build on this initial work to answer two key questions:
• How do the architecture and mechanical properties of the kinetochore adapt as they progress from meiosis to mitosis?
• What are the originating chromosome mis-segregation events during the meiotic and early mitotic divisions in the human embryo?
Methodology
It is envisaged that the following approaches will be used:

• Human oocytes will be fixed and stained with antibodies to components of the kinetochore structure and image stacks acquired using spinning disk confocal microscopy. We can then build up a 3D model of kinetochore architecture (see: Smith et al, eLife, 2016 e161159) and test its responses to changed conditions.

• We will begin analysis of human embryos in the first 5 days of development. Comparisons will be made between kinetochores in cells with normal and abnormal numbers of chromosomes to investigate how missing or additional chromosomes might relate to alterations in kinetochore architecture.

• We will use live cell imaging to follow the movements of chromosomes (and kinetochores) during meiotic and mitotic divisions of the human embryo. These experiments will build on our previous work in human cells (Burroughs et al, eLife, 2015 e09500) and use our existing computational biology tools (Armond et al, Bioinformatics, 2016 32:1917-9).
Techniques to be employed

• Culture of human somatic cells and oocytes.
• Standard molecular biology.
• Quantitative immunofluorescence in human oocytes and somatic cells.
• Individual or multicolour FISH to identify chromosomes abnormalities.
• Microinjection of human oocytes.
• Live cell imaging using spinning disk confocal and/or light sheet microscopy.
• MATLAB software for kinetochore tracking.

The successful candidate will join a vibrant research team at the University of Warwick within the Division of Biomedical Sciences, working in conjunction with the Biomedical Research Unit in Reproductive Health and the Centre for Reproductive Medicine at University Hospital Coventry. The student will be expected to spend approximately 30% of his/her time at the hospital site and the rest at the Gibbet Hill campus of Warwick Medical School. The project will be jointly supervised by Professors Andrew McAinsh and Geraldine Hartshorne, Warwick Medical School.

This project is at the interface of cell biology, reproductive medicine and computational biology/mathematics. Students will need a strong biology background and to be comfortable in both basic science and clinical environments. No direct contact with patients is expected, but appropriate behaviour, a professional appearance and strict adherence to regulations are mandatory in the clinical setting. Background checks will be carried out.

This studentship is available to Home and EU students, according to fee status.
The studentship includes fees for the successful candidate along with a maintenance allowance in line with Research Council UK standard stipend (£14553 for 2017/18) and a consumables allowance.
Start Date
The successful candidate will be expected to start on 3 October 2017.
Closing Date
The closing date for applications is the 6 August 2017.
Interviews will be held on the 15 August 2017 at the University of Warwick.
How to Apply
To apply, please send a copy of your Curriculum Vitae (CV) and a one-page personal statement to
[Email Address Removed] clearly stating the studentship you are applying for.

Please contact Prof Andrew McAinsh or Prof Geraldine Hartshorne for further information:
[Email Address Removed] / [Email Address Removed]