Human Genetics, Genomics and Disease: Preventing and detecting chromosomal aneuploidy in human pluripotent cells

Location:     MRC Human Genetics Unit, University of Edinburgh, UK & Max Delbrück Center, Berlin, Germany 

Supervisors: Prof Ian Adams, Prof Zsuzsanna Izsvák

Applications are invited from outstanding candidates for an MRC funded 3.5-year international visiting PhD studentship in Human Genetics, Genomics and Disease. This studentship will involve a collaborative research project between the MRC Human Genetics Unit (HGU), part of the Institute of Genetics and Cancer at the University of Edinburgh, UK and the Max Delbrück Center for Molecular Medicine (MDC) in Berlin, Germany. This studentship will be primarily based in HGU at the University of Edinburgh and will involve collaborative research visits to MDC in Berlin. Successful candidates will benefit from high quality training, mentorship, cutting-edge technological infrastructure and research excellence across both institutions to develop their abilities to tackle challenging questions in biomedical research.

Project Outline

Early human embryos are prone to mitotic chromosome segregation errors and as a result most human pre-implantation embryos contain some aneuploid cells. Pre-implantation embryos with high levels of mosaic aneuploidy are generally associated with higher rates of implantation failure and miscarriage. Factors that influence mitotic chromosome segregation in the pluripotent cells within human pre-implantation embryos, and the way that these cells respond to aneuploidy, remain poorly characterised. The aim of this project is to model mechanisms that help prevent or detect chromosomal aneuploidies in early stages of human development.

Research from the Izsvák and Adams labs suggests that transposable elements (TEs), sequences derived from mobile DNA that comprise over half of our genomes, can influence genome stability in pre-implantation mammalian embryos. TEs are usually highly expressed during early embryogenesis and germline specification and may contribute to the rapid evolution of these developmental stages and influence genome stability in a positive or negative way. While active TEs can mediate novel virus-like integration events in the genome of the early embryo, transposition-incompetent, inactive TE-derived sequences that are co-opted by the host can support genome stability. The central hypothesis of this proposal is that co-opted TEs (such as HERVH) play a role in supporting chromosome stability in pluripotent cells and/or germ cells during development.

To test this hypothesis, this project will genetically manipulate candidate TEs (HERVH) and/or host genes involved in regulating both TEs and chromosome stability (e.g. TEX19) through CRISPR/Cas9-editing in pluripotent human embryonic stem cells (hESCs), and subsequently differentiating these cells into human primordial germ cell-like cells (PGCLCs) in vitro. We will use assays for premature sister chromatid separation to assess the effects of these genetic manipulations on chromosome behaviour and aneuploidy, and multi-omic analyses to investigate how human pluripotent cells detect and respond to chromosomal aneuploidy. This project will allow us to better understand the mechanisms underlying some of the chromosomal abnormalities associated with implantation failure and miscarriage in humans.

Who should apply?

We are seeking motivated students excited by new opportunities who are keen to engage in high quality biomedical research. Applicants should have a UK or international 1st class or 2.1 degree or a Masters in any relevant discipline in biological or biomedical sciences. Applications are open to all individuals irrespective of nationality or country of residence. All applicants should satisfy the University of Edinburgh’s English language requirements. 

Studentships are available to start in September 2024. These studentships are fully funded and include tuition fees, an allowance for research consumables and an enhanced UKRI stipend of £20,122 p/a.

Application procedure

Closing date: 19 May 2024.

Interviews: 12-13 June 2024.

To apply for this PhD studentship, please go to our Graduate Research and Training website (www.ed.ac.uk/mrc-human-genetics-unit/graduate-research-and-training).

For informal enquiries about this project, please contact Ian Adams ([email protected]).

For more information about the research that we do, please visit our websites (www.ed.ac.uk/mrc-human-genetics-unit and http://www.mdc-berlin.de).