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Massively parallel genome sequencing has revolutionised the identification of Mendelian disease genes. This project will apply this approach to craniosynostosis, the premature fusion of the sutures of the skull. 1,2 . Oxford is one of 4 national referral centres for this condition, which has a prevalence of 1 in 2,250; we have one of the best characterised sample collections internationally, and we have a proven track record of success having identified and published more novel disease genes (MEGF8, TCF12, ERF, ZIC1, SMO, CDC45, IL6ST and several others still undergoing investigation) than any other group working on this group of diseases. The UK’s Genomics England 100,000 Genomes project (https://www.genomicsengland.co.uk/), with which we are closely involved, will provide further opportunities for discovery during the course of the studentship. The aim of this project will be to identify new human disease genes in craniosynostosis and other craniofacial malformations and understand their associated clinical features and pathophysiology.

Training Opportunities

You will be able to follow through the entire experimental process from choice of DNA sample to identification of a new disease gene. On the way you will learn how DNA is processed for whole exome capture and massively parallel sequencing and how the raw sequence is filtered. For the sequence variants remaining you will use a combination of bioinformatics tools, biological knowledge and analysis of the literature to identify the most likely candidate changes. You will then verify these in the original samples and, for the best candidate mutations, analyse the DNA sequence of a large number of independent samples to seek independent mutations. Success in this venture would lead to further molecular analysis of pathophysiology of the mutations using approaches tailored to the biological problem, potentially including modelling in mice. Several of the references provide examples of the types of experimental approach undertaken, tailored to the gene and mutations identified.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford. Students are also able to attend the Methods and Techniques course run by the MRC Weatherall Institute of Molecular Medicine. This course runs through the year, ensuring that students have the opportunity to build a broad-based understanding of differing research techniques.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.

The department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to support the careers of female students and staff.

Publications

1

Twigg SR, Vorgia E, McGowan SJ, Peraki I, Fenwick AL, Sharma VP, Allegra M, Zaragkoulias A, Sadighi Akha E, Knight SJ, Lord H, Lester T, Izatt L, Lampe AK, Mohammed SN, Stewart FJ, Verloes A, Wilson LC, Healy C, Sharpe PT, Hammond P, Hughes J, Taylor S, Johnson D, Wall SA, Mavrothalassitis G, Wilkie AO. 2013. Reduced dosage of ERF causes complex craniosynostosis in humans and mice and links ERK1/2 signaling to regulation of osteogenesis.Nat. Genet.,  45 (3), pp. 308-13.

2

Taylor JC, Martin HC, Lise S, Broxholme J, Cazier JB, Rimmer A, Kanapin A, Lunter G, Fiddy S, Allan C, Aricescu AR, Attar M, Babbs C, Becq J, Beeson D, Bento C, Bignell P, Blair E, Buckle VJ, Bull K, Cais O, Cario H, Chapel H, Copley RR, Cornall R, Craft J, Dahan K, Davenport EE, Dendrou C, Devuyst O, Fenwick AL, Flint J, Fugger L, Gilbert RD, Goriely A, Green A, Greger IH, Grocock R, Gruszczyk AV, Hastings R, Hatton E, Higgs D, Hill A, Holmes C, Howard M, Hughes L, Humburg P, Johnson D, Karpe F, Kingsbury Z, Kini U, Knight JC, Krohn J, Lamble S, Langman C, Lonie L, Luck J, McCarthy D, McGowan SJ, McMullin MF, Miller KA, Murray L, Németh AH, Nesbit MA, Nutt D, Ormondroyd E, Oturai AB, Pagnamenta A, Patel SY, Percy M, Petousi N, Piazza P, Piret SE, Polanco-Echeverry G, Popitsch N, Powrie F, Pugh C, Quek L, Robbins PA, Robson K, Russo A, Sahgal N, van Schouwenburg PA, Schuh A, Silverman E, Simmons A, Sørensen PS, Sweeney E, Taylor J, Thakker RV, Tomlinson I, Trebes A, Twigg SR, Uhlig HH, Vyas P, Vyse T, Wall SA, Watkins H, Whyte MP, Witty L, Wright B, Yau C, Buck D, Humphray S, Ratcliffe PJ, Bell JI, Wilkie AO, Bentley D, Donnelly P, McVean G. 2015. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders.Nat. Genet.,  47 (7), pp. 717-26.

3

Twigg SR, Wilkie AO. 2015. A Genetic-Pathophysiological Framework for Craniosynostosis.Am. J. Hum. Genet.,  97 (3), pp. 359-77.

4

Fenwick AL, Kliszczak M, Cooper F, Murray J, Sanchez-Pulido L, Twigg SR, Goriely A, McGowan SJ, Miller KA, Taylor IB, Logan C, WGS500 Consortium, Bozdogan S, Danda S, Dixon J, Elsayed SM, Elsobky E, Gardham A, Hoffer MJ, Koopmans M, McDonald-McGinn DM, Santen GW, Savarirayan R, de Silva D, Vanakker O, Wall SA, Wilson LC, Yuregir OO, Zackai EH, Ponting CP, Jackson AP, Wilkie AO, Niedzwiedz W, Bicknell LS. 2016. Mutations in CDC45, Encoding an Essential Component of the Pre-initiation Complex, Cause Meier-Gorlin Syndrome and Craniosynostosis.Am. J. Hum. Genet.,  99 (1), pp. 125-38.

Research Themes, Tools and Technologies

Supervisors

Key Dates for October 2018 Entry

Application deadline:  12 noon GMT on Monday 8 January 2018

Interviews for shortlisted candidates: Week commencing Monday 22 January 

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How to apply

To apply for a place on the DPhil in Medical Sciences you will need to submit an application using the online application form.

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