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Hypertrophic cardiomyopathy is a common and medically important inherited heart muscle disease. Genetic analysis using classical genetic approaches revealed that mutations in myofilament genes cause this condition in about 50% of affected families; this knowledge has led to major impacts on clinical care, including direct use of genetic testing. Our understanding of the pathways by which these mutations cause the condition has led to clinical trials of new medical therapies that are looking very promising. However, mutations in these genes are not found in around one half of affected individuals and families.

New high-throughput sequencing approaches now make it possible for the first time to try to identify the remaining disease genes and we have assembled whole genome sequence data on over two hundred unrelated individuals with HCM. We will also have extensive gene panel data on > 2,500 unrelated HCM patients. This project will use bioinformatic and potentially functional genomic analysis to identify novel disease genes and their downstream consequences.  Our group has an established track record in this area and will be able to deploy the necessary techniques to make important new discoveries (reviewed in Watkins et al. 2011; see also Carballo et al. 2009, Hastings 2016).  This is likely to include statistical genetic analysis (in collaboration with Prof Martin Farrall, e.g. see Walsh 2017) and potentially biochemical analysis of mutant proteins (in collaboration with Prof Charles Redwood), and/or creation through CRISPR genome editing of cellular or murine models (in collaboration with Prof Houman Ashrafian and/or Dr Katja Gehmlich (e.g. Yavari et al. 2016, Hastings 2016)).

Training Opportunities

This project has the scope to provide training in a wide range of analytical and experimental techniques, such that the science direction taken can be tailored to the individual student’s interests and goals.  Bioinformatics and computational approaches will draw on the substantial expertise of the Welcome Centre for Human Genetics (where part of my lab group is based). Downstream functional evaluation will provide essential wet lab skills with the support of an established group, both in the Welcome Centre for Human Genetics and the West Wing, John Radcliffe Hospital, including day to day supervision by a senior post-doc scientist or research fellow.

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

Carballo S, Robinson P, Otway R, Fatkin D, Jongbloed JD, de Jonge N, Blair E, van Tintelen JP, Redwood C, Watkins H. 2009. Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy.Circ. Res.,  105 (4), pp. 375-82.

2

Watkins H, Ashrafian H, Redwood C. 2011. Inherited cardiomyopathies.N. Engl. J. Med.,  364 (17), pp. 1643-56.

3

Hastings R, de Villiers CP, Hooper C, Ormondroyd L, Pagnamenta A, Lise S, Salatino S, Knight SJ, Taylor JC, Thomson KL, Arnold L, Chatziefthimiou SD, Konarev PV, Wilmanns M, Ehler E, Ghisleni A, Gautel M, Blair E, Watkins H, Gehmlich K. Combination of Whole Genome Sequencing, Linkage, and Functional Studies Implicates a Missense Mutation in Titin as a Cause of Autosomal Dominant Cardiomyopathy With Features of Left Ventricular Noncompaction. Circ Cardiovasc Genet. 2016 Oct;9(5):426-435

4

Yavari A, Stocker CJ, Ghaffari S, Wargent ET, Steeples V, Czibik G, Pinter K, Bellahcene M, Woods A, Martínez de Morentin PB, Cansell C, Lam BY, Chuster A, Petkevicius K, Nguyen-Tu MS, Martinez-Sanchez A, Pullen TJ, Oliver PL, Stockenhuber A, Nguyen C, Lazdam M, O'Dowd JF, Harikumar P, Tóth M, Beall C, Kyriakou T, Parnis J, Sarma D, Katritsis G, Wortmann DD, Harper AR, Brown LA, Willows R, Gandra S, Poncio V, de Oliveira Figueiredo MJ, Qi NR, Peirson SN, McCrimmon RJ, Gereben B, Tretter L, Fekete C, Redwood C, Yeo GS, Heisler LK, Rutter GA, Smith MA, Withers DJ, Carling D, Sternick EB, Arch JR, Cawthorne MA, Watkins H, Ashrafian H. Chronic Activation of γ2 AMPK Induces Obesity and Reduces β Cell Function. Cell Metab. 2016 May 10;23(5):821-36. doi: 10.1016/j.cmet.2016.04.003.

5

Watkins H. 2015. Tackling the achilles' heel of genetic testing. Sci Transl Med,  7 (270), pp. 270fs1.

6

Walsh R, Thomson KL, Ware JS, Funke BH, Woodley J, McGuire KJ, Mazzarotto F, Blair E, Seller A, Taylor JC, Minikel EV, Exome Aggregation Consortium, MacArthur DG, Farrall M, Cook SA, Watkins H. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 Feb;19(2):192-203.

Research Themes, Tools and Technologies

Supervisor

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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