Functional analyses of newly implicated genes for inherited heart muscle diseases

Cardiomyopathies are common and medically important inherited heart muscle diseases, typically showing autosomal domain inheritance. Genetic analysis using classical genetic approaches revealed that the commonest cardiomyopathy, Hypertrophic Cardiomyopathy, is caused by mutations in myofilament genes 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 myofilament genes are not found in around one third of affected individuals and families. In other cardiomyopathies, such as Dilated Cardiomyopathy (DCM), and Left Ventricular Non-Compaction (LVNC), it is clear that many new genes remain to be discovered.

We have used whole genome sequencing in families with unexplained or novel cardiomyopathy phenotypes to discover novel disease genes and syndromes. This work often generates plausible, but not proven, novel disease genes and variants that then require further human genetic and functional validation. This project will use bioinformatic and 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 Marston et al. 2009). This is likely to include biochemical analysis of mutant proteins in collaboration with Prof Charles Redwood (eg see Oliveira 2012), analysis of human iPS lines derived from patients with Dr Daniels, and/or creation and phenotyping of animal models through genome-editing techniques such as CRIPSR, in collaboration with Prof Houman Ashrafian and/or Dr Katja Gehmlich (e.g. see e.g. Cahill 2015, Yavari et al. 2016, Hastings 2016).

TRAINING OPPORTUNITIES

This project has the scope to provide training in a wide range of experimental techniques, including work in iPSCs and genome editing, 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 Trust 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.