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  • Martin Farrall, Anuj Goel, Hugh Watkins

about the research

Large-scale genetic epidemiological studies have been used to reassess the pathogenicity of genes for Mendelian inherited cardiac conditions (ICCs) such as cardiomyopathy (Walsh et al. 2017; Thomson et al. 2019). These studies rely primarily on quantifying the burden of rare exonic variants in patients noting that annotation of variants (amino-acid position, protein domain, bioinformatically predicted functional effects etc.) can provide useful supplementary information on pathogenicity. We are developing analysis frameworks to integrate these information sources to: 1) produce a computationally rapid and statistically powerful association methods to scan for novel ICC genes in whole-exome sequence data 2) to explore flexible generalized regression methods using adaptive smoothing functions to evaluate the pathogenic potential of individual rare variants and 3) develop models to simultaneously fit the effects of rare variants with common modifier alleles.

We are also interested in the natural rates of rare exonic variant burden across ancestry groups. This question has broad implications for the interpretation of burden-based association statistics, is subject to different population genetic forces to those that drive common variant allele frequencies, and is tractable using large population reference databases of whole-genome sequence (WGS) data.

training opportunities

There will opportunities to develop and apply research methodologies in statistical genetics and bioinformatics. Students will attain fluency in programming in at least one high-level statistical analysis package (e.g. R, Stata). Projects are based in the Wellcome Centre for Human Genetics, which has local access to high-performance computer facilities and a thriving community of statistical geneticists and bioinformaticians who enjoy focussed seminars and workshops.

Students are encouraged to attend the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide-range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

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.

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.

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 build a happy and rewarding environment where all staff and students are supported to achieve their full potential.


Walsh et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017 19(2):192-203

Thomson et al. Analysis of 51 proposed hypertrophic cardiomyopathy genes from genome sequencing data in sarcomere negative cases has negligible diagnostic yield. Genet Med. 2019 21(7):1576-84