Goriely Group: Investigating the role of genetic mosaicism in congenital disease

About the Research 

Genetic diseases are usually caused by mutations that are either inherited from a parent or occur de novo in the parental germline. In both cases all the cells in the affected child will carry the causative mutation. However, in some cases pathogenic mutations occur after fertilisation - during early development of the embryo - and in this case, only a proportion of an individual’s cells carry the mutation, a phenomenon known as mosaicism. With improved sequencing technologies, it has become apparent that mosaicism is not as rare as previously thought. Moreover, there are conditions which are much more frequently caused by mosaic mutations. For example, up to 20% of cases of Cornelia de Lange Syndrome are caused by mosaic mutations and the pathogenic mutation is almost always missing from blood cells. Similarly, focal cortical dysplasia, a common cause of epilepsy, is commonly associated with mosaic mutations. In this DPhil project, you will work with the Goriely lab (based at the MRC Weatherall Institute of Molecular Medicine) and with the Beagrie lab (based at the Wellcome Centre for Human Genetics) to study how mosaic mutations affect development and cause disease. Specifically, you will use develop methods to quantify low level of mosaic variants and use a conditional inducible mouse models to study how cells bearing mutations in known disease genes expand and compete with their wild-type counterparts in different tissues.

Training Opportunities 

This project represents a unique opportunity to gain in-depth training in Human and mouse Molecular Genetics, and the application of Next-generation sequencing technologies for detection of rare variants. The project can be tailored to suit personal interests and need for training but will typically involve a main wet-lab component combined with bioinformatic and statistical analysis. Training will be provided both in basic molecular biology (DNA extraction, PCR, sequencing, genotyping, haplotyping) as well as use in the use of advanced technologies. It should be of particular value to individuals with an interest in analysis of mutation, genomic mechanisms of disease, clinical diagnosis and application of state-of-the-art genomics technologies. Attendance at (international) meetings to present and discuss data is encouraged.

Students will be enrolled on 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.

Additional Supervisors 

Publications