De Novo Mutations and Human Disease

De novo mutations (DNMs) are a significant contributor to human disease, affecting ~1:300 new births. We study the mechanisms by which these spontaneous mutations arise in the first instance, concentrating on the tissue where most originate, the human testis. We aim to understand why some pathogenic mutations arise more frequently than others and how the mechanisms regulating the production of sperm influences this process.

Most (>80%) DNMs originate in the paternal germline during spermatogenesis, explaining why the main risk factor for DNMs is the age of the father at conception. The human testis represents a ‘repository’ of DNMs that can be exploited to study the process by which new mutations are acquired at each generation. We have previously described a mechanism contributing to the paternal age-related increase in pathogenic DNMs called ‘selfish selection’, a process equivalent to neoplasia but occurring in the unique context of the male germline stem cell.  These ‘selfish’ DNMs become enriched with age, because they “hijack” the normal homeostatic mechanisms controlling spermatogonial stem cells to their own advantage, thorugh a process akin to ‘clonal hematopoiesis’ or tumorigenesis. However, unlike somatic variants in tumours, selfish mutations are transmitted across generations and have the potential to cause disease and/or shape human genome evolution.  

Although most DNMs are one-off events that occur during spermatogenesis, they can also originate through a process called ‘gonadal mosaicism’. In this case, the DNM would have arisen early during one of the parents’ development and will be present in multiple eggs or sperm, leading to an increased recurrence risk (as high as 50%). Hence it is essential to be able to single-out DNMs caused by gonadal mosaicism from the more common one-off events which have no risk of recurring in another child.  

This project will aim to develop methods for identification of new genes/molecular pathways subject to selfish selection in the human testis (and within large population datasets) and establish how the male germline’s regulative properties influence the rate and type of new mutations we all acquire at each generation.  Deciphering the landscape of de novo germline mutations will allow the development of non-invasive prenatal screening approaches and support personalised reproductive counselling for couples who are at increased risk of having a child affected by a spontaneous disorder caused by a DNM. 

Additional supervision may be provided by Dr Nicky Whiffen and Professor Jenny Taylor from the Wellcome Centre of Genetics.

This project represents a unique opportunity to gain in-depth training in Human Molecular Genetics, analysis of large-scale genomics datasets 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 wet-lab component combined with bioinformatic and statistical analysis of large-scale genomic datasets. 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 large datasets, 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.