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De Novo Mutations and Human Disease


About the Research

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 of them originate, the human testis. We aim to understand why some pathogenic mutations arise more frequently than others and develop non-invasive prenatal screening approaches for the most commonly recurring DNMs

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. 

We have been able to visualise this process in situ and suggested that the mechanisms involved in selfish selection are similar to those described for tumorigenesis. However, unlike somatic variants in cancer, selfish mutations are transmitted across generations and have the potential to 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 within the human testis and establish the potential impact that this process has on human disease and genome evolution. Understanding the landscape of selfish mutations will allow the development of non-invasive screening approaches for the most commonly recurring selfish DNMs. 


Training Opportunities

This project represents a unique opportunity to gain in-depth training in Human Genetics, development and sequencing  technologies. It will combine the use of novel molecular technologies (such as molecular inversion probes and LockDown probes) with the implementation of next generation sequencing (Illumina, PacBio, Oxford Nanopore Technologies) using human tissue and/or cell free fetal (cff) DNA, in order to develop approaches to the molecular analysis of rare DNMs. 

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 such as those listed above. A significant portion of the project will involve development of bioinformatic pipelines and statistical analysis. It should be of particular value to individuals with an interest in analysis of rare 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 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.



Maher GJ, Ralph HK, Ding Z, Koelling N, Mlcochova H, Giannoulatou E, Dhami P, Paul DS, Stricker SH, Beck S, McVean G, Wilkie AOM & Goriely A*, 2018: Selfish mutations dysregulating RAS-MAPK signaling are pervasive in aged human testes, Genome Res28(12):1779-1790 - [PMC6280762]

Guo J, Grow EJ, Yi C, Mlcochova H, Maher GJ, Lindskog C, Murphy PJ, Wike CL, Carrell DT, Goriely A, Hotaling JM & Cairns BR, 2017: Transcription, Signaling and Metabolic Transitions During Human Spermatogonial Stem Cell Differentiation”, Cell Stem Cell21(4):533-546. [PMC5832720]  

See also: Guo et al, 2020: The Dynamic Transcriptional Cell Atlas of Testis Development During Human Puberty, Cell Stem Cell26(2):262-276 [PMC7298616] 

Goriely A*, 2016 Decoding germline de novo mutations. Nat Genet 48(8), 823-824 [PMID: 27463396]

Maher GJ, McGowan SJ, Giannoulatou E, Verrill C, Goriely A*, Wilkie AOM* 2016Visualizing the origins of selfish de novo mutations in individual seminiferous tubules of human testes, Proc Natl Acad Sci USA113(9):2454-2459 - [PMC3864328]

Bernkopf M, Morgan T, Hunt D, Collins AL, Fairhurst J, Robertson SP, Douglas AGL, Goriely A, 2017: Quantification of transmission risk in a male patient with a FLNBmosaic mutation causing Larsen syndrome: implications for genetic counselling in post-zygotic mosaicism cases, Hum Mutat, 38(10):1360-1364 [PMC5638069]]