Characterising the role of the spliceosome in dominant forms of monogenic male infertility

Supervisors: Professor Joris Veltman, Dr Margot Wyrwoll, Dr Alex Marin-Geary

Application deadline: 30th September 1PM

Funding information: Home-rate Students only

Infertility affects roughly 1 in 7 couples, and in approximately half of these cases the cause lies with the male partner. Despite this, research into the genetic underpinnings of male infertility lags behind other fields, with only a small number of genes linked to male infertility having been identified.

Severe male infertility, by definition, cannot be passed from father to son. Monogenic causes can be either inherited recessively or X-linked, whereas dominant infertility can only arise de novo or through maternal inheritance. Dominant variants are the hardest to find because confidently identifying them requires sequencing the patient and both parents, and such “trio” designs remain rare in this field. As a result, the known genetic architecture of male infertility is heavily skewed towards recessive and X-linked genes, and the dominant landscape remains largely unexplored.

Our group holds one of the few large sequencing cohorts of infertile men worldwide that includes a substantial proportion of parent offspring trios, combining short- and long-read whole-genome sequencing. Using these data, we have recently identified a set of maternally inherited and de novo variants implicated in dominant male infertility and found that strikingly, the genes carrying these variants are enriched for components of the spliceosome.

Splicing, where introns are removed and exons are joined to create the final mRNA product, is highly conserved across all kingdoms of life. It is a key contributor to transcriptdiversity, and cell and time-point specific isoform expression, with particularly high levels of alternative splicing being observed during spermatogenesis. However, determining the contribution of, and mechanisms by which disruption to genes involved in splicing lead to male infertility remains an open challenge. 

This is a mixed computational and experimental project where the balance can be tailored to the successful candidate.

On the computational side you will use ‘in-house’ short, and long-read whole-genome sequencing data to identify and analyse genetic variants in spliceosomal genes in individuals with male infertility. You will leverage existing and novel state-of-the-art computational tools and methods, alongside a deep understanding of the mechanisms of human disease, to predict the potential for these variants to be pathogenic, incorporating large publicly available datasets to determine burden of these variants in the wider population.

By looking at both protein-coding variants, and those that arise outside of coding regions you will develop a comprehensive understanding of the genomic landscape of spliceosomal variants leading to male infertility in these individuals. This will allow us to better interpret genetic variants implicated in male infertility in diagnostic settings moving forward.

On the experimental side, you will functionally test the most promising candidate variants, for example using minigene splicing assays, CRISPR-engineered cell models, and transcriptomic readouts to demonstrate splicing disruption directly. 

You will be based at the Institute of Genetics and Cancer, University of Edinburgh, a leading centre for human genetics and genome analysis, with access to high-performance computing and core facilities. The project sits within an active international collaboration network in male infertility genetics, offering exposure to multi-centre cohort studies and the opportunity to co-author gene discovery publications. You will receive training in statistical genetics, long-read sequencing analysis, variant interpretation to clinical standards, and molecular functional assays.

We are looking for a curious, motivated scientist with a background in genetics, molecular biology, biomedical sciences, bioinformatics, or a related field. Essential and desirable attributes:

• A strong interest in human genetics and mechanisms of disease
• Willingness to work across computational and wet-lab approaches
• Prior laboratory experience in molecular biology  

We are sorry that this opportunity is open to home-rate students only.

Subject areas: Fertility, Bioinformatics, Reproductive science, Splicing, Male infertility, Genetics