Aarhus University Seal

BiRC seminar: Old men, their selfish testes, de novo mutations and human disease

Anne Goriely, MRC Weatherall Institute of Molecular Medicine, University of Oxford

Info about event


Friday 31 March 2023,  at 14:15 - 15:00


Faculty Club (1870-816)


It is now well-established that our genomes mutate at a slow but constant rate of 30-100 new point mutations per generation. Although most new point mutations (>80%) originate from the father and increase in frequency at the rate 1-2 mutation/paternal year, very little is known about the cellular mechanisms that allow adult testicular stem cells to reconcile the contradictory demands of maintaining a low mutation rate across generations while ensuring abundant sperm production over many decades.

We have previously described a process where some pathogenic mutations hijack the homeostatic mechanisms of sperm production to their own advantage. This so-called ‘selfish selection’ mechanism was originally proposed to explain the paternal age-effect and high birth prevalence observed for some Mendelian disorders, such as Apert syndrome (FGFR2) or achondroplasia (FGFR3). It relies on principles similar to oncogenesis to explain why these mutations occur spontaneously at levels up to 1000-fold higher than the background rate. Importantly, this process emphasizes the intimate link that exists between sperm production/fertility, germline mutation rate and ageing.

I will summarise our current understanding of de novo mutations in humans, the contribution of mosaicism, the impact of paternal age and their importance in human disease and genome heterogeneity. I will then describe the data that have led to the discovery of the selfish selection process and the novel strategies we are developing to study de novo mutations directly within human testes. Finally, I will speculate on the broader implications of selfish selection and the importance of the regulation of spermatogenesis for human disease, genome diversity and evolution.