Goriely Group: Investigating the role of genetic mosaicism in congenital disease — Radcliffe Department of Medicine (ox.ac.uk)

As mutations are at the origin of all genetic variations, understanding the factors that influence mutational rates and patterns (and the reason for which they occur) is crucial to the study of disease, evolution and genome diversity. It is now well established that 30-100 point mutations are acquired spontaneously at each generation. Although these point mutations initially arise as random miscopying events, preferentially from the paternal germline, we have described a new mechanism which predicts that some pathogenic mutations may hijack the way sperm production is controlled to their own advantage.  In doing so, these ‘selfish’ mutations become progressively enriched in the testis as men age and are therefore associated with an increased risk of transmission to the next generation. 

The concept of 'Selfish Spermtogonial Selection’ was originally proposed to explain the paternal age-effect and high birth prevalence observed for a group of rare Mendelian diseases, which we collectively called ‘paternal age-effect (PAE) disorders’, such as Apert syndrome (caused by activating mutations in FGFR2), achondroplasia (FGFR3) or Costello (HRAS) and Noonan (PTPN11/SHP2) syndromes. It relies on principles similar to oncogenesis to explain why these disorders occur spontaneously at levels up to 1000-fold higher than background mutation rates.

So far our data – gathered originally through direct quantification of these ultra-rare pathogenic mutations in human sperm and testes – have shown that molecularly this process relies on specific oncogenic pathways, such as the growth factor-receptor-RAS signalling cascade, which are key determinants of spermatogonial cell self-renewal. As these molecular pathways are also implicated in many other cellular contexts, including growth control and neurogenesis, it raises the possibility that this mechanism has broader implications.

This process, which affects all men as they age, is anticipated to be associated with an increased risk of transmission of functional (pathogenic) alleles and is likely to be relevant to the pathology of common disorders, including cancer predisposition and neurodevelopmental disorders, such as schizophrenia and autism - for which paternal age-effects have been described epidemiologically. It is also predicted to be particularly relevant for ageing reproductive populations.