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.