Selfish selection of de novo mutations in the male germline (360G-Wellcome-219476_Z_19_Z)

Understanding the factors determining the occurrence of de novo mutations (DNMs) in the human genome is central to genetic disease and genome biology. DNMs arise predominantly in the male germline and increase in frequency with paternal-age. Despite the fact that germline mutation rates are intimately linked to spermatogenesis, very little is known about testicular homeostasis in humans. This proposal aims to address this gap in knowledge by focusing on a new disease-mechanism whereby pathogenic DNMs are preferentially transmitted because they hijack the mechanisms controlling spermatogenesis. This selfish selection process relies on principles similar to oncogenesis to explain why some paternally-derived mutations occur spontaneously up to 1000-fold more frequently than background. Exploiting our current knowledge of selfish selection, this proposal will deploy novel methodologies to describe mutations/genes/pathways subject to this phenomenon, including (1) cataloguing DNMs at single-seminiferous tubule resolution, in geographically-mapped testicular biopsies and in sperm; (2) modelling clonal DNM distribution in tubules to describe spermatogonial dynamics; (3) mining large DNM databases from family trios to detect mutational enrichment. We will also investigate 'selfish mitotic drive', a novel mechanism of mutation enrichment. Together these approaches will allow us to assess the significance of selfish selection for human disease and genome evolution.