Grant: Project Grant

Genetic diversity is provided by de novo transmittable mutations and it is now known that most new mutations are male- driven. During the formation of spermatozoa, the final steps involves a major change in the way DNA is packaged and we demonstrated that this is accompanied by the formation of transient DNA double-strand breaks (DSBs) in spermatids of both human and mouse pointing to an evolutionary-conserved mechanism. These DSBs arise in haploid cells where there is a single set of chromosome. The repair process cannot therefore proceed using the homologous chromosome as template as in normal somatic cells and must rather rely on a end-joining process. These end-joining repair processes are less reliable and known to induce DNA deletions and insertions. Our hypothesis is that mutations can therefore be induced when the DSBs are repaired in the subsequent steps of the spermatid's differentiation process. Our goal is therefore to confirm whether this process is indeed genetically unstable and if specific regions are involved in the ethiology of genetic diseases since our first screen suggest that neurodevelopmental genes are targeted with high significance. DSBs are also observed during yeast gamete formation emphasizing the conserved nature of this transition and providing a powerful genetic tool to decipher the DSBs mechanism. These investigations may confirm the discovery of a novel mechanism contributing to genetic diversity, evolution and possibly to neurodevelopment disorders such as autism.