Gametogenesis is a pivotal part of the reproductive cycle, which acts as a genetic bottleneck determining the hereditary makeup of the next generation. De novo mutations and large-scale chromosomal aberrations arising from faulty DNA repair, replication or chromosome segregation can be transmitted to offspring, exemplified by specific conditions such as Neurofibromatosis type 1, Trisomy 21 and Fragile X syndrome. However, the genome-wide view of de novo germline genomic instability and its heritability remains largely unexplored.
In this study, we leveraged a germline knockout model of the DNA repair factor Fancm to investigate the transmission of de novo genomic instability. We established two distinct mouse populations, termed "advanced inter-cross lines," which were mated for five generations to facilitate the stable inheritance of de novo structural variations. Notably, these populations were fixed for either Fancm+/+ or Fancm-/- genotypes, allowing us to differentiate events occurring during in utero germ cell expansion from those during meiosis.
Our findings revealed a significantly higher occurrence of de novo structural variations in the population lacking functional Fancm. We will present unpublished data characterizing the nature of these de novo structural variants in both the wildtype and Fancm-deficient populations. This research is relevant for fundamental and evolutionary biology, but also for potential clinical implications for individuals with rare genomic instability conditions who are planning to start a family.