Medicine (St Vincent's) - Theses
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ItemA genome stability pathway with dual roles in meiosis and germ cell development( 2022)Chromosome segregation errors because of meiotic recombination of are a leading cause of pregnancy loss. In the case of live births can cause serious congenital aneuploidy such as trisomy 21. Meiotic recombination pairs homologous chromosomes to promote large scale exchanges of genetic information, resulting in recombinant haploid gametes (sperm or eggs). Meiotic recombination begins with many programmed DNA double strand breaks (DSBs). The vast majority of these DSBs is repaired directly and only a small subset leads to genetic exchange between the two parental chromosomes, also known as crossing over. This suggests there are factors that actively promote DSB repair as non-crossovers. In my PhD project, I studied the role of a DNA repair protein, FANCM, and how crossover rates are altered in a Fancm knockout mouse model. My results indicate that FANCM deletion leads to two distinct but related outcomes: 1) increased genome instability in the all the cells of the body and 2) increased crossover rates between homologous chromosomes in meiotic cells. As a result of overall genome instability, there is increased spontaneous DNA damage leading to perturbed germ cell production, reducing spermatogenesis in Fancm-knockout males and reduced fertility in Fancm-knockout females. The absence of FANCM alters the DSB repair pathway choice in meiotic cells, resulting in more crossovers compared to wild-type conditions. Therefore, FANCM plays an important role in regulating crossover designation and balancing the exchange of genetic information during each reproductive generation. My work and further investigations into reproductive biology will provide more insight into how DNA repair defects may cause human congenital aneuploidies and could shed light on earlier diagnostic opportunities.