Inefficient cell cycle checkpoints allow errors at multiple stages of oogenesis to cause aneuploidy in mouse oocytes

Chromosome segregation errors during meiosis pose a significant threat to the survival of a species, because aneuploidy that arises due to segregation errors can lead to the demise of any resulting embryos. Therefore, production of aneuploid gametes is strongly suppressed in many organisms. Surprisingly, human females are the rare exception. It is estimated at least 10% of all human pregnancies are aneuploid, with a majority of errors originating during female meiosis. Importantly, the rate of errors increases exponentially with advancing maternal age and may exceed 50% for women nearing the end of their reproductive lifespan. Many causative factors have been proposed to explain the high incidence of aneuploidy and the effect of advancing maternal age, but the basis of human aneuploidy has remained elusive. Central to the prevention of chromosome segregation errors is the presence of a cell cycle checkpoint that stops chromosomally abnormal cells from further development. We hypothesized that the checkpoint mechanism is not stringent in the oocyte in eliminating cells with errors, therefore increasing the likelihood of generating aneuploid gametes. In my research, I tested the stringency of meiotic checkpoints in response to errors that arise at multiple stages of oogenesis by utilizing mutant mice defective in homologous chromosome synapsis and/or meiotic crossover formation.;The results from studies presented in this thesis show that cell cycle checkpoints in the oocyte are inefficient at halting meiotic progression of cells with errors. Specifically, checkpoints fail to arrest meiotic progression when errors occur at two distinct developmental time points: 1) when homologous chromosomes fail to synapse properly in prophase, and 2) when chromosomes fail to align at metaphase I. Consequently, the inability of these checkpoints to halt progression of defective cells increases the likelihood of chromosome segregation errors. Importantly, these findings provide vital contributions in understanding the origin of human aneuploidy. Accumulating evidence suggests that the genesis of human aneuploidy involves errors at multiple developmental time points, and the presence of inefficient checkpoints allows the survival of cells with errors, ultimately leading to the genesis of aneuploidy.