Insights into the Maternal Age Effect on Aneuploidy

Thesis (Ph.D.), School of Molecular Biosciences, Washington State UniversityHumans face extraordinary difficulties in reproduction, as over 10% of all pregnancies are aneuploid. In most cases, aneuploidy causes complications in development; indeed, it is the leading known cause of miscarriage and congenital birth defects in our species. In addition, high rates of aneuploidy in pregnancy appear to be a human-specific condition, as levels of aneuploidy are orders of magnitude lower in commonly studied model organisms. For decades, researchers have known that increased maternal age goes hand in hand with increased risk of aneuploid pregnancy, a relationship known as the maternal age effect. However, the cause of this age effect remains unclear, though numerous hypotheses have been proposed. Our ability to analyze prophase stage oocytes has allowed us to examine two of the most provocative of these models. In an examination of cells entering meiosis, we did not observe aneuploidy, leading us to conclude that the errors that lead to aneuploidy occur at some point in the meiotic process, and are not due to "predestination" events before meiosis begins. Our focus then shifted to recombination in meiotic prophase, as abnormal recombination is the only known molecular process linked to aneuploidy. We observed extraordinary variation in recombination rate among individuals, but no apparent relationship with the timing of meiotic entry. Overall, our studies led us to conclude that while recombination indeed plays a role in the genesis of the maternal age effect, it remains only a part of the whole, and errors in later stages of meiosis also likely to contribute to the maternal age effect.School of Molecular Biosciences, Washington State Universit