| The goal of the work presented in this dissertation is to understand mechanisms underlying human chromosome nondisjunction. Nondisjunction is defined as the failure of chromosomes to segregate during meiosis. This results in the production of aneuploid gametes. Trisomy 21 is the most viable of all human autosomal aneuploidies and served as a model to explore risk factors associated with nondisjunction. In this study, a series of short tandem repeat markers along 21q were genotyped on DNA collected from individuals with trisomy 21 and their parents. This information was used to determine (1) the origin of nondisjunction (i.e., if nondisjunction happened in the sperm or egg), (2) if nondisjunction happened during meiosis I, meiosis II or post-zygotically, and (3) the location of recombination along the nondisjoined chromosome 21. This information, combined with data on parental age and astute statistical analyses enabled us to (1) examine the association between maternal age and recombination in maternal cases of trisomy 21, (2) identify risk factors associated with nondisjunction of chromosome 21 within sperm, and (3) further understand mechanisms underlying nondisjunction. The results from the analysis of nondisjunction within oocytes showed that the recombination-associated risk for a meiosis I error was the same for women of all ages with respect to both the absence of exchange and when a single exchange occurred within the most distal 2.5 Mb of 21q. In contrast, the risk for a meiosis II error increased with increasing maternal age when a single exchange occurred within the most proximal 5.2 Mb of 21q. As it relates to risk factors associated with nondisjunction of chromosome 21 in sperm, we found that MII errors predominate among paternal cases of trisomy 21. In addition, we did not find that either the absence or altered placement of exchange were associated with nondisjunction of chromosome 21. Also, we did not find that the sex ratio among paternally-derived errors differed from the sex ratio among live births. By combining these findings with data from other studies we have been able to propose how risk factors may lead to nondisjunction of chromosome 21 within human gametes. |
