New Insights into Human Nondisjunction of Chromosome 21 in Oocytes

Abstract

Nondisjunction of chromosome 21 is the leading cause of Down syndrome. Two risk factors for maternal nondisjunction of chromosome 21 are increased maternal age and altered recombination. In order to provide further insight on mechanisms underlying nondisjunction, we examined the association between these two well established risk factors for chromosome 21 nondisjunction. In our approach, short tandem repeat markers along chromosome 21 were genotyped in DNA collected from individuals with free trisomy 21 and their parents. This information was used to determine the origin of the nondisjunction error and the maternal recombination profile. We analyzed 615 maternal meiosis I and 253 maternal meiosis II cases stratified by maternal age. The examination of meiosis II errors, the first of its type, suggests that the presence of a single exchange within the pericentromeric region of 21q interacts with maternal age-related risk factors. This observation could be explained in two general ways: 1) a pericentromeric exchange initiates or exacerbates the susceptibility to maternal age risk factors or 2) a pericentromeric exchange protects the bivalent against age-related risk factors allowing proper segregation of homologues at meiosis I, but not segregation of sisters at meiosis II. In contrast, analysis of maternal meiosis I errors indicates that a single telomeric exchange imposes the same risk for nondisjunction, irrespective of the age of the oocyte. Our results emphasize the fact that human nondisjunction is a multifactorial trait that must be dissected into its component parts to identify specific associated risk factors. Nondisjunction occurs when chromosomes fail to segregate during meiosis; when this happens, gametes with an abnormal number of chromosomes are produced. The clinical significance is high: nondisjunction is the leading cause of pregnancy loss and birth defects. We have studied trisomy 21 using DNA from individuals with Down syndrome and their parents to identify mechanisms underlying nondisjunction. The results from these studies show that altered patterns of recombination, e.g., no exchange, a single telomeric exchange and a single pericentromeric exchange, were associated with nondisjunction of chromosome 21 within the oocyte. In this report, we stratified maternal cases of trisomy 21 by the type of nondisjunction error (meiosis I or meiosis II) and by maternal age (ages 34 years) and examined both the number and location of recombination by age group. Our results suggest that the risk imposed by the absence of exchange or by a single telomeric exchange is the same, irrespective of the age of the oocyte. In contrast, the risk imposed by a single pericentromeric exchange increases with increasing maternal age. These findings, put into the context of proteins involved in the meiotic process, have enabled us to further understand mechanisms underlying nondisjunction.