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.

Altered incidence of meiotic errors and Down syndrome birth under extreme low socioeconomic exposure in the Sundarban area of India

“…The trend is statistically significant (r=−0.96; p=0.04) by linear regression. This pattern of interaction between maternal age and amount of recombination in MI error groups is concordant with our previous report for urban and semi-urban population of West Bengal as well as with the US DS population (Oliver et al 2008). Pairwise comparison by chi-square test revealed statistically significant difference (p=0.0001) between the young and older age groups.…”

“…We observed a surprisingly lower value for MI/MII error ratio (Table 2) for maternally originating cases as compared to other published data (Allen et al 2009;Oliver et al 2008;Ghosh et al 2009). This observation suggests higher frequency of MII errors among these poor, tribal women who have a child with DS.…”

“…The average number of detectable exchanges in the maternal MI NDJ group is 0.78 in this rural population, which is much higher than we observed in the urban DS population (∼0.22) as estimated in our previous study (Ghosh et al 2009). It is also greater than the average of 0.43 reported in a US population (Oliver et al 2008(Oliver et al , 2012. The age-stratified distribution of achiasmate maternal MI errors, which can be used to examine interaction between amount of recombination and maternal age, exhibits gradual linear decrease in the frequency of achiasmate meiosis with advancing age.…”

“…Failure of chiasma formation between homologous pair causes random chromosome movement towards the poles, leading to NDJ (Cheung et al 2007). For Ch21, absence of chiasma and subsequent nonrecombination have been identified as major risks for NDJ at the MI phase of maternal meiosis (Lamb et al 2005a, b;Sherman et al 2007;Oliver et al 2008;Ghosh et al 2009). In this regard, the results of the present study are absolutely new.…”

“…Previously, DS samples from several different ethnic populations have been studied and for all of them the meiosis I (MI) stage of oogenesis has been identified as the most vulnerable phase for NDJ errors to occur (Sherman et al 2007). Advanced maternal age at conception and altered patterns of recombination of the Ch21 are the two welldocumented maternal risk factors for Ch21 NDJ (Lamb et al 2005a, b;Sherman et al 2007;Oliver et al 2008;Ghosh et al 2009). In particular, absence of chiasma formation and a single telomeric chiasma have been identified as risk factors for maternal MI NDJ, whereas a pericentromeric single chiasma has been reported as risk for meiosis II (MII) errors.…”