Altered patterns of multiple recombinant events are associated with nondisjunction of chromosome 21

Abstract

We have previously examined characteristics of maternal chromosomes 21 that exhibited a single recombination on 21q and proposed that certain recombination configurations are risk factors for either meiosis I (MI) or meiosis II (MII) nondisjunction. The primary goal of this analysis was to examine characteristics of maternal chromosomes 21 that exhibited multiple recombinant events on 21q to determine whether additional risk factors or mechanisms are suggested. In order to identify the origin (maternal or paternal) and stage (MI or MII) of the meiotic errors, as well as placement of recombination, we genotyped over 1,500 SNPs on 21q. Our analyses included 785 maternal MI errors, 87 of which exhibited two recombinations on 21q, and 283 maternal MII errors, 81 of which exhibited two recombinations on 21q. Among MI cases, the average location of the distal recombination was proximal to that of normally segregating chromosomes 21 (35.28 vs. 38.86 Mb), a different pattern than that seen for single events and one that suggests an association with genomic features. For MII errors, the most proximal recombination was closer to the centromere than that on normally segregating chromosomes 21 and this proximity was associated with increasing maternal age. This pattern is same as that seen among MII errors that exhibit only one recombination. These findings are important as they help us better understand mechanisms that may underlie both age-related and nonage-related meiotic chromosome mal-segregation.

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

“…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.…”

Prenatal diagnosis of structuralmal formations and chromosome anomalies : Detection, influence of Body Mass Index and ways to improve screening

“…However, this hypothesis has been questioned. A recent large study found little evidence for this -only at a maternal age ≥35 and a meiosis II error was an association seen but this could be the result of multiple testing (Oliver 2012). The possible link between obesity and aneuploidy needs to be investigated further, also with the aim to find the etiology to Down syndrome.…”

“…There is, however, no certain known association between maternal pre-pregnancy obesity and the prevalence of Down syndrome in offspring. Down syndrome or trisomy 21 is a result from a non-disjunction in gametogenesis, either in maternal meiosis I or II (Oliver 2012). Little is known about the etiology of trisomy 21, other than the wellknown age effect.…”

Genetic Etiology of Chromosome 21 Nondisjunction and Down syndrome Birth: Aberrant Recombination and Beyond

“…This observation on model organisms led scientist to evaluate the association of multiple chiasama formation on Ch21 segregation. In their study for analyzing the spatial distribution of two exchange events on Ch21 that non-disjoined at MI Oliver et al [27] found that the position of proximal chiasma remains same as that on the normally disjoined Ch21, but it is the distal chiasma that dislocates more proximally. In other words the distal chiasma displaces more proximally on the nondisjoined chromosome and it reduces the distance between two chiasmata and the authors hypothesized that is reduction of distance between chiasmata reduces the 'good effect' of two chiasma formation as two or more chiasmata usually stabilizes the chromosome and ensure proper segregation.…”

“…In extending their analyses to examine MII errors with two observed recombination events Oliver et al [27] Found that the average location of proximal recombination event was closer to the centromere in compare to normally disjoined Ch21. With respect to maternal age the proximal exchange, not the distal exchange, exhibits statistically significant displacement towards centromere.…”