Characterization of susceptible chiasma configurations that increase the risk for maternal nondisjunction of chromosome 21

Recent studies of trisomy 21 have shown that altered levels ofrecombination are associated with maternal non-disjunction occurring atboth meiosis I (MI) and meiosis II (MII). To comprehend better theassociation of recombination with nondisjunction, an understanding of thepattern of meiotic exchange, i.e. the exchange of genetic material at thefour-strand stage during prophase, is required. We examined this underlyingexchange pattern to determine if specific meiotic configurations areassociated with a higher risk of non-disjunction than others. We examinedthe crossover frequencies of chromosome 21 for three populations: (i)normal female meiotic events; (ii) meiotic events leading to MInon-disjunction; and (iii) those leading to MII non-disjunction. From thesecrossover frequencies, we estimated the array of meiotic tetrads thatproduced the observed crossovers. Using this approach, we found that nearlyone-half of MI errors were estimated to be achiasmate. The majority of theremaining MI bivalents had exchanges that clustered at the telomere. Incontrast, exchanges occurring among MII cases clustered at thepericentromeric region of the chromosome. Unlike the single exchangedistributions, double exchanges from the non-disjoined populations seemedto approximate the distribution in the normal population. These datasuggest that the location of certain exchanges makes a tetrad susceptibleto non- disjunction. Specifically, this susceptibility is associated withthe distance between the centromere and closest exchange. This resultchallenges the widely held concept that events occurring at MII are largelyindependent of events occurring at MI, and suggests that allnon-disjunction events may be initiated during MI and simply resolved ateither of the two meiotic stages.