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 of recombi nation are associated with maternal non-disjunction occurring at both meiosis I (MI) and meiosis II (MII), To comprehend better the associat ion of recombination with nondisjunction, an understanding of the patt ern of meiotic exchange, i.e. the exchange of genetic material at the four-strand stage during prophase, is required. We examined this under lying exchange pattern to determine if specific meiotic configurations are associated with a higher risk of non-disjunction than others, We examined the crossover frequencies of chromosome 21 for three populati ons: (i) normal female meiotic events; (ii) meiotic events leading to MI non-disjunction; and (iii) those leading to MII non-disjunction. Fr om these crossover frequencies, we estimated the array of meiotic tetr ads that produced the observed crossovers, Using this approach, we fou nd that nearly one-half of MI errors were estimated to be achiasmate, The majority of the remaining MI bivalents had exchanges that clustere d at the telomere, In contrast, exchanges occurring among MII cases cl ustered at the pericentromeric region of the chromosome, Unlike the si ngle exchange distributions, double exchanges from the non-disjoined p opulations seemed to approximate the distribution in the normal popula tion, These data suggest that the location of certain exchanges makes a tetrad susceptible to non-disjunction. Specifically, this susceptibi lity is associated with the distance between the centromere and closes t exchange, This result challenges the widely held concept that events occurring at MII are largely independent of events occurring at MI, a nd suggests that all non-disjunction events may be initiated during MI and simply resolved at either of the two meiotic stages.