Maternal age and trisomy – a unifying mechanism of formation

Abstract.

The mechanism of trisomy formation and its relationship to increased maternal age is not understood. Molecular analysis of the pattern of inheritance of DNA markers in trisomy families shows trisomies can be grouped according to whether the affected chromosomes inherited from their mothers are heterozygous or homozygous with respect to the centromeres. Furthermore, molecular analysis reveals that those that are heterozygous have fewer chiasmata, which are located more distally, while those that are homozygous have more chiasmata proximally located. Cytogenetic analysis of human oocytes shows that the kind of imbalance predicted by the classic hypothesis of nondisjunction, i.e. extra whole chromosomes at the second metaphase, is rarely found, whereas the common expression of imbalance is seen as single chromatids. We hypothesise that one mechanism links these data: the mechanism depends on the prediction from the cytogenetic data that cohesion within the bivalent complex is severely weakened during the extended dictyate stage in older women. Consequently, when meiosis resumes, at the time of ovulation, the bivalent emerges as four chromatids held together only by its chiasmata. In accordance with the rules of orientation on the spindle, the final balanced shape of the configuration achieved at metaphase I, in this case determined by the position of the chiasmata, will dictate whether the subsequent segregation of the chromatids will result in their heterozygosity or homozygosity. It follows that the concept of "first division" and "second division" errors, i.e. of nondisjunction originating at first or second meiotic division as defined by centromeric hetero- or homozygosity, may be erroneous.