Non-disjunction of chromosome 21 in maternal meiosis I: evidence for a maternal age-dependent mechanism involving reduced recombination

Abstract

Over 300 cases of trisomy 21 were analyzed to characterize the causes of maternal non-disjunction and to evaluate the basis for maternal age-dependent trisomy 21. We confirmed the observation that recombination along 21q is reduced among non-disjoined chromosomes 21 and further demonstrated that the alterations in recombination are restricted to meiosis I origin. Analysis of the crossover distribution indicates that reduction in recombination is not due simply to failure of pairing and/or absence of recombination in a proportion of cases. Instead, we observed an increase in both zero- and one-exchange events among trisomy 21-generating meioses suggesting that an overall reduction in recombination may be the underlying cause of non-disjunction. Lastly, we observed an age-related reduction in recombination among the meiosis I cases, with older women having less recombination along 21q than younger women. Thus, reduced genetic recombination may be responsible, at least in part, for the association between advancing maternal age and trisomy 21.

A fascination with chromosome rescue in uniparental disomy: Mendelian recessive outlaws and imprinting copyrights infringements

“…In contrast, trisomies 18 are not always of maternal origin and are caused, in the majority, by an me2 nondisjunction (reviewed by Jacobs and Hassold 64 ). The implications for UPD16 may be straightforward: the noted frequency of trisomy 16, its unique and constant maternal origin, and the reduced recombination going along with me1-generated disomies 64 should explain the relatively high frequency of UPD16 mat void of isodisomy (reviewed by 20 A somewhat similar commentary could hold true for the UPD's 21 derived from a trisomy 21 where the trend seems as follows: the risk of isodisomy is lowered and the chance of heterodisomy maintained if a lack or a dearth of crossing over recombination is a cause for me1 nondisjunction, as is indeed the case 66 ; such a risk is lessened as well if a (proximal) increase in recombination at me1 favours me2 nondisjunction, which has also been well documented. 67 We see therefore that the mood of chromosome 21, in pathology, is against isodisomic deviancy and does not at all favour the works of 'recessive outlaws'!…”

Cytogenetic and molecular study of four couples with multiple trisomy 21 pregnancies

“…The parents and cell divisions of origin and the reduction in recombination seen in the probands born to the two older mothers are very similar to those seen in a large series of singleton Down syndrome pregnancies. 12 Whilst it is impossible to exclude a genetic predisposition to trisomy 21 non-disjunction in these women, it is an unattractive suggestion because there is no convincing evidence for a genetic predisposition to non-disjunction in our species, either for a specific chromosome 9 or for non-disjunction in general. 14 It therefore seems reasonable to consider that the three trisomic probands in the older women arose by chance.…”

“…In the absence of parental mosaicism for a trisomy 21 cell line, the trisomic pregnancies may have arisen either by a nondisjunctional error during meiosis, or by a post-zygotic mitotic error resulting in the gain of a chromosome 21. The majority of trisomy 21 conceptions has been shown to be the result of errors during maternal MI 12 and associated with an increased maternal age at conception.…”

Polimorfismos del gen ApoE en individuos con síndrome de Down y sus progenitores en una población colombiana

“…En estos casos, el 75 % se atribuye a la falta de disyunción durante la meiosis I y, el 25 % restante por errores en la meiosis II. La trisomía 21 de origen paterno se ha reportado en 5 % de los casos por errores en la meiosis II (3,4).…”