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.

Inefficient Crossover Maturation Underlies Elevated Aneuploidy in Human Female Meiosis

“…If tension is sub-optimal, sister kinetochores tend to deteriorate into the equational/back-to-back configuration characteristic of mitotic/MII segregation, giving premature segregation of sister chromatids at MI (Watanabe, 2012; Zielinska et al, 2015; Hugerat and Simchen, 1993; Figure 6A middle, right). In fact, premature separation of sister chromatids is a common type of mis-segregation (Nagaoka et al, 2012; Ottolini et al, 2015; Wolstenholm and Angell, 2000). …”

“…This “maternal age effect” is proposed to result from age-dependent loss of sister-chromatid cohesion (e.g. Wolstenholm and Angell, 2000; Storlazzi et al, 2008; Jessberger, 2012; reviews in Nagaoka et al, 2012; Handyside et al, 2012; Chiang et al, 2012). Thus: (i) loss of cohesion centromere-distal to all COs will eliminate the corresponding chiasma(ta) connections, minimizing tension (Figure 6C iv-to-vi).…”

The alternative Ctf18-Dcc1-Ctf8-replication factor C complex required for sister chromatid cohesion loads proliferating cell nuclear antigen onto DNA

“…F aithful inheritance of a complete set of the chromosome complement by daughter cells is essential for cell survival (1)(2)(3)(4). In eukaryotes, newly synthesized sister chromatid DNAs are linked together physically by the cohesin complex (called cohesion) from the time they are replicated until their distribution between daughter cells in anaphase (1,(5)(6)(7).…”

A new case of tetrasomy X in a 8 years old girl

“…Sex chromosome aneuploidy as well as trisomy 21 are known to increase with maternal age (8,9). Several studies have indicated a possible age-related degradation of the cohesion complex that leads to the inappropriate separation of chromosomes (10)(11)(12).…”