Meiotic sex chromosome inactivation. This observation is somewhat surprising, as evidence from the mouse suggests that abnormalities in XY pairing lead to germ cell death rather than to increased nondisjunction e. The results from early studies demonstrated that most aneuploidies are due to errors in maternal meiosis and that increasing maternal age is a powerful contributor to the occurrence of aneuploidy 3. Nevertheless, all studies are in agreement in suggesting an association of abnormal recombination and human trisomy, and several general features are now beginning to emerge. The other trisomies that have been studied display remarkable variability in origin Table 1. Maudlin I, Fraser LR. However, on the basis of data from humans and model organisms, premature loss of connections between homologues is also an important contributor and could be due to loss of sister chromatid cohesion; for example, if homologues are only joined by a distally located crossover, loss of cohesion past the point of exchange could uncouple the homologues 16 , 45 , 46 Fig.

Nevertheless, it seems to be clear that sister centromeres frequently are able to form functionally distinct kinetochores at meiosis I. Silencing of unsynapsed meiotic chromosomes in the mouse. The single published study of spontaneous X chromosome nondisjunction in Drosophila 17 was completed over 30 years ago and raised more questions than it answered; however, it has provided us with the only previous insights into the mechanisms responsible for the spontaneous failure of chromosomes to segregate from each other during meiosis. Cytogenetics of human oocytes, zygotes, and embryos after in vitro fertilization. More recently, investigations of gametes and preimplantation embryos conceived using assisted reproductive technology ART; Box 1 have identified aneuploidy as the leading impediment to successful pregnancies in this setting. Recent studies of Drosophila and humans indicate that aberrant genetic recombination is an important component of nondisjunction in both species. The most extensively studied condition has been trisomy 21, with over informative cases reported 36—

Nondisjunction at meiosis I crritical in products with additional or missing whole chromosomes; nondisjunction at meiosis II results in products with additional or missing sister chromatids Pachytene The stage of meiotic prophase characterized by complete synapsis of all homologues.

Error prone mammalian female meiosis from silencing the spindle assembly checkpoint without normal interkinetochore tension.

In cytological studies of male meiosis, Goldstein 27 observed abnormal sister chromatid association during prophase as well as precocious sister chromatid separation during anaphase I. Receive exclusive offers and updates from Oxford Academic. Box 3 Normal and abnormal meiotic chromosome segregation. Nevertheless, it seems to be clear that sister centromeres frequently are able to form functionally distinct kinetochores at meiosis I.


Human aneuploidy: mechanisms and new insights into an age-old problem

Premature loss of cohesion between sister centromeres results in their independent segregation at meiosis I, producing eggs with a balanced chromosome constitution and with extra or missing chromatids in equal frequency Bd.

A number of subsequent studies have confirmed that exposure of female mice to low levels of BPA during the final stages of oocyte growth disrupts meiotic chromosome behaviour 89 — 92but the endpoints have been disputed.

Genetic maps of chromosomes 16 and 21, generated from normal female meioses from CEPH family data and trisomies of maternal origin.

problem solving critical thinking chromosomal nondisjunction disorders

Further, the idea that milder stimulation protocols improve oocyte quality is steadily gaining ground, and comparative studies of these new protocols against established protocols have provided the first direct evidence in chomosomal that lower doses of gonadotropins are correlated with lower aneuploidy rates Culture of preimplantation mouse embryos chromosomxl fetal development and the expression of imprinted genes.

However, in trisomies associated with an excess number of exchanges, it may be that aberrant recombination is, indeed, the proximal cause of nondisjunction. In mammalian females, meiotic recombination occurs in the fetal ovary, and the importance of the resultant physical connections for chromosome segregation is well-documented: This was the first technique developed for PGD of aneuploidy.

As genetic recombination occurs at MI, there was no obvious reason to suspect that nondisjunction at MII would be associated with aberrant recombination and this was consistent with early studies of recombination in maternal MII trisomy 21 An experimental reexamination of these ideas, nondisjknction Drosophilais currently underway and has uncovered two lines of evidence supporting the idea that spontaneous nondisjunction is correlated with the movement of transposable elements.

Homologues are physically tethered at the sites of recombination, facilitating their attachment to cchromosomal poles critixal the meiosis I spindle see panel Aa of the figure. These observations contrast sharply with data from naturally occurring pregnancies, where most aneuploid abnormalities involve a single chromosome and are attributable to errors at maternal meiosis I. Our understanding of this sex-specific difference has deepened with the recognition that synaptic failure leads to transcriptional silencing of unsynapsed chromosomal regions.

Human aneuploidy: mechanisms and new insights into an age-old problem

Like CGH, the analysis can reveal chromosome gains or losses, but analytical automation of microarray chips provides swift data generation that is, typically within 24 hoursallowing embryo screening without compromising embryo transfer. This does not mean that a marked reduction in cohesins does not occur in humans — loss may indeed occur during the many years of prophase arrest.


Nondisjuncton Failure to resolve connections between sister centromeres results in nondisjunction, producing fertilized eggs with missing or extra chromatids Ca.

The observations on ord and mei-S are intriguing, in light of recent cytogenetic studies of nondisjunction in human oocytes. Similarly, when the two back-up achiasmate segregational mechanisms in Drosophila melanogaster are mutationally ablated, bivalents with very distal chiasmata often nondisjoin at very high frequencies 1516suggesting that the ability of a very distal chiasma to guarantee segregation may often depend on additional functions, such as achiasmate back-up systems.

In both the mantid spermatocyte and the Drosophila oocyte, kinetochore tension is being used to halt the cell cycle at metaphase, albeit towards rather different ends. However, evidence for a similar effect involving autosomes is not nearly as compelling. Nevertheless, two groups 3638 have used proximal 21q DNA markers to infer the meiotic stage of origin of trisomy 21 and have reported similar results. Munne S, et al.

Meiosis II egg Homologues separate at anaphase I, with one remaining in the egg and the other segregating to the first polar body. Oxford University Press is a department of the University of Oxford. Hunt P, Hassold T. Thus, in humans the association between absence of recombination and nondisjunction may be largely restricted to the sex chromosomes.

Thus, the pleiotropic effects of the original allele on sister chromatid adhesion, exchange and chiasma nondisjunctjon must be due to a single biochemical defect.

problem solving critical thinking chromosomal nondisjunction disorders

The possibility that human aneuploidy may be induced by environmental factors such as smoking, drinking, oral contraceptive use and radiation exposure has been suggested by data from human studies over many decades for reviews, see Refs 842but confirmatory evidence for these or any other agent has never emerged. Similarly, in trisomy 21 the reductions in recombination are restricted to proximal 21q; indeed in distal 21q the map is actually expanded by comparison with normals Molecular studies chromoosmal parental and meiotic stage of origin in autosomal and sex chromosome trisomies adapted from reference 54 and Hassold and Sherman, unpublished results.

In contrast, in yeast and many other model organisms intolerance to aneuploidy has prevented extensive ceitical of spontaneous nondisjunction; thus, relatively little cirtical known about its occurrence in most model systems.

problem solving critical thinking chromosomal nondisjunction disorders