Describe Nondisjunction and the Effect It Can Have on a Human.

Abstract

Recent studies of Drosophila and humans point that aberrant genetic recombination is an important component of nondisjunction in both species. In both, a proportion of nondisjunction is associated with failure to pair and/or recombine and in both, exchanges which are either too distal or likewise proximal increase the likelihood of malsegregation. In this review we provide ii perspectives on these observations: first, a review of commutation and chromosome segregation in model organisms, focusing on Drosophila, and secondly an overview of nondisjunction in humans. This format allows united states of america to describe the paradigms developed from studies of model organisms and to enquire whether these paradigms apply to the human being situation.

Introduction

Over the past decade, studies of model organisms—in detail, studies of yeast and Drosophila—have yielded remarkable advances in our understanding of how meiotic chromosome pairing, synapsis and segregation occur in lower eukaryotes (1,2). Further, these studies have provided compelling evidence that abnormalities in genetic recombination perturb normal meiotic chromosome segregation. Meiotic mutants which reduce the level of recombination invariably increase the frequency of nondisjunction and, in some situations, the location of exchanges on the bivalent also affects the likelihood of nondisjunction.

Our understanding of the homo meiotic process, and of factors which affect meiotic chromosome segregation, is much less advanced. Nevertheless, recent studies of human being trisomies suggest similarities between nondisjunction in our species and nondisjunction in model organisms. Specifically, reductions in recombination are a feature of all human trisomies thus far studied and, in several trisomies, the location of the exchanges is different than those observed in normal meioses.

In this review we provide a summary of nondisjunction from 2 perspectives: outset, a review of exchange and chromosome segregation in model organisms, focusing on Drosophila, and secondly an overview of nondisjunction in humans. This format allows u.s. to describe the paradigms developed from studies of model organisms and to ask whether these paradigms use to the human state of affairs.

Substitution and Chromosome Segregation in Model Organisms

Genetic recombination, or crossing-over, is the principal means by which the disjunction of homologous chromosomes at meiosis I (MI) is ensured. Recombination events themselves do not commit chromosomes to segregate; rather, disjunction is mediated by specific structures, known equally chiasmata, that are formed at the sites of exchange. We and others have recently shown that, in addition to ensuring the segregation of homologous chromosomes, chiasmata play a crucial part in the control of the meiotic cell cycle (3–six).

How chiasmata work

Chiasmata serve to link homologous chromosomes together past taking advantage of the stiff sis chromatid cohesion maintained forth both of the homologs. The resulting pair of interlocked chromosomes, known as a bivalent, then attaches to the spindle such that ane kinetochore is oriented towards each pole. The process by which that orientation is achieved—indeed, the process that ensures disjunction—is explained by the simple physical model described below.

In centriolar meiotic systems, and thus in the male person meiotic systems of most animals, during prometaphase each kinetochore of the bivalent attaches to the spindle and begins to motion toward one of the two poles. Well-nigh bivalents achieve a bipolar orientation immediately (7). The high frequency of initial proper orientation is due both to the fact that chromosomal spindle fibers connect to the pole to which a given centromere nigh nearly points and to the observation that at the start of prometaphase, the 2 homologous centromeres are usually oriented in reverse directions, such that if ane centromere is pointed at ane pole the other centromere is pointed at the reverse pole [Ostergren (viii), as modified past Nicklas (7)]. To quote Nicklas (9), 'while the upper one-half-bivalent'southward kinetochores most nearly face the upper pole, those of its partner most nearly face the lower pole, just because bivalents are so constructed'. One time the ii centromeres accept oriented towards contrary poles, the progression of the two centromeres towards the poles is halted at the metaphase plate by the chiasmata. This represents a stable position in which the bivalent volition remain until anaphase I.

Although the machinery described higher up is sufficient to explicate bivalent attachment in many meiotic systems, it should exist remembered that in some oocytes the spindle appears to be acentriolar and is organized by the chromosomes themselves. A well-studied example of this miracle occurs in the oocytes of the fruit fly Drosophila melanogaster. Prior to metaphase, the chromosomes of Drosophila oocytes are condensed into a single mass known as the karyosome. Meiotic spindle formation begins with the establishment of an array of microtubules, lacking a divers pole, that emanate from the major chromosomes. As prometaphase continues, these bundles of microtubules are sculpted together on each side of the metaphase plate to class a bipolar spindle. Information technology is oftentimes possible to observe that the early spindle is comprised of four sets of microtubule bundles, presumably respective to each of the four pairs of homologous chromosomes. The spindle then lengthens and tapers.

The ability of chromosomes to organize a functional spindle is not limited to Drosophila oocytes. Chromosomes have been shown to organize the spindle in the absenteeism of centrosomes in several meiotic systems. At least in Drosophila, and probably in other similar meiotic systems also, the co-orientation of homologous chromosomes appears to reverberate maintenance of heterochromatin pairing in the vicinity of the centromeres (ten,11). Because these paired centromeres are both involved in organizing the spindle, their get-go poleward movements along the developing spindles will serve to lock them in contrary orientations.

Thus, the ability of bivalents to orient their centromeres towards opposite poles is accomplished by balancing the tension between the bivalent and the two spindle poles. This balancing of tension requires chiasmata to agree the ii homologs together. This rather simple mechanism of chiasma role requires that each bivalent must be capable of orienting independently of other bivalents in the cell.

The functional significance of chiasma position

The number and position of recombination events is also tightly controlled. In metazoans, exchange just occurs in the euchromatin, and the amount of exchange is not proportional to physical distance (12). For each of the v major chromosome arms of Drosophila melanogaster, the frequency of exchange is extremely low virtually the base and tip of the euchromatin and reaches its highest levels in an interval kickoff approximately 30% of the altitude from the tip to the base of the euchromatin and catastrophe some l–lx% of that distance. This pattern is not unique to Drosophila females merely is a general feature of chiasma distribution in a large number of organisms (13).

The distribution of meiotic recombinational events results from the combined action of three types of genetic command: (i) trans-acting regulators of substitution position, which announced to human action at the level of unabridged chromosome arms; (two) local cis-acting regulators of exchange; and (3) chromosomal elements such as centromeres and telomeres that can suppress exchange in a polar fashion over long chromosomal distances (2). All three of these levels of regulation announced to human activity towards 1 uncomplicated purpose: to keep exchanges, and hence chiasmata, a substantial distance away from the centromeres and telomeres.

Every bit almost all exchanges are sufficient to ensure segregation, it seems paradoxical that the organism goes to such enormous efforts to position precisely its exchanges. The positioning of exchanges reflects a compromise between the bug inherent in resolving exchanges at anaphase I, which will forbid more than proximal exchanges, and the fact that very distal exchanges occasionally do not ensure segregation. Recall that the resolution of chiasmata occurs non by a terminalization process, but rather by a precise release of sister chromatid cohesion between the chiasma and the telomere (xiii). Moreover, sister chromatid cohesion must be maintained proximal to that chiasma and most essentially in the centromeric regions to ensure reductional separation at MI. Resolution of extremely proximal exchanges would crave the release of sister chromatid cohesion in regions too close to the centromere to allow normal centromere function at MI. Past limiting nearly exchanges to regions in the more distal euchromatin, the cell also limits the extent of sister chromatid release required for proper separation and chiasma resolution at the onset of anaphase, thus keeping its centromeres out of jeopardy.

Evidence in both flies and yeast argues that distal exchanges are not e'er by themselves sufficient to ensure segregation (reviewed in 2). In an elegant series of studies of mini-chromosome recombination in yeast, Dawson and his collaborators (14) accept shown that the 'ability of an substitution to enhance segregation allegiance appears to exist proportional to its distance from the telomere'. Similarly, when the ii back-up achiasmate segregational mechanisms in Drosophila melanogaster are mutationally ablated, bivalents with very distal chiasmata oft nondisjoin at very high frequencies (15,xvi), suggesting that the power of a very distal chiasma to guarantee segregation may ofttimes depend on additional functions, such every bit achiasmate dorsum-up systems. We are fond of the thought that very distal exchanges are simply locked in past far too trivial chromosomal material and that the resolution of chiasmata at the very kickoff of sister chromatid release may well result in a precocious separation of homologous centromeres. Indeed, as noted below, the ord and mei-S332 mutations, which cause precocious sister chromatid separation at anaphase I, also crusade high levels of nondisjunction.

In summary, the precise genetic command of exchange position reflects a delicate balance between sites of exchange that allow chiasma function and those sites which tin can permit the sister chromatid release required for chiasma resolution. Exchanges must be proximal enough to provide sufficient sister chromatid adhesion distal to the cross-over in order to ensure that the bivalents stay locked together. This requirement for more proximal exchanges is balanced against the need to prevent sis chromatid separation anywhere even remotely in the vicinity of the centromere.

Cases where fifty-fifty properly positioned chiasmata practise not ensure segregation

In that location are two important categories into which the nondisjunction of exchange bivalents autumn: then-chosen 'spontaneous' nondisjunction and nondisjunction due to meiotic mutations (a third category, radiations-induced nondisjunction, volition not be considered here). Although each blazon of event is discussed in detail beneath, information technology may be said in summary that in each case information technology is a failure of some other component of the meiotic process, such as the non-repair of DNA impairment or the construction of a faulty spindle, that induces the nondisjunction. Chiasmata cannot be blamed for these segregational failures whatever more than automobiles tin can exist blamed for the effects of adverse road conditions.

Spontaneous nondisjunction in Drosophila. In humans, considerable information is available on the the incidence and origin of spontaneous nondisjunction, as described afterward in this article. In contrast, in yeast and many other model organisms intolerance to aneuploidy has prevented all-encompassing studies of spontaneous nondisjunction; thus, relatively little is known about its occurrence in most model systems. It is best characterized in Drosophila melanogaster. Instead of trisomic conceptuses or disomic gametes, nondisjunctional events in Drosophila can be recovered as 'exceptional' females who have received both of their X chromosomes from their mothers and no sexual activity chromosomes from their fathers. The single published study of spontaneous 10 chromosome nondisjunction in Drosophila (17) was completed over 30 years ago and raised more questions than information technology answered; however, it has provided usa with the merely previous insights into the mechanisms responsible for the spontaneous failure of chromosomes to segregate from each other during meiosis.

In many means the data of Merriam and Frost (17) parallel the basic observations in humans. They suggested, albeit without the use of a centromere marker for verification, that the majority of spontaneous Ten chromosome nondisjunction in flies occurred at MI; as demonstrated in Table one and discussed later in this newspaper, this is also the example for most human trisomies. Additionally, they noted that exchange precedes spontaneous nondisjunction in as many as 75% of cases, although at that place was also an excess of achiasmate bivalents among nondisjunctional X chromosomes. As discussed later, the majority of cases of human being nondisjunction are preceded by substitution but—especially for the sex chromsomes—a proportion are associated with achiasmate bivalents. Thus, it is reasonable to expect that the origin of nondisjunction in flies volition be useful and relevant in elucidating similar mechanisms in humans.

This archetype study in Drosophila (17) too reported a number of unusual phenomena that remained unaddressed until recently (18). 1 such ascertainment was the possible occurrence of pericentromeric exchange, a phenomenon recently reported for human X chromosome nondisjunction (xix). Another unusual result was the appearance of new lethal mutations at a charge per unit several orders of magnitude greater than background levels on nondisjunctional X chromosomes. Although this idea has non been addressed experimentally in humans, at least one instance of trisomy 21 has been noted to carry a new cytogenetic heteromorphism not owing to either parent (20).

These findings in flies and humans led Hawley et al. (xviii) to advise that at least some spontaneous nondisjunction—in both species—is the effect of the repair of double-stranded breaks (DSBs) generated by the movement of transposable elements during meiotic prophase (Fig. 1). Such repair events will form Holliday junctions and thus strongly resemble normal meiotic recombination intermediates. Hawley et al. (eighteen) further suggested that if such repair events occur at the wrong time or wrong place during meiosis, either outside of the narrow temporal window allowed for normal meiotic exchange or in a location in which recombination is unremarkably prohibited, such equally the centromeric heterochromatin, the resulting physical connection between the homologs could interfere with rather than ensure their proper segregation at anaphase I.

Effigy 1.

A possible transposon-based model for spontaneous nondisjunction (A) Hawley et al. (18) accept proposed a model in which at least some spontaneous nondisjunction is the outcome of the repair of DSBs generated by the movement of transposable elements during meiotic prophase. DSBs in the DNA resulting from transposon excision (1) are repaired off of the homolog of the damaged chromosome (ii), and the resulting repair events are thought to form recombination intermediates (iii) similar or identical to those produced by normal meiotic recombination. (B) This model further suggests that such a concrete connection between the ii homologous chromosomes could, if it occurred at the wrong time or place, actually impair the proper segregation of homologs during anaphase I. For example, an exchange of meiotic origin in the central euchromatin (4) ensures regular disjunction, while a proximal DSB-repair event in the heterochromatin (5) may cause nondisjunction, either by interlocking the homologs at anaphase I or by compromising the integrity of the centromere. The latter event could consequence in precocious sis chromatid separation at MI.

An experimental reexamination of these ideas, using Drosophila, is currently underway and has uncovered 2 lines of evidence supporting the thought that spontaneous nondisjunction is correlated with the motion of transposable elements. First, a reversion rate of at to the lowest degree 1% due to the excision of a transposable element has been observed (Koehler and Hawley, unpublished observations) at a locus whose normal reversion rate is 1.5×10⁻⁵ (21). Second, we have recovered new lethal mutations at a rate of roughly 2% from a population of spontaneously nondisjoining Drosophila 10 chromosomes (Koehler and Hawley, unpublished observations). The transposon-based model for spontaneous nondisjunction postulated by Hawley et al. (18) predicts that the molecular lesions associated with the elevated mutation rate originally observed past Merriam and Frost (17) will be defects due to the insertion of a transposable element into a vital factor. Regardless of whether this is verified past molecular studies, the origin of these mutations will provide crucial insights into the mechanism of spontaneous nondisjunction.

Meiotic mutants that let the nondisjunction of exchange bivalents. In that location are 6 Drosophila meiotic mutations that crusade chiasmate bivalents (commutation bivalents) to nondisjoin at high frequency, two of which also impair sister chromatid cohesion. These mutations are ald, mei-38, ord, mei-S332, nod ^DTW (when homozygous), and ncd. The functions of the first two genes, ald and mei-38, remain unclear. Other than noting that these two mutations apparently define some function necessary for chiasma function, these mutants will non exist considered further. Both nod ^DTW and ncd define functions required for spindle assembly and/or maintenance at prometaphase, while ord and mei-S332 ascertain functions required for the command of sister chromatid cohesion. Each of these functions is considered in detail below. Chiasma failure under weather condition where spindle structure and/or assembly is perturbed. The nod gene in Drosophila melanogaster encodes a kinesin-like protein required for normal meiotic segregation (15,22,23). Although recessive loss-of-function nod alleles touch only the segregation of achiasmate bivalents, a ascendant allele (nod ^DTW) impairs the segregation of both chiasmate and achiasmate bivalents at MI (16,23). Interestingly, the number and frequency of exchanges in nondisjoining bivalents of nod ^DTW-bearing oocytes parallel those observed for nondisjoining chromosomes 21 in humans (18). Both are enriched not only for achiasmate chromosomes simply for bivalents with distally located exchange events; indeed, as discussed later, in trisomy 21-generating meioses, recombination in distal 21q is really increased over that observed in normal female meioses (Fig. ii).

Even so, information technology is important to note that the defect in nod ^DTW is non in recombination per se; due east.g. the mutation does not affect the frequency of recombination. Instead, the chromosomes in mutant oocytes are defective in their ability to maintain contact with both the homolog comprising the other half of the bivalent and with the forming meiotic spindle, resulting in precocious disassociation of one or more bivalents or univalent chromosomes from the defective spindle. Although proximal exchanges are still sufficient to ensure proper segregation in this state of affairs, bivalents with very distal exchanges or without any chiasmata at all are much more than likely to nondisjoin (16,24). Such chromosomes, ejected from the developing spindle, might oft either be lost or reform a connectedness with i of the two poles at random. We understand these observations and ideas in very simple mechanical terms: on a normal spindle there are several mechanisms, including tight centromere apposition every bit a issue of a proximal chiasma and/or proper NOD function, to concur homologs together and to agree bivalents on the spindle.

Nosotros take previously proposed that age impairs the ability of human females to grade a normal meiotic spindle (18), possibly through the time-dependent decay of an important component on which spindle function is dependent. Observations similar to those made for nod ^DTW accept been made for mutations at the ncd locus in Drosophila melanogaster (Paul Szauter, personal communication). It is possible that there are multiple elements whose functional deterioration could potentially have such an impact in human females as well. Like the nod gene, ncd encodes a kinesin that is required for proper meiotic spindle assembly (25). Information technology has been recently demonstrated that the NCD poly peptide is disquisitional to the stable assembly of a bipolar spindle in living Drosophila oocytes (26).

The ord and mei-S332 mutations and sister-chromatid cohesion. In both males and females ord causes a dramatic increment in both reductional and equational nondisjunction as detected genetically. In cytological studies of male meiosis, Goldstein (27) observed abnormal sister chromatid association during prophase too as precocious sister chromatid separation during anaphase I. In fact, the majority of chromosome misbehavior in ord mutants appears to be precocious sister chromatid separation at the first rather than the second meiotic division (27).

Recently, five additional alleles of ord take been characterized (28); a subtract in the frequency of sister chromatid cohesion is observed cytologically in the male germline for all five of these alleles (female meiosis has not been examined). Indeed, for the strongest allele, both genetic and cytological studies are consistent with random segregation at both divisions in both sexes. Like the original allele, these new alleles too decrease the frequency of exchange in females by ten–20-fold and ablate the ability of those exchanges that do occur to ensure segregation. Thus, the pleiotropic effects of the original allele on sis chromatid adhesion, exchange and chiasma function must exist due to a single biochemical defect. Presumably, that defect is in sis chromatid adhesion, and the effects on commutation and chiasma function are consequences of that defect. The ord factor has been recently cloned and found to encode a novel protein; mutational analysis of a number of ord alleles suggests that the C-terminal portion of this poly peptide is required for proper sister chromatid adhesion and plays a part in moderating poly peptide binding (29).

The mei-S332 mutation elevates equational nondisjunction in both sexes. Like ord, it has been shown cytologically to exhibit defects in sister chromatid cohesion in spermatocytes, although these practise not appear until anaphase I, later than the first manifestation of the ord defect. Withal, unlike ord, mei-S332 does not alter recombination location or frequency. Considering of this and the other phenotypic differences between these two mutations, mei-S332 has been postulated to define a function important for maintaining sis chromatid cohesion in the centromeric region (27,30). Consistent with this idea, MEI-S332 has recently been localized specifically to meiotic centromeres, where it remains until dissociation or degradation at anaphase II, concomitant with sister centromere separation (30). The cytology of mei-S332 mutants suggests that the bulk of nondisjunction occurs through the following pathway: sis chromatids separate precociously by anaphase I, but complete the reductional sectionalization in this separated state. Still at meiosis II (MII) the two sister chromatids segregate randomly.

The observations on ord and mei-S332 are intriguing, in light of contempo cytogenetic studies of nondisjunction in human oocytes. In analyses of unfertilized MII oocytes obtained from patients attending fertility clinics, Angell et al. (31) found a high proportion of oocytes contain either missing or extra single chromatids—not missing or extra intact chromosomes. While these observations are yet to be confirmed, they propose that errors in segregation at MI may result in the premature segregation of sis chromatids prior to MII. As the precocious equational segregation of chromosomes that nondisjoin at MI has been documented in a number of experimental systems (for review meet 13,32), this may represent an important potential mechanism for nondisjunction in many organisms.

Chiasma release and the cell cycle

Control of the metaphase-to-anaphase transition is a primal component of cell cycle regulation, and abort at metaphase I is a common component of oogenesis in both flies and mammals. In many male meiotic systems, the failure to recombine will result in the production of two univalent chromosomes, neither of which can be counterbalanced at the metaphase plate. Several lines of evidence point that the absenteeism of kinetochore tension in these organisms results in the production of a chemical signal that triggers a concluding metaphase abort. For instance, Li and Nicklas (33) recently reported that in praying mantid spermatocytes, the absence of tension on even a single kinetochore is sufficient to signal a meiotic error and trigger a prolongation of metaphase which results in cell decease. Restoration of tension on that kinetochore past micromanipulation relieves that fault signal and allows the cell to continue into anaphase I. The triggering of a terminal metaphase I abort past unaligned chromosomes acts to foreclose these spermatocytes from producing mature, but potentially aneuploid, sperm (33). Thus, in these males the part of an arrest at metaphase is to arrest an aberrant meiotic procedure.

Nosotros have recently shown that metaphase I arrest in Drosophila is triggered by the presence of chiasmata (34). Although the presence of even a unmarried chiasmate bivalent is sufficient to trigger metaphase arrest, in the absence of chiasmata metaphase arrest does non occur. While information technology is possible that the arrest reflects nothing more than the physical inability of homologs to separate until all of the chiasmata are resolved, we favor a model in which the presence of chiasmata induces one of a number of prison cell bike regulators to cause abort. According to either model, the release of this metaphase abort is concomitant with chiasma resolution. In both the mantid spermatocyte and the Drosophila oocyte, kinetochore tension is being used to halt the cell bike at metaphase, albeit towards rather different ends. This dramatic sexual asymmetry reflects the fact that development has immune tension to be used in two very different ways to regulate the meiotic process in males and females.

The absence of a chromosome misalignment checkpoint during Drosophila female meiosis (and many others, reviewed in 35) is striking. Meiosis proceeds unarrested with whatsoever number of univalent chromosomes or spindle disorganization, demonstrating that there is no checkpoint for mono-oriented or misaligned chromosomes in Drosophila female person meiosis. A like case can be made for oocytes from XO female mice. In this example, oocytes enter anaphase with a single unpaired Ten chromosome and without signaling a metaphase I checkpoint. Furthermore, the univalent segregates either equationally or reductionally at the first division, showing that the nature of the spindle attachment (bipolar or monopolar) does not effect the metaphase-to-anaphase transition (35). It is conceivable that most or all oocyte systems lack a method to notice mono-oriented chromosomes on the meiotic spindle. This may exist related to the fact that, unlike spermatocytes and yeast cells, most oocytes naturally arrest at some point during MI or 2. The lack of a metaphase checkpoint in human oocytes may cause the very loftier frequency of meiotic errors in human oocytes equally compared with sperm (35).

Effigy two.

Genetic maps of chromosomes xvi and 21, generated from normal female meioses (from CEPH family data) and trisomies of maternal origin. (A) For trisomy 16, in that location is an overall reduction in map length, attributable to a reduction of recombination in proximal 16p and 16q. (B) For trisomy 21, both MI and MII maps are associated with aberrant recombination; in the sometime case, the map is shorter, especially in proximal 21q and in the latter, the map is longer, especially in proximal 21q.

Molecular Studies of Human Nondisjunction

As is obvious from the preceding discussion, assay of meiotic mutants has guided our thinking about the relationship of substitution and chromosome segregation in lower organisms. In contrast, meiotic mutants which impact human chromosome segregation have not yet been identified; thus, this approach has not been available. Instead, investigations of man meiotic nondisjunction accept typically involved studying the incidence or origin of the boosted chromosome in trisomic conceptuses. The occurrence of such abnormalities is a major concern to human reproductive health. Trisomy is the near common class of man chromosome aberration, occurring in at least 0.3% of all newborns and in approximately 25% of spontaneous abortions. Considered as a class, it is the most common known crusade of mental retardation and the leading crusade of pregnancy wastage.

Table ane.

Molecular studies of parental and meiotic stage of origin in autosomal and sex activity chromosome trisomies (adjusted from reference 54 and Hassold and Sherman, unpublished results)

Despite the high frequency of human being trisomy and its obvious clinical importance, until recently little was known about the origin or causes of homo nondisjunction. Nonetheless, beginning in the late 1980s, several laboratories initiated DNA polymorphism studies of trisomic fetuses or liveborns and their parents; subsequently, a considerable corporeality of information has accrued on the parent and meiotic phase of origin of human trisomy and, more recently, on the clan of aberrant recombination and nondisjunction.

Near human trisomies originate in maternal meiosis

Molecular studies of the origin of trisomy are now available on over 1000 trisomic conceptuses (Table 1). The most extensively studied condition has been trisomy 21, with over 750 informative cases reported (36—38). Maternal errors predominate, bookkeeping for over 90% of cases. It has non been possible to determine unequivocally the meiotic stage of origin due to the lack of a chromosome 21-specific centromeric polymorphism. Notwithstanding, two groups (36,38) accept used proximal 21q DNA markers to infer the meiotic stage of origin of trisomy 21 and have reported similar results. For maternally derived cases, over 75% are compatible with MI nondisjunction, while for paternal trisomy MII cases predominate (Tabular array one). A small proportion, approximately 5%, of cases are apparently due to mitotic nondisjunction (36).

The other trisomies that have been studied display remarkable variability in origin (Tabular array i). For example, paternal MI nondisjunction is responsible for nearly 50% of cases of 47,XXY, while in trisomy xviii maternal MII errors predominate and for trisomy 16, all cases may derive from maternal MI nondisjunction. For the other trisomies, relatively few cases accept yet been studied. Nevertheless, the available evidence suggests that maternal errors predominate for most trisomies, but that individual chromosomes may have specific liabilities to paternal and maternal nondisjunctional mechanisms.

Aberrant recombination is a feature of human trisomy

Several groups have used centromere mapping techniques (39) either (i) to compare the frequency and location of genetic exchanges occurring between nondisjoining chromosomes in trisomy-generating meioses with those occurring between usually disjoining chromosomes in normal meioses or (two) to compare genetic linkage maps based on trisomy-generating meioses with those constructed from normal meioses (e.g. from conventional linkage studies of CEPH families). Using these approaches, information on recombination have been obtained for six nondisjunctional conditions: paternally derived cases of 47,XXY, maternally derived cases of sex chromosome trisomy and autosomal trisomies xvi, 18 and 21, and maternal uniparental disomy fifteen (Table 2). With the exception of trisomy 21, all mapping studies of individual trisomies have been based on a relatively small number of cases, with the reported furnishings of recombination appearing to vary amid the different conditions. Thus, interpretations of the data must be made with caution. All the same, all studies are in agreement in suggesting an association of aberrant recombination and man trisomy, and several full general features are now beginning to emerge.

A proportion of human trisomy is associated with failure of recombination. Similar to the observations of Merriam and Frost (17) for Drosophila, a meaning excess of nil-exchange events has been reported for several of the human trisomies. This is specially truthful for paternally derived 47,XXYs, as indicated by studies of crossing-over in the XpYp pseudoautosomal region in 39 paternally derived 47,XXYs (xl). Assuming that normally, a single chiasma within this region joins the MI XY bivalent, approximately one-half of the 47,XXYs would be expected to show evidence of recombination (in the other half, both recombinant or both not-recombinant meiotic products would be recovered, and the exchange would go undetected). Instead, Hassold et al. (40) found evidence for recombination in simply six of the 39 cases, a significant reduction from expectation. Subsequently, they used the data to generate a genetic linkage map of the pseudoautosomal region and found it to exist significantly shorter than the normal male map of the region (13 cM vs. 52 cM).

Tabular array 2.

Summary of studies of aberrant recombination and the genesis of human trisomy

Thus, the overwhelming majority of paternal 47,XXYs are obviously associated with failure of pairing and/or recombination. This observation is somewhat surprising, as testify from the mouse suggests that abnormalities in XY pairing lead to germ cell death rather than to increased nondisjunction (e.thou. 41). However, Ashley et al. (42) have recently suggested that, rarely, unrecombined sex chromosomes may complete meiosis to form functional (although frequently aneuploid) sperm. They studied male mice with a rearranged Y chromosome and a high frequency of sexual activity chromosome univalency in which—using FISH—it was possible to distinguish between sperm or spermatids carrying recombinant and those conveying non-recombinant sex chromosomes. Most sperm were chromosomally normal and had normal levels of XY recombination, indicating that most cells with unrecombined sexual activity chromosomes were eliminated at MI. However, a modest proportion (4%) of gametes were aneuploid, either XY or 'O', suggesting that some of the cells with unrecombined sex activity chromosomes were able to proceed to MII and beyond. In humans, the available data propose that a like process may well be the most common crusade of male person sex chromosome nondisjunction.

Failure of recombination also appears to be a feature of maternal nondisjunction, especially cases involving the 10 chromosome. In studies of sexual activity chromosome trisomy of maternal MI origin (nineteen,43), approximately forty% (32 of 82) of all examined cases showed no evidence of recombination betwixt the nondisjoined Xs. As at least three to four exchanges are predicted for the X chromosome bivalent, this represents a pregnant difference from expectation.

However, evidence for a similar effect involving autosomes is not virtually as compelling. In trisomies 16 and 21, an backlog of achiasmate bivalents has been reported (44,38). Yet, in trisomy 16, exchanges were identified in approximately 80% (44 of 56) of cases, with the most significant divergence from normal female meioses being an increased frequency of one-exchange events (44); and in trisomy 21 as well, studies of 173 cases of maternal MI origin indicated a significant increase in the frequency of i-exchange events (38). Similarly, there has been relatively little evidence for a significant increase in the frequency of zero-exchange events in either maternal uniparental disomy 15, based on studies of 27 cases (45) or maternal MI trisomy eighteen, based on studies of 16 cases (46). These observations are uniform with a role of reduced-but non absent-recombination in the genesis of most cases of autosomal trisomy. Thus, in humans the association betwixt absenteeism of recombination and nondisjunction may be largely restricted to the sex chromosomes.

Reduced recombination is a feature of most, if not all, human being trisomies of MI origin. Reductions in recombination have been observed in all trisomies of MI origin, with most trisomy-based genetic linkage maps being approximately half to two-thirds the length of the comparable maps from normal meioses (Table ii). Still, there is mounting evidence that the reductions are non randomly located on the chromosome arms; instead, there announced to exist specific 'cold spots' in the trisomy-generating meioses. This is especially true for trisomies 16 and 21, the two autosomal weather condition for which there are the most information (Fig. 2). In trisomy 16, in that location is little evidence for a reduction in recombination in either distal 16p or 16q. However, in the proximal regions of the chromosome Hassold et al. (44) reported a 20-fold decrease in recombination, with a map length of 77 cM in normals being reduced to only four cM in the trisomy 16 cases. 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 (38). Less data is available for other autosomal trisomies, merely preliminary data from UPD xv suggest that proximal exchanges may exist diminished in this status also (45,47).

Figure 3.

The possible association of chiasma location and human nondisjunction. (A) Bivalents joined only past distally placed chiasmata may be susceptible to premature separation at MI. When followed by a normal MII, the resulting disomic gamete would comprise nondisjoined chromosomes having genetically different centromeres; thus nondisjunction would be scored as occurring at MI. Nosotros suggest that any of several abnormalities—including harm of meiotic motors or sister chromatid cohesion proteins—may increase the likelihood of nondisjunction of these bivalents. (B) Bivalents joined past proximally-placed chiasmata may exist unable to carve up at MI. At MII, the bivalent might undergo a reductional partition, resulting in a disomic gamete in which the nondisjoined chromosomes have identical centromeres; thus, nondisjunction would be scored equally arising at MII, even though the precipitating event was at MI. We suggest that some such nondisjunction is attributable to transposon mobilization (Fig. 1), and that this process may contribute to the maternal age effect on man trisomy.

Thus it may be that, at to the lowest degree for autosomal trisomies of maternal MI origin, the absence of a proximally located chiasma imparts an increased risk for nondisjunction. This mimics observations on the nod ^DTW mutation in Drosophila (run across preceding discussion of model organisms), raising the possibility that—in humans also as flies—there is a back-up system to normal chiasmate segregation. If components of this organisation (such equally a human being homolog of NOD) degrade, achiasmate bivalents or bivalents with distal-just exchanges may exist preferentially affected; eastward.g. the centromeres may be less able to align when the commutation is physically distant, resulting in a bipolar attachment for one or both members of the bivalent. Alternatively, distal-only exchanges may increase the likelihood of premature separation of the bivalent—resulting in functional univalency—because of a decreased ability to maintain sister chromatid cohesion (Fig. three). Impairment in the functioning of sister chromatid cohesion proteins (such as a human homolog of ORD) might well preferentially touch this blazon of bivalent.

Regardless of the correctness of these or other models, the available evidence from humans suggests that it is altered placement of recombinational events, and not just reduced recombination per se, which is the important determinant of maternal MI nondisjunction.

'MII' nondisjunction is associated with aberrant recombination. As genetic recombination occurs at MI, there was no obvious reason to suspect that nondisjunction at MII would exist associated with aberrant recombination and this was consequent with early on studies of recombination in maternal MII trisomy 21 (38). However, with the conquering of new data, it is clear that this estimation is incorrect. Studies of maternal MII trisomy 21 at present indicate a significant effect of aberrant recombination although, in contrast to the situation with MI trisomy, the association is with increased recombination. Sherman (unpublished observations) has estimated the overall length of the MII map to be 107 cM, significantly elevated from the 72 cM for normal female meioses (Fig. 2). The distribution of exchanges is likewise different from normal, with an increased frequency of proximal exchanges in the MII population.

In that location is too suggestive evidence that aberrant recombination is of import in MII nondisjunction involving other chromosomes. In maternal MII sexual activity chromosome trisomy, significantly increased pericentromeric recombination has been reported, although the overall length of the 10 chromosome map is shorter than the normal map (nineteen). In maternal MII trisomy 18, in that location is an increase—although non-significant—in the overall length of the map (46).

How can an outcome which occurs at MI touch segregation at MII? Ane explanation may exist that the precipitating event occurs at MI, with aberrant segregation occurring at both divisions (Fig. 3). For example, proximal chiasmata may predispose to 'chromosome entanglement' (48) at MI, with the bivalent being unable to split up and passing intact to the MII plate; at MII the bivalent divides reductionally, resulting in a disomic gamete. In this state of affairs, the boosted chromosomes would take identical centromeres, and thus be scored as an MII trisomy, fifty-fifty though the origin of the abnormality was at MI.

Ane implication of this model is that 'true' MII errors may be relatively rare in humans. That is, in studies of trisomies of maternal origin, MII errors are typically reported to business relationship for approximately 20–30% of all cases (Table 1). If these errors instead reflect abnormal processing of specific MI chiasmate configurations, it may be that about all human nondisjunction is attributable to errors at maternal MI, with errors at maternal MII and paternal MI and MII occurring at low, 'groundwork' levels. This is intuitively an attractive thought, every bit the first meiotic sectionalisation in females is unique in that it takes at least 10 and possibly equally many as 40–50 years to consummate. However, before seriously considering this posssibility, it will be important to verify the apparent association between abnormal recombination and MII nondisjunction.

Maternal age-dependent trisomy is associated with aberrant recombination. An obvious implication of the above studies is an association betwixt aberrant recombination and age-dependent nondisjunction. For example, in trisomy 16, thought to be completely maternal historic period-dependent (49), the genetic map is significantly shorter than the normal map (44); in trisomy 21, significant reductions in recombination have been identified in both older and younger women (38); and in maternal sex chromosome trisomy, the mean maternal age is significantly elevated for the zero-exchange cases (19). Thus, it is clear that aberrant recombination plays an of import part in the genesis of the maternal age event on trisomy.

Yet, there is less certainty regarding the underlying basis of the clan. An early on, and still much debated, model was proposed by Henderson and Edwards over 25 years agone (l). Based on observations of declining chiasma frequencies and an increased frequency of univalents in aging mouse oocytes, they suggested that reductions in crossing-over with resultant univalent germination might explicate age-dependent trisomy. However, as chiasma formation occurs prenatally in the female, they were forced to postulate the being of a gradient, or 'production line', in the fetal ovary that causes the first formed oocytes to have a higher chiasma frequency than those formed after. Assuming that oocytes are ovulated in the same order that they enter meiosis, those that are ovulated last would be the virtually susceptible to nondisjunction due to a reduction in chiasmata.

Recent studies of the mouse suggest that the last-formed oocytes are, indeed, the last to exist ovulated (51), fulfilling one prediction of the 'production line' model. Studies of human trisomies fulfill a 2d prediction, namely, that historic period-dependent trisomy is associated with reductions in recombination. All the same, other predictions of the model are less easily reconciled with the mapping data from normal and trisomy-generating meioses. For example, conventional linkage studies of chromosome 21 (Audrey Lynn, personal communication) and chromosome 22 (52) provide no evidence that recombination declines with maternal age in normal meioses. Further, in studies of trisomies 16 and 21 of maternal MI origin, the magnitude of the reduction in recombination is similar in younger and older women (Hassold and Merrill, unpublished observations; Sherman, unpublished observations). Finally, cases of trisomy 21 of maternal MII origin are associated with increased recombination, despite the fact that this condition is clearly maternal historic period-dependent.

Thus, the mapping information provide lilliputian evidence that the association of recombination and age-related trisomy is established prenatally. Instead, it seems more than likely that the outcome involves 2 'hits': first, the institution in fetal meiosis of a 'susceptible' meiotic configuration and second, age-related degradation of a meiotic process which increases the chance of nondisjunction of bivalents with susceptible configurations. For example, for the chromosome 21 bivalent the presence of a single, distally placed exchange may constitute a susceptible configuration (Fig. three). In the 'immature' ovary, the presence of a unmarried chiasma—regardless of its location—may be sufficient to ensure normal segregation. However, with advancing historic period normal segregation may become increasingly dependent on the presence of a proximal, 'anchoring' chiasma. In its absence, the homologs may separate prematurely; for example, due to an historic period-related defect in a motor protein (such every bit NOD in Drosophila) which normally helps to hold the homologs in shut annals (two), or to age-related degregation of a protein involved in sister chromatid cohesion (such equally ORD or MEI-S332 in Drosophila). As a consequence in the older ovary, bivalents with distal-simply exchanges may function independently of 1 another at MI, increasing the likelihood that they will drift to the same pole.

However, what is the explanation for the increase in exchanges—particularly in the proximal regions of the chromosome—observed in some maternal age-dependent conditions (e.thousand. trisomy 21 of maternal MII origin)? One possibility is that such configurations also confer an increased susceptibility, but for a reason opposite that for distally placed exchanges; i.e. in these instances the configurations interfere with the ability of the bivalent to become disentangled at MI (Fig. three). This might be a consequence of an historic period-related shortening in the meiotic cell cycle (53), which limits the amount of time to resolve chiasmata, or to age-related degradation of human homologs of proteins, such as NCD, which commonly promote poleward motility of the chromosomes. As a result, the bivalent fails to separate and the homologs move together to the pole. At MII reduction occurs, leading to disomy and an credible MII error.

In the above two models of age-dependent trisomy information technology is assumed that aberrant recombination is correlated with, but is not the proximal crusade of, age-related trisomy. Rather, it is causeless that with increasing maternal historic period, bivalents joined together by too few chiasmata (or by distally placed chiasmata) or by likewise many chiasmata (or proximally placed chiasmata), are more susceptible to nondisjunction.

Nevertheless, in trisomies associated with an excess number of exchanges, it may be that aberrant recombination is, indeed, the proximal cause of nondisjunction. Every bit discussed before, Hawley et al. (18) have suggested that some nondisjunction in Drosophila results from the repair of double strand breaks generated past transposon mobilization and we propose that some historic period-related human trisomy arises in a similar way. In this instance, the 'recombinational' events occur in the arrested (dictyotene) stage of oogenesis. They practise not lead to functional chiasmata, just rather may cause the chromosomes to interlock and prevent their separation at MI (Fig. 1). If the bivalent passes intact to the MII plate, the nondisjunctional production may again appear to result from an MII event, as in Figure 3. One implication of this model is that at that place may exist an environmental component to human age-related nondisjunction. That is, in addition to repair of tranposition events, other Dna dissentious agents may lead to chromosome interlocking and eventual nondisjunction. With age, the likelihood of such an issue presumably increases, generating an historic period outcome on trisomy; and, if pericentromeric 'exchanges' promote interlocking, recombination in trisomy-generating meioses will appear to be increased in the proximal regions. Still, such recombination should non display interference, providing a possible means for testing this model.

Summary

Studies of Drosophila and humans point several similarities in nondisjunctional mechanisms in the 2 species. In both, a proportion of nondisjunction is associated with achiasmate bivalents and in both, exchanges which are either too distal or likewise proximal increase the likelihood of mal-segregation.

Analyses of meiotic mutants in Drosophila have identified several probable candidates for these recombination-associated events: abnormalities in meiotic motors and sister chromatid cohesion proteins accept been shown to increase the likelihood of nondisjunction in distal-only exchange bivalents, and transposon mobilization in the pericentromeric region may also exist a source of nondisjunction in flies. The relevance of these mutational processes to human being nondisjunction is not yet clear, and the technical and ethical difficulties associated with man meiotic analyses will complicate attempts to examine them. Yet, recent advances in molecular cytogenetic technology now make it possible to study chromosome segregation in human gametes (35), and the utilization of knockout mice makes it possible to study the effect of specific mutations on meiotic chromosome behavior. By combining these with other emerging technologies, we may finally be able characterize the mechanisms underlying human being nondisjunction; given the extraordinary incidence and clinical significance of trisomy to human well-being, it is important that such attempts begin.

Acknowledgements

We gratefully acknowledge Drs Patricia Chase and Helen Salz for their critical reading of the manuscript. Some of the research described in this manuscript was supported past NIH grants R01-HD21341 (to T.H.), P01-HD32111 (to T.H. and S.South.) and R01-GM51444 (to R.S.H.), and by American Cancer Society grant DB-39E (to R.S.H.).

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Source: https://academic.oup.com/hmg/article/5/Supplement_1/1495/663563

Describe Nondisjunction and the Effect It Can Have on a Human.

Abstract

Introduction

Substitution and Chromosome Segregation in Model Organisms

How chiasmata work

The functional significance of chiasma position

Cases where fifty-fifty properly positioned chiasmata practise not ensure segregation

Chiasma release and the cell cycle

Molecular Studies of Human Nondisjunction

Near human trisomies originate in maternal meiosis

Aberrant recombination is a feature of human trisomy

Summary

Acknowledgements

References

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