Our understanding of the human meiotic process, and of factors which affect meiotic chromosome segregation, is much less advanced. Nevertheless, recent studies of human 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 two perspectives: first, a review of exchange and chromosome segregation in model organisms, focusing on Drosophila , and secondly an overview of nondisjunction in humans. Genetic recombination, or crossing-over, is the primary 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 as 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—6. Chiasmata serve to link homologous chromosomes together by taking advantage of the strong sister chromatid cohesion maintained along both of the homologs. The resulting pair of interlocked chromosomes, known as a bivalent, then attaches to the spindle such that one 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 meiotic systems of most animals, during prometaphase each kinetochore of the bivalent attaches to the spindle and begins to move toward one of the two poles.
Most 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 most nearly points and to the observation that at the start of prometaphase, the two homologous centromeres are usually oriented in opposite directions, such that if one centromere is pointed at one pole the other centromere is pointed at the opposite pole [Ostergren 8 , as modified by Nicklas 7 ].
Once the two centromeres have oriented towards opposite 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 will remain until anaphase I. Although the mechanism described above is sufficient to explain bivalent attachment in many meiotic systems, it should be remembered that in some oocytes the spindle appears to be acentriolar and is organized by the chromosomes themselves.
A well-studied example of this phenomenon 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 defined 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 form a bipolar spindle.
It is often possible to observe that the early spindle is comprised of four sets of microtubule bundles, presumably corresponding 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 absence of centrosomes in several meiotic systems. At least in Drosophila , and probably in other similar meiotic systems as well, the co-orientation of homologous chromosomes appears to reflect maintenance of heterochromatin pairing in the vicinity of the centromeres 10 , Because these paired centromeres are both involved in organizing the spindle, their first poleward movements along the developing spindles will serve to lock them in opposite orientations.
Thus, the ability of bivalents to orient their centromeres towards opposite poles is achieved by balancing the tension between the bivalent and the two spindle poles. This balancing of tension requires chiasmata to hold the two homologs together. This rather simple mechanism of chiasma function requires that each bivalent must be capable of orienting independently of other bivalents in the cell. The number and position of recombination events is also tightly controlled.
In metazoans, exchange only occurs in the euchromatin, and the amount of exchange is not proportional to physical distance This pattern is not unique to Drosophila females but is a general feature of chiasma distribution in a large number of organisms The distribution of meiotic recombinational events results from the combined action of three types of genetic control: i trans -acting regulators of exchange position, which appear to act at the level of entire chromosome arms; ii local cis -acting regulators of exchange; and iii 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 appear to act towards one simple purpose: to keep exchanges, and hence chiasmata, a substantial distance away from the centromeres and telomeres.
As virtually 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 problems inherent in resolving exchanges at anaphase I, which will preclude more proximal exchanges, and the fact that very distal exchanges occasionally do not ensure segregation.
Recall that the resolution of chiasmata occurs not by a terminalization process, but rather by a precise release of sister chromatid cohesion between the chiasma and the telomere 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 require the release of sister chromatid cohesion in regions too close to the centromere to allow normal centromere function at MI. By limiting most 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 always by themselves sufficient to ensure segregation reviewed in 2. 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 15 , 16 , suggesting that the ability of a very distal chiasma to guarantee segregation may often depend on additional functions, such as achiasmate back-up systems.
We are fond of the idea that very distal exchanges are simply locked in by far too little chromosomal material and that the resolution of chiasmata at the very start of sister chromatid release may well result in a precocious separation of homologous centromeres. Indeed, as noted below, the ord and mei-S mutations, which cause precocious sister chromatid separation at anaphase I, also cause high levels of nondisjunction.
In summary, the precise genetic control of exchange position reflects a delicate balance between sites of exchange that allow chiasma function and those sites which 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 sister chromatid separation anywhere even remotely in the vicinity of the centromere. Although each type of event is discussed in detail below, it may be said in summary that in each case it is a failure of some other component of the meiotic process, such as the non-repair of DNA damage or the construction of a faulty spindle, that induces the nondisjunction.
Chiasmata cannot be blamed for these segregational failures any more than automobiles can be 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 later in this article. In contrast, in yeast and many other model organisms intolerance to aneuploidy has prevented extensive studies of spontaneous nondisjunction; thus, relatively little is known about its occurrence in most model systems.
It is best characterized in Drosophila melanogaster. 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. In many ways 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 X chromosome nondisjunction in flies occurred at MI; as demonstrated in Table 1 and discussed later in this paper, this is also the case for most human trisomies. As discussed later, the majority of cases of human nondisjunction are preceded by exchange 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 will be useful and relevant in elucidating similar mechanisms in humans.
This classic study in Drosophila 17 also reported a number of unusual phenomena that remained unaddressed until recently One such observation was the possible occurrence of pericentromeric exchange, a phenomenon recently reported for human X chromosome nondisjunction Another unusual result was the appearance of new lethal mutations at a rate several orders of magnitude greater than background levels on nondisjunctional X chromosomes.
Although this idea has not been addressed experimentally in humans, at least one case of trisomy 21 has been noted to carry a new cytogenetic heteromorphism not attributable to either parent These findings in flies and humans led Hawley et al. Such repair events will form Holliday junctions and thus strongly resemble normal meiotic recombination intermediates. Hawley et al. A possible transposon-based model for spontaneous nondisjunction A Hawley et al. DSBs in the DNA resulting from transposon excision 1 are repaired off of the homolog of the damaged chromosome 2 , and the resulting repair events are thought to form recombination intermediates 3 similar or identical to those produced by normal meiotic recombination.
B This model further suggests that such a physical connection between the two 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 result in precocious sister chromatid separation at MI. An experimental reexamination of these ideas, using Drosophila , is currently underway and has uncovered two lines of evidence supporting the idea that spontaneous nondisjunction is correlated with the movement of transposable elements. The transposon-based model for spontaneous nondisjunction postulated by Hawley et al. Regardless of whether this is verified by molecular studies, the origin of these mutations will provide crucial insights into the mechanism of spontaneous nondisjunction.
Meiotic mutants that allow the nondisjunction of exchange bivalents. There are six Drosophila meiotic mutations that cause chiasmate bivalents exchange bivalents to nondisjoin at high frequency, two of which also impair sister chromatid cohesion.
These mutations are ald, mei, ord, mei-S, nod DTW when homozygous , and ncd. The functions of the first two genes, ald and mei , remain unclear. Other than noting that these two mutations apparently define some function necessary for chiasma function, these mutants will not be considered further.
Each of these functions is considered in detail below. The nod gene in Drosophila melanogaster encodes a kinesin-like protein required for normal meiotic segregation 15 , 22 , Although recessive loss-of-function nod alleles affect only the segregation of achiasmate bivalents, a dominant allele nod DTW impairs the segregation of both chiasmate and achiasmate bivalents at MI 16 , Interestingly, the number and frequency of exchanges in nondisjoining bivalents of nod DTW -bearing oocytes parallel those observed for nondisjoining chromosomes 21 in humans Both are enriched not only for achiasmate chromosomes but for bivalents with distally located exchange events; indeed, as discussed later, in trisomy generating meioses, recombination in distal 21q is actually increased over that observed in normal female meioses Fig.
However, it is important to note that the defect in nod DTW is not in recombination per se ; e. 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 situation, bivalents with very distal exchanges or without any chiasmata at all are much more likely to nondisjoin 16 , Such chromosomes, ejected from the developing spindle, might frequently either be lost or reform a connection with one of the two poles at random.
We have previously proposed that age impairs the ability of human females to form a normal meiotic spindle 18 , perhaps through the time-dependent decay of an important component on which spindle function is dependent. Observations similar to those made for nod DTW have 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 It has been recently demonstrated that the NCD protein is critical to the stable assembly of a bipolar spindle in living Drosophila oocytes The ord and mei-S mutations and sister-chromatid cohesion. In both males and females ord causes a dramatic increase in both reductional and equational nondisjunction as detected genetically.
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. 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 Recently, five additional alleles of ord have been characterized 28 ; a decrease 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. Environmental Influences on Gene Expression. Epistasis: Gene Interaction and Phenotype Effects.
Genetic Dominance: Genotype-Phenotype Relationships. Phenotype Variability: Penetrance and Expressivity. Citation: Miko, I. Nature Education 1 1 Although mitosis and meiosis both involve cell division, they transmit genetic material in very different ways.
What happens when either of these processes goes awry? Aa Aa Aa. Gene Transmission in Mitosis. Figure 1. Gene Transmission in Meiosis. Figure 2: Examples of polytene chromosomes. Pairing of homologous chromatids results in hundreds to thousands of individual chromatid copies aligned tightly in parallel to produce giant, "polytene" chromosomes. High-pressure treatment of polytene chromosomes improves structural resolution.
Nature Methods 4, All rights reserved. Aberrations That Alter Chromosome Number. Figure 3: Nondisjunction results in daughter cells with unusual chromosome numbers. Nondisjunction, in which chromosomes fail to separate equally, can occur in meiosis I first row , meiosis II second row , and mitosis third row. These unequal separations can produce daughter cells with unexpected chromosome numbers, called aneuploids. When a haploid gamete does not receive a chromosome during meiosis as a result of nondisjunction, it combines with another gamete to form a monosomic zygote.
When a gamete receives a complete homologous chromosome pair as a result of nondisjunction, it combines with another gamete to form a trisomic zygote. Genetics: A Conceptual Approach , 2nd ed. Figure 4: Jimsonweed seed pod shapes. Trisomy in any of Jimsonweed's 12 chromosomes will cause seed pods to deviate from a wild-type, spherical shape.
References and Recommended Reading Belling, J. Genetics: A Conceptual Approach W. Freeman, New York, Article History Close. Share Cancel. Revoke Cancel. Keywords Keywords for this Article. Save Cancel. Flag Inappropriate The Content is: Objectionable. Flag Content Cancel. Email your Friend. Submit Cancel. This content is currently under construction.
Explore This Subject. Gene Linkage. The Foundation of Inheritance Studies. Methods for Studying Inheritance Patterns. Variation in Gene Expression. Topic rooms within Gene Inheritance and Transmission Close. No topic rooms are there. Or Browse Visually. Other Topic Rooms Genetics.
Student Voices. Creature Cast. Simply Science. Green Screen. Green Science. Bio 2. The Success Code. Why Science Matters. The Beyond. Of all the chromosomal disorders, abnormalities in chromosome number are the most easily identifiable from a karyogram.
Disorders of chromosome number include the duplication or loss of entire chromosomes, as well as changes in the number of complete sets of chromosomes. They are caused by nondisjunction , which occurs when pairs of homologous chromosomes or sister chromatids fail to separate during meiosis.
The risk of nondisjunction increases with the age of the parents. Nondisjunction can occur during either meiosis I or II, with different results Figure 7. If homologous chromosomes fail to separate during meiosis I, the result is two gametes that lack that chromosome and two gametes with two copies of the chromosome. If sister chromatids fail to separate during meiosis II, the result is one gamete that lacks that chromosome, two normal gametes with one copy of the chromosome, and one gamete with two copies of the chromosome.
An individual with the appropriate number of chromosomes for their species is called euploid; in humans, euploidy corresponds to 22 pairs of autosomes and one pair of sex chromosomes. An individual with an error in chromosome number is described as aneuploid, a term that includes monosomy loss of one chromosome or trisomy gain of an extraneous chromosome. Monosomic human zygotes missing any one copy of an autosome invariably fail to develop to birth because they have only one copy of essential genes.
Most autosomal trisomies also fail to develop to birth; however, duplications of some of the smaller chromosomes 13, 15, 18, 21, or 22 can result in offspring that survive for several weeks to many years.
Trisomic individuals suffer from a different type of genetic imbalance: an excess in gene dose. Cell functions are calibrated to the amount of gene product produced by two copies doses of each gene; adding a third copy dose disrupts this balance.
The most common trisomy is that of chromosome 21, which leads to Down syndrome. Individuals with this inherited disorder have characteristic physical features and developmental delays in growth and cognition. The incidence of Down syndrome is correlated with maternal age, such that older women are more likely to give birth to children with Down syndrome Figure 7. Concept in Action Visualize the addition of a chromosome that leads to Down syndrome in this video simulation.
Humans display dramatic deleterious effects with autosomal trisomies and monosomies. Therefore, it may seem counterintuitive that human females and males can function normally, despite carrying different numbers of the X chromosome. In part, this occurs because of a process called X inactivation. Early in development, when female mammalian embryos consist of just a few thousand cells, one X chromosome in each cell inactivates by condensing into a structure called a Barr body.
The genes on the inactive X chromosome are not expressed. The particular X chromosome maternally or paternally derived that is inactivated in each cell is random, but once the inactivation occurs, all cells descended from that cell will have the same inactive X chromosome. By this process, females compensate for their double genetic dose of X chromosome. Females heterozygous for an X-linked coat color gene will express one of two different coat colors over different regions of their body, corresponding to whichever X chromosome is inactivated in the embryonic cell progenitor of that region.
When you see a tortoiseshell cat, you will know that it has to be a female. In an individual carrying an abnormal number of X chromosomes, cellular mechanisms will inactivate all but one X in each of her cells. As a result, X-chromosomal abnormalities are typically associated with mild mental and physical defects, as well as sterility.
If the X chromosome is absent altogether, the individual will not develop. Several errors in sex chromosome number have been characterized. Individuals with three X chromosomes, called triplo-X, appear female but express developmental delays and reduced fertility.
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