Two of the gametes will have an extra copy of the chromosome and the other two will not get any copies of that chromosome. The bottom row of the diagram shows what the cells would look like after fertilization. Notice that the diagrams only include the chromosome which undergoes nondisjunction, meaning that the "empty" cells actually contain other chromosomes which did not undergo nondisjunction. When nondisjunction occurs in meiosis II , cells divide normally during anaphase I homologous chromosomes separate correctly , but sister chromatids fail to separate during anaphase II as seen in the diagram above, on the left.
This again results in four possible haploid gametes. Two of the gametes have the normal, single copy of the chromosome, one will have two copies of the chromosome, and one won't have any copies of the chromosome. The bottom row shows what the cells would look like after fertilization. Here only two of the cells are affected. This video describes meiotic nondisjunction, a process where chromosomes don't split correctly during anaphase.
This results in a sex cell that either has too many or too few chromosomes. Nondisjunction is an error during meiosis that creates eggs or sperm cells that have the wrong number of chromosomes. Alright, recall that meiosis is the process of making haploid gametes from diploid cells. During fertilization, two of these haploid cells combine to create a new diploid cell with a set of chromosomes from each haploid. This basically means a diploid cell that has a chromosome from each parent.
Well, sometimes meiosis goes a bit wrong and the chromosomes do not separate properly during anaphase. When this happens, you end up with haploids that have a different number of chromosomes—either one too many or one too few.
If one of these haploid cells becomes fertilized, the offspring produced will have an abnormal number of chromosomes. Interphase : The longest part of the cell cycle where the cell grows and DNA is replicated to prepare for nuclear division. These aneuploid cells may also exhibit chromosome instability and acquire further numerical and segmental chromosomal aberrations [ , , , , ]. However, it is also common that in cancer cells, multiple centrosomes can cluster to form bipolar spindles [ ].
Strategies to inhibit centrosome clustering and thus purposefully drive spindle multipolarity have been proposed as potential cancer therapies [ , ].
Indeed, it has been proposed that the well-established anti-cancer drug Taxol may function in this manner [ 87 ]. On the other hand, in human tumors, the presence of abnormal mitotic figures such as multipolar spindles in biopsies is considered a feature of advanced malignancy.
Understanding the positive and negative consequences of spindle multipolarity remains an important topic for future study. Tetraploid cells in tissue culture can also reveal increased resistance to certain chemotherapeutic drugs compared to their parental diploid cells [ , , , , ]. This effect is reminiscent of the elevated antibiotic resistance detected in polyploid fungi, although the mechanisms underlying this resistance in mammalian cells have not been discovered.
In mammals, aneuploidy- and polyploidy-driven evolution of single cells is restrained by the tumor suppressor protein p53 [ 2 , 3 , 5 , , , ]. Yeast cells do not have the p53 gene, and homologues of mammalian p53 first appeared in protostomes molluscs, annelids and arthropods [ ]. As mentioned previously, plants also lack p53 [ ]. Animals with a large body size require many more cells and often exhibit longer lifespans than smaller animals.
Thus, long-lived, large animals might be expected to have an increased susceptibility to cancer. However, no correlation between body size or lifespan and the occurrence of cancer can be found [ , , ]. Interestingly, elephants possess 20 copies of the p53 gene and show a hyperactive pdependent DNA damage response, potentially contributing to cancer resistance in this large, long-lived animal [ ].
More than half of human malignancies harbor mutations of the p53 gene [ ], and together with alterations in other components of the p53 network, the p53 pathway is suppressed or inactivated in most human cancers [ ]. Inactivation of the p53 pathway likely unleashes cancer evolution, enabling cancer cells with abnormal karyotypes to proliferate, limited only by their fitness in a given environment.
Determining this has been challenging because transcriptional activation of p53 can be triggered by a wide variety of external and internal stresses [ , , ], and the range of stresses that may occur in polyploid and aneuploid cells is also broad.
The roles of p53 in sensing DNA damage as well as oxidative and proteotoxic stresses are well established. These stressors can accompany some cases of ploidy alterations. In addition, the stoichiometry of ribosomal proteins caused by changes in gene dosages can activate the p53 pathway by protecting p53 from ubiquitination by its key negative regulator, the ubiquitin ligase Mdm2, which targets it for degradation by the proteasome [ ].
Moreover, polyploid and aneuploid cells frequently have an aberrant number of centrosomes, and recent studies show that the p53 may be activated by extra or missing centrosomes [ , , ].
A recent study of chromosome missegregation in anaphase demonstrated that lagging or misaligned chromosomes stabilize p53 through retained phosphorylation of histone H3. When non-transformed cells in culture are induced to become polyploid by disruption of the actin or microtubule cytoskeleton, they usually block proliferation through the expression of p53 [ 2 , , , , , , , ].
Direct imaging of cells in culture suggests that the pdependent arrest may be delayed for up to three cell cycles after the induction of polyploidy [ ]. The pathways linking polyploid cell formation to p53 activation remain unclear. One mechanism may be activation of the Hippo tumor suppressor pathway, induced, at least in part, by extra centrosomes [ ]. In tissue culture, proliferating lines of tetraploid cells can grow out from cultures experimentally induced to become tetraploid.
These karyotypically stable tetraploid cells adapt to contain normal numbers of centrosomes and build bipolar mitotic spindles [ 43 , ]. As yet, a full understanding of how aneuploid and polyploid cells circumvent pmediated arrest remains incomplete, but two recent studies indicated that overexpression of D-type Cyclins allows the continued proliferation of tetraploid cells despite the presence of wild-type p53 [ 43 , ].
In a variety of cell lines, loss of function mutations of the Rb tumor suppressor caused significant chromosome segregation errors but only a modest increase in aneuploidy, unless p53 was also inactivated, whereupon aneuploidy was greatly enhanced [ ].
In cells, heterozygous for an inactivating p53 mutation, loss of Rb function could increase the probability that a segregation error causes loss of the chromosome containing the wild-type p53 allele loss of heterozygosity and thus generate proliferative progeny permissive for further chromosome instability and increased aneuploidy. Of note, aneuploid cells also occur naturally in some tissues such as the adult liver [ ] and the brain [ ].
As discussed earlier, polyploidization is a part of a normal differentiation program in certain cell lineages.
In tissue culture, human pluripotent stem cells and RPE-1 with normal p53 expression were found to gain extra copies of chromosome 12 and proliferate at a high rate [ 43 ]. It is not yet fully clear how, in various circumstances, acquisition of extra chromosomes in non-malignant pexpressing cells in culture allows cells to evade detection or overcome activation of p The simple use of the terms mitotic or meiotic errors presupposes that such events are detrimental.
In many, perhaps most cases, abrupt changes in chromosome content in humans will have unfavorable consequences, for example meiotic aneuploidies giving rise to abnormal embryos or cancer cells developing increased malignancy. However, studies in unicellular eukaryotes have demonstrated that aneuploidy and genomic instability can empower adaptive evolution. Here, there are distinct differences between single-cell eukaryotes and metazoans.
In yeast, karyotypic diversity is limited only by the fitness cost and may allow exploitation of new environmental conditions. In multicellular organisms, proliferative competition of individual cells leads to cancer and compromises the fitness of the whole organism.
However, there are clear instances where altered mitotic events have been subsumed into differentiation, providing evolutionary advantages in metazoans. The study of the paths leading from segregation errors to adverse consequences has important potential for human health.
For example, in individual cancers, what is the relationship among chromosome instability, aneuploidy, and malignancy? Which pathways—sister chromatid cohesion, cell cycle checkpoints, chromosome movement, and others—are affected? Can we design treatments that specifically target cells that are aneuploid? Can prevention of centrosome clustering be a viable cancer therapy? After many years of study, the complex role of p53 in tumor progression still holds secrets.
How can these be revealed and exploited? What are the most important contributors of the maternal age effect? Is it possible to design interventions that might promote normal fertility and development? As we learn more about the mechanisms underlying mitosis and meiosis, we are sure to uncover more surprising insights into the complex interplay of the regulation of cell division with disease, health, and evolution.
Gary J. National Center for Biotechnology Information , U. Journal List Biology Basel v. Biology Basel. Published online Feb 8. Tamara Potapova 1 and Gary J. Richard McIntosh, Academic Editor. Author information Article notes Copyright and License information Disclaimer.
Received Nov 10; Accepted Jan This article has been cited by other articles in PMC. Abstract Mistakes during cell division frequently generate changes in chromosome content, producing aneuploid or polyploid progeny cells. Keywords: aneuploidy, polyploidy, microtubule, chromosome instability, cancer, birth defects, fertility, drug resistance, centromere, kinetochore. Open in a separate window. Figure 1. Table 1 Definitions. Ploidy is the number of sets of chromosomes in a cell or in an organism.
Haploid number refers to one set of chromosomes 1N , as in gametes or certain strains of budding yeast. Diploid number refers to two sets of chromosomes 2N that are homologous one from each parent. Most animals are diploid.
Polyploid denotes a cell with more than two sets of chromosomes triploid — 3N, tetraploid — 4N, pentaploid — 5N, etc. Euploid denotes the normal chromosome number in a species, usually an exact multiple of the haploid number i. Chromosomal Instability is the tendency of a cell to gain or lose chromosomes or large segments of chromosomes. It is often abbreviated CIN. Aneuploidy denotes the state of a cell having a chromosome number that deviates from a multiple of the haploid, i.
Whole chromosomal aneuploidy is having entire chromosomes gained or lost. Segmental aneuploidy is having large regions of chromosomes deleted, duplicated or translocated from one chromosome to another. Cancer cells often exhibit both whole chromosome aneuploidy and segmental aneuploidy. Trisomy 21 indicates an extra chromosome 21 in a diploid genome.
Aneuploidy in Mitosis 2. Effects of Aneuploidy on Gene Dosage In diploid organisms, apart from special instances such as the sex chromosomes of animals, genes are present in two copies that are both transcribed.
Effects of Aneuploidy on Cellular Fitness The euploid karyotype is a product of natural selection for the best fitness for a species in an ecological niche.
Figure 2. Aneuploidy in Fungi Despite the overall fitness cost of carrying extra chromosomes, variation in the chromosome copy number can be found in many fungal species. Aneuploidy in Mammalian Cells Aneuploidies commonly emerge in mammalian cell cultures, but this phenomenon has been traditionally viewed as an annoyance rather than a topic worthy of study.
Aneuploidy as a Driver for Genomic and Chromosomal Instability Chromosomal instability refers to an increased propensity for chromosome segregation errors, resulting in aneuploidy and genomic imbalances [ 48 , 49 ]. Aneuploidy and Cancer In the late 19th century, it was recognized that tumor cells often exhibit abnormal, asymmetric mitotic figures [ 57 ]. Cohesion Fatigue and Centromere Fission Another potential source of aneuploidy in tumor cells is cohesion fatigue in cells that are delayed or arrested at metaphase.
Figure 3. Figure 4. Modern Analysis and Implications of Cancer Aneuploidy For many years, aneuploidy in tumors was studied using cytogenetic methods, which can accurately detect large karyotypic alterations but are less accurate in identifying small alterations.
Aneuploidy and Drug Resistance Aneuploidy may promote the emergence of antibiotic-resistant infections and chemotherapy-resistant cancers. Micronuclei 3. Footprint of Mitotic Error Micronuclei, as an outcome of mitotic errors in higher eukaryotes, have long been observed, but only in recent years have researchers begun to pay close attention to their causes and consequences.
Figure 5. Causes and Consequences of Chromosome Entrapment in Micronuclei It has been reported that cytokinesis can directly generate certain structural disruptions chromosome breakage, nuclear envelope rupture due to entrapment of chromatin from lagging chromosomes or chromosome bridges in the cleavage furrow [ , ]. Aneuploidy in Meiosis 4. Causes of Aneuploidy in Meiosis Meiosis is a specialized form of cell division.
Figure 6. The Maternal Age Effect In humans, maternal age is a major risk factor for conception of aneuploid embryos. Figure 7. Consequences of Aneuploidy in Meiosis In mammals, whole chromosome aneuploidies on the level of the entire organism are highly detrimental for all chromosomes except sex chromosomes.
Meiotic Aneuploidy and Cancer Increased rates of chromosome instability lead to higher risks of certain malignancies in meiotic aneuploidy patients. Polyploidy 5. Sources for Polyploidy There are several ways for cells to become polyploid. Polyploidy in Fungi In many lower eukaryotes, the genome displays a high degree of plasticity in terms of both polyploidy and aneuploidy. Polyploidy in Animals and Plants Most species of the animal kingdom, with few exceptions, are diploid, and polyploidy of whole animals is unusual.
Polyploidy Can Lead to Aneuploidy Polyploid animal cells are prone to chromosome missegregation during mitosis [ ]. Figure 8. Polyploidy in Cancer Oncogenesis is a multi-step evolutionary progression that selects for traits that allow malignant cells to survive and proliferate. Ploidy Aberrations and P53 6. Ideas in Evolution and Cancer In mammals, aneuploidy- and polyploidy-driven evolution of single cells is restrained by the tumor suppressor protein p53 [ 2 , 3 , 5 , , , ].
Concepts for Activation and Function p53 is one of the most extensively studied proteins, yet it is still not clear what specific factor, or combination of factors, triggers its activation in cells with aberrant ploidies. Conclusions and Perspectives for Human Health The simple use of the terms mitotic or meiotic errors presupposes that such events are detrimental.
Conflicts of interest The authors declare no conflicts of interest. References 1. Gascoigne K. Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. Cancer Cell. Andreassen P. Tetraploid state induces pdependent arrest of nontransformed mammalian cells in G1. Aylon Y. P Guardian of ploidy. Duensing A. Guilt by association? P53 and the development of aneuploidy in cancer.
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Therefore, the same cell contains thick arrangements of duplicate chromosomes side by side, which look like strands of very thick rope. Scientists believe that these chromosomes are hyper-replicated to allow for the rapid and copious production of certain proteins that help larval growth and metamorphosis Gilbert, The greatest impact of Sutton's work has far more to do with providing evidence for Mendel's principle of independent assortment than anything else. Specifically, Sutton saw that the position of each chromosome at the midline during metaphase was random, and that there was never a consistent maternal or paternal side of the cell division.
Therefore, each chromosome was independent of the other. Thus, when the parent cell separated into gametes, the set of chromosomes in each daughter cell could contain a mixture of the parental traits, but not necessarily the same mixture as in other daughter cells.
To illustrate this concept, consider the variety derived from just three hypothetical chromosome pairs, as shown in the following example Hirsch, Each pair consists of two homologues: one maternal and one paternal.
Here, capital letters represent the maternal chromosome, and lowercase letters represent the paternal chromosome:. When these chromosome pairs are reshuffled through independent assortment , they can produce eight possible combinations in the resulting gametes:.
A mathematical calculation based on the number of chromosomes in an organism will also provide the number of possible combinations of chromosomes for each gamete. In particular, Sutton pointed out that the independence of each chromosome during meiosis means that there are 2 n possible combinations of chromosomes in gametes, with "n" being the number of chromosomes per gamete.
Thus, in the previous example of three chromosome pairs, the calculation is 2 3 , which equals 8. Furthermore, when you consider all the possible pairings of male and female gametes, the variation in zygotes is 2 n 2 , which results in some fairly large numbers.
But what about chromosome reassortment in humans? Humans have 23 pairs of chromosomes. That means that one person could produce 2 23 different gametes. In addition, when you calculate the possible combinations that emerge from the pairing of an egg and a sperm, the result is 2 23 2 possible combinations.
However, some of these combinations produce the same genotype for example, several gametes can produce a heterozygous individual. Of course, there are more than 23 segregating units Hirsch, While calculations of the random assortment of chromosomes and the mixture of different gametes are impressive, random assortment is not the only source of variation that comes from meiosis.
In fact, these calculations are ideal numbers based on chromosomes that actually stay intact throughout the meiotic process. In reality, crossing-over between chromatids during prophase I of meiosis mixes up pieces of chromosomes between homologue pairs, a phenomenon called recombination. Because recombination occurs every time gametes are formed, we can expect that it will always add to the possible genotypes predicted from the 2 n calculation. In addition, the variety of gametes becomes even more unpredictable and complex when we consider the contribution of gene linkage.
Some genes will always cosegregate into gametes if they are tightly linked, and they will therefore show a very low recombination rate. While linkage is a force that tends to reduce independent assortment of certain traits, recombination increases this assortment.
In fact, recombination leads to an overall increase in the number of units that assort independently, and this increases variation. While in mitosis, genes are generally transferred faithfully from one cellular generation to the next; in meiosis and subsequent sexual reproduction , genes get mixed up. Sexual reproduction actually expands the variety created by meiosis, because it combines the different varieties of parental genotypes.
Thus, because of independent assortment, recombination, and sexual reproduction, there are trillions of possible genotypes in the human species. During cell division, chromosomes sometimes disappear. This occurs when there is some aberration in the centromere , and spindle fibers cannot attach to the chromosome to segregate it to distal poles of the cell.
Consequently, the lost chromosome never properly groups with others into a new nuclear envelope , and it is left in the cytoplasm , where it will not be transcribed.
Also, chromosomes don't always separate equally into daughter cells. This sometimes happens in mitosis, when sister chromatids fail to separate during anaphase. One daughter cell thus ends up with more chromosomes in its nucleus than the other. Likewise, abnormal separation can occur in meiosis when homologous pairs fail to separate during anaphase I. This also results in daughter cells with different numbers of chromosomes. The phenomenon of unequal separation in meiosis is called nondisjunction.
If nondisjunction causes a missing chromosome in a haploid gamete, the diploid zygote it forms with another gamete will contain only one copy of that chromosome from the other parent, a condition known as monosomy. Conversely, if nondisjunction causes a homologous pair to travel together into the same gamete, the resulting zygote will have three copies, a condition known as trisomy Figure 3.
The term " aneuploidy " applies to any of these conditions that cause an unexpected chromosome number in a daughter cell. Aneuploidy can also occur in humans. For instance, the underlying causes of Klinefelter's syndrome and Turner's syndrome are errors in sex chromosome number, and Down syndrome is caused by trisomy of chromosome However, the severity of phenotypic abnormalities can vary among different types of aneuploidy. In addition, aneuploidy is rarely transferred to subsequent generations, because this condition impairs the production of gametes.
Overall, the inheritance of odd chromosome number arises from errors in segregation during chromosome replication. Often, it is these very exceptions or modifications of expected patterns in mitosis and meiosis that enrich our understanding of how the transfer of chromosomes is regulated from one generation to the next. Belling, J. On the attachment of non-homologous chromosomes at the reduction division in certain chromosome daturas. Proceedings of the National Academy of Sciences 12 , 7—11 Farmer, J.
On the maiotic phase reduction divisions in animals and plants. Quarterly Journal of Microscopical Science 48 , — Gilbert, S.
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