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PubMed1986

Methodological aspects of flow cytometric analysis of DNA polyploidy in human heart tissue.

The purpose of the study was to investigate the possibilities of flow cytometry (FCM) for the analysis of DNA polyploidy in human heart tissue. Suspensions of single nuclei were prepared with the detergent-trypsin procedure and stained with propidium iodide. A mathematical correction procedure was developed to correct for background and clumping. For diploid model populations of chicken and trout red blood cells this correction reduced artifactual fractions in the FCM DNA profile to less than 0.5%, indicating that interference by background and clumping was almost completely overcome by this correction procedure. FCM DNA profiles were obtained from 12 hypertrophic and 7 normal human adult hearts. Clear differences were found between DNA profiles from the normal and the hypertrophic hearts, the latter showing a higher degree of polyploidization. From the corrected DNA profiles, six different polyploidization parameters were computed, all of which showed a significant correlation with at least three out of four different parameters for heart hypertrophy. FCM appears to be a reliable method for the measurement of polyploidization in heart tissue, provided background and clumping are corrected for.

Adult↗
PubMed2006

Activation of the human FP prostanoid receptor disrupts mitosis progression and generates aneuploidy and polyploidy.

Studies have shown prostaglandin F(2alpha) (PGF(2alpha)) to be an endogenous tumor promoter in mouse models of skin carcinogenesis; however, the mechanisms by which PGF(2alpha) affects cell cycle events remain unknown. Here we performed cell cycle analyses on HEK cells stably expressing the human FP receptor and found that treatment with PGF(2alpha) delays mitosis and is associated with an increased expression of cyclin B1 and Cdc2 kinase activity. In addition, multipolar spindles and misaligned chromosomes were observed in a significant proportion of cells treated with PGF(2alpha). Defective cytokinesis was also observed which resulted in gross aneuploidy and polyploidy. Expression of dominant negative Rho attenuated the cell cycle delay and prevented the generation of micronuclei following treatment with PGF(2alpha). This suggests that FP receptor activation of Rho signaling by PGF(2alpha) can interfere with nuclear division. Aneuploidy is associated with genomic instability and may underlie the tumor-promoting properties of PGF(2alpha).

Aneuploidy↗
PubMed2003

Endoreplication and polyploidy in primary culture of rat hepatic stellate cells.

Hepatic stellate cells (HSCs), the pericytes of hepatic sinusoids, and liver myofibroblasts (rMFs), cells located in the portal field and around the pericentral area, are the principal fibrogenic cell types of the liver. In cases of liver damage HSCs undergo "activation," i.e., they acquire a myofibroblast-like appearance and synthesize huge amounts of extracellular matrix proteins (ECMs). Their proliferation ability, however, is a matter of debate. In fact, during culture the number of rat HSCs decreases, while DNA synthesis activity and DNA content per cell increase (4+/-0.6 times). Together with the decrease in cell number (60+/-19% at day 6 of primary culture compared to day 3), cell volume increases and many HSCs become multinuclear. On the other hand, in cultures of rMFs, cell number increases along with DNA synthesis, and these cells do not become multinuclear. "Activated" HSCs produce higher levels of cyclin D(1) and E(1) transcripts than rMFs, which correlates with their increased levels of phosphorylated retinoblastoma (Rb) protein. In activated HSCs DNA synthesis seems to be associated with polyploidy and increase in cell volume, while DNA synthesis is followed by mitosis in rMFs.

Animals↗
PubMed2005

Overexpression of an Aurora-C kinase-deficient mutant disrupts the Aurora-B/INCENP complex and induces polyploidy.

Aurora kinases are emerging as key regulators of centrosome function, chromosome segregation and cytokinesis. We previously isolated Aurora-C (Aie1), a third type of Aurora kinase, in a screen for kinases expressed in mouse sperm and eggs. Currently, we know very little about the precise localization and function of Aurora-C. Immunofluorescence analysis of ectopically expressed GFP-Aurora-C has revealed that Aurora-C is a new member of the chromosomal passenger proteins localizing first to the centromeres and then to the central spindles during cytokinesis. In order to study the potential role of Aurora-C, we examined the effects of a kinase-deficient (KD) mutant (AurC-KD) in HeLa Tet-Off cells under tetracycline control. Our results showed that overexpression of AurC-KD causes defects in cell division and induces polyploidy and apoptosis. Interestingly, AurC-KD overexpression also inhibits centromere/kinetochore localization of Aurora-B, Bub1, and BubR1, reduces histone H3 phosphorylation, and disrupts the association of INCENP with Aurora-B. Together, our results showed that Aurora-C is a chromosomal passenger protein, which may serve as a key regulator in cell division.

Apoptosis↗
PubMed2026

Polyploidy Arithmetic.

Polyploidy occurs in plants and animals, and is an important force in speciation and genome evolution. The main focus of this paper is the following fundamental question that was recently posed by Huber and Maher: Given the ploidy numbers of a collection of extant species, or their ploidy profile, what is the smallest number of hybridizations needed in any evolutionary history for these species to completely represent these numbers? In this paper, we shall show that this question can be rephrased in terms of addition chains and the closely related addition sequences, which have been studied for over a century in mathematics and computer science. These are sequences of natural numbers that start with 1, so that each number in the sequence larger than 1 is the sum of two other numbers arising earlier in the sequence. In our first main result, we show that finding the smallest number of hybridization events to explain a ploidy profile, or the hybrid number, is equivalent to solving the so-called addition sequence problem. This immediately implies that computing the hybridization number is computationally intractable. Even so, it also leads to new connections to representing polyploid evolution using networks. More specifically, in our second main result we show that ploidy profiles representable by tree-child networks are exactly the addition chains, implying a polynomial-time algorithm for identifying these profiles. We then consider beaded tree-child networks, which permit the representation of autopolyploidy events, and in our third main result we provide a greedy polynomial-time algorithm to decide whether a given profile can be realized by such a network. We expect that our results can be leveraged in future work through, for example, making use of known algorithms for computing short addition sequences to give bounds for the hybrid number, and in guiding network reconstruction for polyploid species.

Polyploidy↗
PubMed1991

Polyploidy induction as a consequence of topoisomerase inhibition. A flow cytometric assessment.

Following recovery from a 4-hr exposure to clinically achievable concentrations of the topoisomerase II inhibitors Adriamycin, teniposide, or amsacrine or the putative topoisomerase II inhibitor crisnatol, murine erythroleukemic cells remained viable for up to 48 hr, but did not proliferate. Cell cycle analysis after a 24-hr recovery revealed blocks in G2 (4N DNA) or greater than G2 (up to 8N DNA) polyploid stages. The relative percentages of cells in either stage was a function of drug concentration and cell cycle stage at time of exposure: typically, cells exposed during S phase became blocked in G2, whereas those exposed during G2/M progressed into greater than G2 polyploid stages. G2-blocked cells exhibited a 2- to 3-fold increase in nuclear protein content and cellular/nuclear volume (i.e. unbalanced growth) and approximately 5% more DNA stainability (as a consequence of nuclear conformational changes rather than redundant DNA synthesis). In all cases, at the drug concentrations studied, mitotic figures were absent and G2 and greater than G2 blocks were irreversible, indicating that the mechanism of polyploidy induction differs from that of microtubule inhibitors. These findings suggest that although topoisomerase inhibitors interfere with DNA synthesis in the S phase, their induction of greater than G2 polyploid blocks may involve direct or indirect inhibition of chromosome condensation.

Amsacrine↗
PubMed1982

Polyploidy and aneuploidy induced by colcemid in Drosophila melanogaster.

Colcemid was fed to Drosophila melanogaster larvae throughout most of the larval period. Surviving individuals were then mated with untreated flies, and their progeny were examined for polyploid flies or flies resulting from X-chromosome nondisjunction. A total of 251 polyploid offspring was recovered from the experimental matings, none from the control. All of the polyploids were evidently triploids, and all but one were obtained from colcemid-fed females: males produced significantly lower frequencies of triploid offspring than females. The highest average frequency of triploid offspring obtained from any treatment group was 18%. Nonrandom distributions of triploid offspring were observed among females raised identically, indicating tht polyploidization occurs mitotically, rather than meiotically, giving rise to clones of tetraploid oogonia. 9 colcemid-fed females produced exclusively triploid offspring. Colcemid also caused a significant increase in X-chromosome nondisjunction in females, though the frequencies of such offspring were at least several-fold lower than the frequencies of triploid offspring. Somatic polyploidy was apparently also indiced since patches of large cells were found on the wings of some flies raised on colcemid-containing food. Various teratological abnormalities were observed among the treated flies, including deformed or missing eyes and partially duplicated thoraxes.

Abnormalities, Drug-Induced↗
PubMed1986

Enhanced polyploidy by glutaraldehyde in cultured HL60 leukemic cells.

Glutaraldehyde 10(-4) M weakened cell proliferation of HL60 cultured cells and enhanced the appearance of giant polyploid cells, up to 32.5% after 6 days. The size and structure of these cells, the quantitative changes in their DNA content with respect to diploid ones demonstrate their polyploid nature, which may be corrected by the occurrence of pluripolar mitoses. However the slowing down of cell proliferation is not enough to orient the cells towards differentiation. Maturation of polyploid cells may be stimulated by retinoic acid and dexamethasone as for diploid ones. Several possible mechanisms of polyploidy are discussed. Except the possibility that the cells may directly fuse, the mechanisms which are considered, may involve a preprophase inhibition, a mitotic arrest at metaphase or a reduction of asters which may result in a defect in cytokinesis, the latter followed by secondary fusion of nuclei.

Aldehydes↗
PubMed1990

Use of a cell hybrid test system to demonstrate that benomyl induces aneuploidy and polyploidy.

We have monitored the segregation of a single human chromosome in a human-Chinese hamster hybrid cell line, EUBI, following exposure to benomyl. We found a dose-dependent increase in frequency of aneuploidy, but a much more marked induction of polyploidy was noted at the highest benomyl concentration. We confirm the usefulness of this assay for determining genetic risk associated with human exposure to environmental chemicals.

Aneuploidy↗
PubMed1995

Heterogeneity, polyploidy, aneusomy, and 9p deletion in human glioblastoma multiforme.

The short arm of chromosome 9 is frequently deleted in malignant gliomas. We used locus-specific probes for interferon-A (IFNA) and D9S3 in combination with a chromosome 9 centromeric probe to detect genetic aberrations on a cell-by-cell basis in touch preparations of 30 glioblastomas by fluorescence in situ hybridization. Seven (23%) of 30 tumors had deletions in > 70% of cells; the IFNA locus was deleted in all seven, but the D9S3 locus was deleted in only five of the seven. The latter data confirm that a tumor suppressor gene on 9p relevant to glioblastoma multiforme lies between D9S3 and IFNA. Eleven tumors had deletions in 20-40% of cells, more than three standard deviations above the level in control tissues. The remaining tumors had deletions in < 20% of cells. The seven tumors with the lowest percentage of deleted cells each had more than one genetically abnormal population of cells. In total, 10 cases were of this type (i.e., aneusomic for chromosome 9). Three of these 10 tumors had hybridization patterns consistent with polyploidy.

Adult↗
PubMed1982

Repetitive DNA and polyploidy in selachians.

1. The DNA reassociation kinetics have been studied in 6 selachian species: Raja asterias, Raja montagui, Dasyatis violacea, Torpedo marmorata, Torpedo ocellata and Oxynotus centrina. 2. The results obtained show that the genomes of the two Torpedo, Dasyatis and Oxynotus are polyploid if compared with those of the two rays, though this finds no correspondence in the diploid chromosome number. 3. The phenomena of polyploidization would often be followed by wide chromosome rearrangements and by a progressive divergence of the various repetitive DNA sequences. 4. The existence of polyploidy in almost all the main superorders of living Selachians suggests that this mechanism of genomic evolution may have played an important role in the phylogeny of this class.

Animals↗
PubMed1975

Hormone-dependent Polyploidy in the glandula orbitalis externa and glandula infraorbitalis of animals of different age.

The Glandula orbitalis externa and Glandular infraorbitalis of castrated and intact male rats were examined by morphological, chemical and cytophotometric methods after one, three, six and twelve months of life. Whereas qualitative changes in the cell nucleus (e.g. nuclear vacuolation, nuclear fusion) and cytoplasm (cytoplasmic vacuolation) can be detectedin the sexually mature control animals, these did not occur in the castrated male rats. An increase the percentage of higher ploid gland cell nuclei occurred only in the intact control animals. The possible cause this clearly hormone-dependent polyploidy is discussed.

Age Factors↗
PubMed1981

Polyploidy in islets of normal and diabetic humans.

This study was designed as a pilot project to determine whether the increased polyploidization of pancreatic B cells in diabetic mice reported from our laboratory is also characteristic of human diabetes. Nuclei of hematoxylin and eosin stained islets cells were traced by camera lucida and their volumes determined by semiautomatic particle size analysis. Previous studies have confirmed that nuclear volume can be used as an index of polyploidy, since, in mouse and human islets, the nuclear DNA content is directly proportional to the nuclear volume. Five insulin independent and three insulin dependent human diabetic patients and their age and sex matched controls were studied. The percentages of polyploid nuclei in insulin independent diabetic islets were elevated significantly over those in control subjects in four of five cases; the exception was an 85 year old male who was diagnosed as a diabetic only two months prior to death. Of the three insulin dependent diabetics, one, whose islets appeared otherwise normal, had a significantly greater percentage of polyploid nuclei than the controls; the other two, whose islets were markedly hyalinized, exhibited percentages of polyploid nuclei within normal ranges. The implications of relative percentages of polyploid nuclei in normal and diabetic islets and the possible relationship with previous studies of genetically diabetic mice are discussed.

Adult↗
PubMed1998

Polyploidy in myelodysplastic syndrome: a case report.

Structural chromosomal abnormalities are common in myelodysplastic syndromes (MDSs), and complex abnormalities are known to confer a poor prognosis. Polyploidy is rare. We report a patient with MDS in whom 8/15 cells were 77,XYY; 2/15 were 83,XYY, and 5/15 were diploid (46,XY). He experienced rapid evolution of disease, transforming to terminal acute leukemia.

Acute Disease↗
PubMed2003

Stathmin expression and megakaryocyte differentiation: a potential role in polyploidy.

OBJECTIVE: Megakaryopoiesis is characterized by two major processes, acquisition of lineage-specific markers and polyploidization. Polyploidy is a result of endomitosis, a process that is characterized by continued DNA replication in the presence of abortive mitosis. Stathmin is a major microtubule-regulatory protein that plays an important role in the regulation of the mitotic spindle. Our previous studies had shown that inhibition of stathmin expression in human leukemia cells results in the assembly of atypical mitotic spindles and abnormal exit from mitosis. We hypothesized that the absence of stathmin expression in megakaryocytes might be important for their abortive mitosis. MATERIALS AND METHODS: The experimental models that we used were human K562 and HEL cell lines that can be induced to undergo megakaryocytic differentiation and primary murine megakaryocytes generated by in vitro culture of bone marrow cells. The megakaryocytic phenotype was evaluated by flow cytometry and light microscopy. The DNA content (ploidy) was analyzed by flow cytometry. Stathmin expression was analyzed by Western and Northern blotting and by RT-PCR. RESULTS: Our studies showed an inverse correlation between the level of ploidy and the level of stathmin expression in megakaryocytic cell lines and in primary cells. More importantly, inhibition of stathmin expression in K562 cells enhanced the propensity of these cells to undergo endomitosis and to become polyploid upon induction of megakaryocytic differentiation. In contrast, inhibition of stathmin expression interfered with the ability of the cells to acquire megakaryocyte-specific markers of differentiation. CONCLUSION: Based on these observations, we propose a model of megakaryopoiesis in which stathmin expression is necessary for the proliferation and differentiation of early megakaryoblasts and its suppression in the later stages of megakaryocytic maturation is necessary for polyploidization.

Animals↗
PubMed2001

Evolution in action through hybridisation and polyploidy in an Iberian freshwater fish: a genetic review.

The Iberian minnow Leuciscus alburnoides represents a complex of diploid and polyploid forms with altered modes of reproduction. In the present paper, we review the recent data on the origin, reproductive modes, and inter-relationships of the various forms of the complex, in order to predict its evolutionary potential. The complex follows the hybrid-origin model suggested for most other asexual vertebrates. Diploid and triploid females from the southern river basins exhibit reproductive modes that cannot be conveniently placed into the categories generally recognised for these vertebrate complexes, which imply continuous shifting between forms, where genomes derived from both parental ancestors are cyclically lost, gained or replaced. Replacement of nuclear genomes allow the introduction of novel genetic material, that may compensate for the disadvantages of asexual reproduction. Contrasting with most other vertebrate complexes, L. alburnoides males are fertile and play an important role in the dynamics of the complex. Moreover, diploid hybrid males may have initiated a tetraploidization process, when a diploid clonal sperm fertilised a diploid egg. This direct route to tetraploidy by originating fish with the right constitution for normal meiosis (symmetric), may eventually lead to a new sexually reproducing polyploid species. This case-study reinforces the significance of hybridisation and polyploidy in evolution and diversification of vertebrates.

Animals↗
PubMed2002

Multiple origins of polyploidy in the phylogeny of southern African barbs (Cyprinidae) as inferred from mtDNA markers.

The cyprinid genus Barbus, with more than 800 nominal species, is an apparently polyphyletic assemblage to which a number of unrelated species, groups and/or assemblages have been assigned. It includes species that exhibit three different ploidy levels: diploid, tetraploid and hexaploid. Several lineages of the family Cyprinidae constitute a major component of the African freshwater ichthyofauna, having about 500 species, and fishes assigned to the genus 'Barbus' have the most species on the continent. We used complete sequences of the mitochondrial cytochrome b gene in order to infer phylogenetic relationships between diploid, tetraploid and hexaploid species of 'Barbus' occurring in southern Africa, the only region where representatives of all of the three ploidy levels occur. The results indicate that most of the lineages are incorrectly classified in the genus 'Barbus'. The southern African tetraploids probably originated from southern African diploids. They constitute a monophyletic group distinct from tetraploids occurring in the Euro-Mediterranean region (Barbus sensu stricto). The 'small' African diploid species seem to be paraphyletic, while the 'large' African hexaploid barbs species are of a single, recent origin and form a monophyletic group. The evidence of multiple, independent origins of polyploidy occurring in the African cyprinine cyprinids thus provides a significant contribution to the knowledge on the systematic diversity of these fishes, and warrants a thorough taxonomic reorganization of the genus.

Africa, Southern↗
PubMed2003

Genes duplicated by polyploidy show unequal contributions to the transcriptome and organ-specific reciprocal silencing.

Most eukaryotes have genomes that exhibit high levels of gene redundancy, much of which seems to have arisen from one or more cycles of genome doubling. Polyploidy has been particularly prominent during flowering plant evolution, yielding duplicated genes (homoeologs) whose expression may be retained or lost either as an immediate consequence of polyploidization or on an evolutionary timescale. Expression of 40 homoeologous gene pairs was assayed by cDNA-single-stranded conformation polymorphism in natural (1- to 2-million-yr-old) and synthetic tetraploid cotton (Gossypium) to determine whether homoeologous gene pairs are expressed at equal levels after polyploid formation. Silencing or unequal expression of one homoeolog was documented for 10 of 40 genes examined in ovules of Gossypium hirsutum. Assays of homoeolog expression in 10 organs revealed variable expression levels and silencing, depending on the gene and organ examined. Remarkably, silencing and biased expression of some gene pairs are reciprocal and developmentally regulated, with one homoeolog showing silencing in some organs and the other being silenced in other organs, suggesting rapid subfunctionalization. Duplicate gene expression was examined in additional natural polyploids to characterize the pace at which expression alteration evolves. Analysis of a synthetic tetraploid revealed homoeolog expression and silencing patterns that sometimes mirrored those of the natural tetraploid. Both long-term and immediate responses to polyploidization were implicated. Data suggest that some silencing events are epigenetically induced during the allopolyploidization process.

DNA, Plant↗