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Sample records for abnormal chromosome segregation

  1. Altered segregation pattern and numerical chromosome abnormalities interrelate in spermatozoa from Robertsonian translocation carriers.

    PubMed

    Godo, Anna; Blanco, Joan; Vidal, Francesca; Sandalinas, Mireia; Garcia-Guixé, Elena; Anton, Ester

    2015-07-01

    The aim of this study was to assess whether there is a relationship between numerical chromosome abnormalities and certain segregation modes in spermatozoa from Robertsonian translocation carriers. A sequential fluorescence in-situ hybridization protocol based on two successive hybridization rounds was performed on sperm samples from one t(13;22) and ten t(13;14) carriers. Patient inclusion criteria included the presence of a positive interchromosomal effect (ICE). In the first round, numerical abnormalities for chromosomes 15/22, 18, 21, X and Y were analysed. In the second round, the segregation outcome of the rearranged chromosomes was evaluated in the numerically abnormal spermatozoa detected in the first round, as well as in randomly assessed spermatozoa. Aneuploid spermatozoa showed statistical differences in all segregation modes when compared with randomly assessed spermatozoa: alternate (50.7% versus 84.3%), adjacent (36.6% versus 14.6%) and 3:0 (10.2% versus 1%). Diploid/multiple disomic spermatozoa showed differences in alternate (3.7% versus 84.3%) and 3:0 (67.6% versus 1%). We concluded that in Robertsonian translocation carriers that exhibit ICE, numerically abnormal spermatozoa preferentially contain unbalanced segregation products. This might be explained by heterosynapsis acting as a rescue mechanism that would lead to aberrant recombination, which is a predisposing factor for non-disjunction events.

  2. Bacterial Chromosome Organization and Segregation

    PubMed Central

    Toro, Esteban; Shapiro, Lucy

    2010-01-01

    Bacterial chromosomes are generally ∼1000 times longer than the cells in which they reside, and concurrent replication, segregation, and transcription/translation of this crowded mass of DNA poses a challenging organizational problem. Recent advances in cell-imaging technology with subdiffraction resolution have revealed that the bacterial nucleoid is reliably oriented and highly organized within the cell. Such organization is transmitted from one generation to the next by progressive segregation of daughter chromosomes and anchoring of DNA to the cell envelope. Active segregation by a mitotic machinery appears to be common; however, the mode of chromosome segregation varies significantly from species to species. PMID:20182613

  3. Chromosome Segregation in Vibrio cholerae

    PubMed Central

    Ramachandran, R.; Jha, J; Chattoraj, DK

    2014-01-01

    The study of chromosome segregation is currently one of the most exciting research frontiers in cell biology. In this review, we discuss our current knowledge of the chromosome segregation process in Vibrio cholerae, based primarily on findings from fluorescence microscopy experiments. This bacterium is of special interest because of its eukaryotic feature of having a divided genome, a feature shared with 10% of known bacteria. We also discuss how the segregation mechanisms of V. cholerae compare with those in other bacteria, and highlight some of the remaining questions regarding the process of bacterial chromosome segregation. PMID:25732338

  4. Chromosome segregation in plant meiosis

    PubMed Central

    Zamariola, Linda; Tiang, Choon Lin; De Storme, Nico; Pawlowski, Wojtek; Geelen, Danny

    2014-01-01

    Faithful chromosome segregation in meiosis is essential for ploidy stability over sexual life cycles. In plants, defective chromosome segregation caused by gene mutations or other factors leads to the formation of unbalanced or unreduced gametes creating aneuploid or polyploid progeny, respectively. Accurate segregation requires the coordinated execution of conserved processes occurring throughout the two meiotic cell divisions. Synapsis and recombination ensure the establishment of chiasmata that hold homologous chromosomes together allowing their correct segregation in the first meiotic division, which is also tightly regulated by cell-cycle dependent release of cohesin and monopolar attachment of sister kinetochores to microtubules. In meiosis II, bi-orientation of sister kinetochores and proper spindle orientation correctly segregate chromosomes in four haploid cells. Checkpoint mechanisms acting at kinetochores control the accuracy of kinetochore-microtubule attachment, thus ensuring the completion of segregation. Here we review the current knowledge on the processes taking place during chromosome segregation in plant meiosis, focusing on the characterization of the molecular factors involved. PMID:24987397

  5. Abnormal human sex chromosome constitutions

    SciTech Connect

    1993-12-31

    Chapter 22, discusses abnormal human sex chromosome constitution. Aneuploidy of X chromosomes with a female phenotype, sex chromosome aneuploidy with a male phenotype, and various abnormalities in X chromosome behavior are described. 31 refs., 2 figs.

  6. Bacterial chromosome organization and segregation

    PubMed Central

    Badrinarayanan, Anjana; Le, Tung BK; Laub, Michael T

    2016-01-01

    If fully stretched out, a typical bacterial chromosome would be nearly one millimeter long, or approximately 1000 times the length of a cell. Not only must cells massively compact their genetic material, but they must also organize their DNA in a manner that is compatible with a range of cellular processes, including DNA replication, DNA repair, homologous recombination, and horizontal gene transfer. Recent work, driven in part by technological advances, has begun to reveal the general principles of chromosome organization in bacteria. Here, drawing on studies of many different organisms, we review the emerging picture of how bacterial chromosomes are structured at multiple length-scales, highlighting the functions of various DNA-binding proteins and impact of physical forces. Additionally, we discuss the spatial dynamics of chromosomes, particularly during their segregation to daughter cells. Although there has been tremendous progress, we also highlight gaps that remain in understanding chromosome organization and segregation. PMID:26566111

  7. Chromosome Segregation Mechanisms

    PubMed Central

    Nicklas, R. Bruce

    1974-01-01

    Most aspects of chromosome distribution to the daughter cells in meiosis and mitosis are now understood, at the cellular level. The most striking evidence that the proposed explanation is valid is that it correctly predicts the outcome of experiments on living cells in which the experimenter (1) can determine the distribution of any chosen chromosome to a chosen daughter cell, (2) can induce a mal-orientation, and (3) can stabilize a mal-orientation, causing non-disjunction of a chosen bivalent. Recent reviews of chromosome distribution mechanisms are also considered, in an attempt to clarify the remaining unsolved problems. PMID:4442702

  8. Epilepsy and chromosomal abnormalities

    PubMed Central

    2010-01-01

    Background Many chromosomal abnormalities are associated with Central Nervous System (CNS) malformations and other neurological alterations, among which seizures and epilepsy. Some of these show a peculiar epileptic and EEG pattern. We describe some epileptic syndromes frequently reported in chromosomal disorders. Methods Detailed clinical assessment, electrophysiological studies, survey of the literature. Results In some of these congenital syndromes the clinical presentation and EEG anomalies seems to be quite typical, in others the manifestations appear aspecific and no strictly linked with the chromosomal imbalance. The onset of seizures is often during the neonatal period of the infancy. Conclusions A better characterization of the electro clinical patterns associated with specific chromosomal aberrations could give us a valuable key in the identification of epilepsy susceptibility of some chromosomal loci, using the new advances in molecular cytogenetics techniques - such as fluorescent in situ hybridization (FISH), subtelomeric analysis and CGH (comparative genomic hybridization) microarray. However further studies are needed to understand the mechanism of epilepsy associated with chromosomal abnormalities. PMID:20438626

  9. The Consequences of Chromosome Segregation Errors in Mitosis and Meiosis.

    PubMed

    Potapova, Tamara; Gorbsky, Gary J

    2017-02-08

    Mistakes during cell division frequently generate changes in chromosome content, producing aneuploid or polyploid progeny cells. Polyploid cells may then undergo abnormal division to generate aneuploid cells. Chromosome segregation errors may also involve fragments of whole chromosomes. A major consequence of segregation defects is change in the relative dosage of products from genes located on the missegregated chromosomes. Abnormal expression of transcriptional regulators can also impact genes on the properly segregated chromosomes. The consequences of these perturbations in gene expression depend on the specific chromosomes affected and on the interplay of the aneuploid phenotype with the environment. Most often, these novel chromosome distributions are detrimental to the health and survival of the organism. However, in a changed environment, alterations in gene copy number may generate a more highly adapted phenotype. Chromosome segregation errors also have important implications in human health. They may promote drug resistance in pathogenic microorganisms. In cancer cells, they are a source for genetic and phenotypic variability that may select for populations with increased malignance and resistance to therapy. Lastly, chromosome segregation errors during gamete formation in meiosis are a primary cause of human birth defects and infertility. This review describes the consequences of mitotic and meiotic errors focusing on novel concepts and human health.

  10. The Consequences of Chromosome Segregation Errors in Mitosis and Meiosis

    PubMed Central

    Potapova, Tamara; Gorbsky, Gary J.

    2017-01-01

    Mistakes during cell division frequently generate changes in chromosome content, producing aneuploid or polyploid progeny cells. Polyploid cells may then undergo abnormal division to generate aneuploid cells. Chromosome segregation errors may also involve fragments of whole chromosomes. A major consequence of segregation defects is change in the relative dosage of products from genes located on the missegregated chromosomes. Abnormal expression of transcriptional regulators can also impact genes on the properly segregated chromosomes. The consequences of these perturbations in gene expression depend on the specific chromosomes affected and on the interplay of the aneuploid phenotype with the environment. Most often, these novel chromosome distributions are detrimental to the health and survival of the organism. However, in a changed environment, alterations in gene copy number may generate a more highly adapted phenotype. Chromosome segregation errors also have important implications in human health. They may promote drug resistance in pathogenic microorganisms. In cancer cells, they are a source for genetic and phenotypic variability that may select for populations with increased malignance and resistance to therapy. Lastly, chromosome segregation errors during gamete formation in meiosis are a primary cause of human birth defects and infertility. This review describes the consequences of mitotic and meiotic errors focusing on novel concepts and human health. PMID:28208750

  11. Chromosomal abnormalities in human sperm

    SciTech Connect

    Martin, R.H.

    1985-01-01

    The ability to analyze human sperm chromosome complements after penetration of zona pellucida-free hamster eggs provides the first opportunity to study the frequency and type of chromosomal abnormalities in human gametes. Two large-scale studies have provided information on normal men. We have studied 1,426 sperm complements from 45 normal men and found an abnormality rate of 8.9%. Brandriff et al. (5) found 8.1% abnormal complements in 909 sperm from 4 men. The distribution of numerical and structural abnormalities was markedly dissimilar in the 2 studies. The frequency of aneuploidy was 5% in our sample and only 1.6% in Brandriff's, perhaps reflecting individual variability among donors. The frequency of 24,YY sperm was low: 0/1,426 and 1/909. This suggests that the estimates of nondisjunction based on fluorescent Y body data (1% to 5%) are not accurate. We have also studied men at increased risk of sperm chromosomal abnormalities. The frequency of chromosomally unbalanced sperm in 6 men heterozygous for structural abnormalities varied dramatically: 77% for t11;22, 32% for t6;14, 19% for t5;18, 13% for t14;21, and 0% for inv 3 and 7. We have also studied 13 cancer patients before and after radiotherapy and demonstrated a significant dose-dependent increase of sperm chromosome abnormalities (numerical and structural) 36 months after radiation treatment.

  12. Chromosomal abnormalities and mental illness.

    PubMed

    MacIntyre, D J; Blackwood, D H R; Porteous, D J; Pickard, B S; Muir, W J

    2003-03-01

    Linkage studies of mental illness have provided suggestive evidence of susceptibility loci over many broad chromosomal regions. Pinpointing causative gene mutations by conventional linkage strategies alone is problematic. The breakpoints of chromosomal abnormalities occurring in patients with mental illness may be more direct pointers to the relevant gene locus. Publications that describe patients where chromosomal abnormalities co-exist with mental illness are reviewed along with supporting evidence that this may amount to an association. Chromosomal abnormalities are considered to be of possible significance if (a) the abnormality is rare and there are independent reports of its coexistence with psychiatric illness, or (b) there is colocalisation of the abnormality with a region of suggestive linkage findings, or (c) there is an apparent cosegregation of the abnormality with psychiatric illness within the individual's family. Breakpoints have been described within many of the loci suggested by linkage studies and these findings support the hypothesis that shared susceptibility factors for schizophrenia and bipolar disorder may exist. If these abnormalities directly disrupt coding regions, then combining molecular genetic breakpoint cloning with bioinformatic sequence analysis may be a method of rapidly identifying candidate genes. Full karyotyping of individuals with psychotic illness especially where this coexists with mild learning disability, dysmorphism or a strong family history of mental disorder is encouraged.

  13. Disruption of human vigilin impairs chromosome condensation and segregation.

    PubMed

    Wei, Ling; Xie, Xiaoyan; Li, Junhong; Li, Ran; Shen, Wenyan; Duan, Shuwang; Zhao, Rongce; Yang, Wenli; Liu, Qiuying; Fu, Qiang; Qin, Yang

    2015-11-01

    Appropriate packaging and condensation are critical for eukaryotic chromatin's accommodation and separation during cell division. Human vigilin, a multi-KH-domain nucleic acid-binding protein, is associated with alpha satellites of centromeres. DDP1, a vigilin's homolog, is implicated with chromatin condensation and segregation. The expression of vigilin was previously reported to elevate in highly proliferating tissues and increased in a subset of hepatocellular carcinoma patients. Other studies showed that vigilin interacts with CTCF, contributes to regulation of imprinted genes Igf2/H19, and colocalizes with HP1α on heterochromatic satellite 2 and β-satellite repeats. These studies indicate that human vigilin might be involved in chromatin remodeling and regular cell growth. To investigate the potential role of human vigilin in cell cycle, the correlations between vigilin and chromosomal condensation and segregation were studied. Depletion of human vigilin by RNA interference in HepG2 cells resulted in chromosome undercondensation and various chromosomal defects during mitotic phase, including chromosome misalignments, lagging chromosomes, and chromosome bridges. Aberrant polyploid nucleus in telophase was also observed. Unlike the abnormal staining pattern of chromosomes, the shape of spindle was normal. Furthermore, the chromatin showed a greater sensitivity to MNase digestion. Collectively, our findings show that human vigilin apparently participates in chromatin condensation and segregation.

  14. Controlling segregation speed of entangled polymers by the shapes: A simple model for eukaryotic chromosome segregation

    NASA Astrophysics Data System (ADS)

    Sakai, Yuji; Tachikawa, Masashi; Mochizuki, Atsushi

    2016-10-01

    We report molecular dynamics simulations of the segregation of two overlapping polymers motivated by chromosome segregation in biological cells. We investigate the relationship between polymer shapes and segregation dynamics and show that elongation and compaction make entangled polymers segregate rapidly. This result suggests that eukaryotic chromosomes take such a characteristic rod-shaped structure, which is induced by condensins, to achieve rapid segregation.

  15. Chromosome segregation and aneuploidy. I

    SciTech Connect

    Vig, B.K.

    1993-12-31

    Of all genetic afflictions of man, aneuploidy ranks as the most prevalent. Among liveborn babies aneuploidy exist to the extent of about 0.3%, to about 0.5% among stillborns and a dramatic 25% among miscarriages. The burden is too heavy to be taken lightly. Whereas cytogeneticists are capable of tracing the origin of the extra or missing chromosome to the contributing parent, it is not certain what factors are responsible for this {open_quote}epidemic{close_quote} affecting the human genome. The matter is complicated by the observation that, to the best of our knowledge, all chromosomes do not malsegregate with equal frequency. Chromosome number 16, for example, is the most prevalent among abortuses - one-third of all aneuploid miscarriages are due to trisomy 16 - yet it never appears in aneuploid constitution among the liveborn. Some chromsomes, number 1, for example, appear only rarely, if at all. In the latter case painstaking efforts have to be made to karyotype very early stages of embryonic development, as early as the 8-cell stage. Even though no convincing data are yet available, it is conceivable that the product of most aneuploid zygotes is lost before implantation.

  16. [Chromosome abnormalities in human cancer].

    PubMed

    Salamanca-Gómez, F

    1995-01-01

    Recent investigation on the presence of chromosome abnormalities in neoplasias has allowed outstanding advances in the knowledge of malignant transformation mechanisms and important applications in the clinical diagnosis and prognosis of leukaemias, lymphomas and solid tumors. The purpose of the present paper is to discuss the most relevant cytogenetic aberrations, some of them described at the Unidad de Investigación Médica en Genética Humana, Instituto Mexicano del Seguro Social, and to correlate these abnormalities with recent achievements in the knowledge of oncogenes, suppressor genes or antioncogenes, their chromosome localization, and their mutations in human neoplasia; as well as their perspectives in prevention and treatment of cancer that such findings permit to anticipate.

  17. Numerically abnormal chromosome constitutions in humans

    SciTech Connect

    1993-12-31

    Chapter 24, discusses numerically abnormal chromosome constitutions in humans. This involves abnormalities of human chromosome number, including polyploidy (when the number of sets of chromosomes increases) and aneuploidy (when the number of individual normal chromosomes changes). Chapter sections discuss the following chromosomal abnormalities: human triploids, imprinting and uniparental disomy, human tetraploids, hydatidiform moles, anomalies caused by chromosomal imbalance, 13 trisomy (D{sub 1} trisomy, Patau syndrome), 21 trisomy (Down syndrome), 18 trisomy syndrome (Edwards syndrome), other autosomal aneuploidy syndromes, and spontaneous abortions. The chapter concludes with remarks on the nonrandom participation of chromosomes in trisomy. 69 refs., 3 figs., 4 tabs.

  18. Are topoisomerases required for mammalian chromosome segregation?

    SciTech Connect

    Sumner, A.T.; Perry, P.E.; Slavotinek, A.

    1993-12-31

    Theoretical considerations indicate that topoisomerase II should be involved in chromosome segregation, since newly replicated daughter DNA molecules must be interwined, and an enzyme such as topoisomerase II is needed to disentangle them. It has been shown, using scanning electron microscopy, that regions of centromeric heterochromatin are the last parts of the chromosomes to separate at anaphase. Such regions generally contain highly repetitive, satellite DNAs, whose function is obscure, since they vary extensively, and apparently randomly, in their sequence and average base composition. However, in spite of this compositional variation, it appears that many satellite DNAs show characteristic curvature, which may, rather than a specific nucleotide sequence, be a recognition site for topoisomerase II. Satellite DNA in centromeric heterochromatin might then, regardless of sequence, provide a specific substrate on which topoisomerase II could act in a concerted fashion at the beginning of anaphase to ensure orderly separation of the daughter chromosomes.

  19. Chromosome and cell wall segregation in Streptococcus faecium ATCC 9790

    SciTech Connect

    Higgins, M.L.; Glaser, D.; Dicker, D.T.; Zito, E.T.

    1989-01-01

    Segregation was studied by measuring the positions of autoradiographic grain clusters in chains formed from single cells containing on average less than one radiolabeled chromosome strand. The degree to which chromosomal and cell wall material cosegregated was quantified by using the methods of S. Cooper and M. Weinberger, dividing the number of chains labeled at the middle. This analysis indicated that in contrast to chromosomal segregation in Escherichia coli and, in some studies, to that in gram-positive rods, chromosomal segregation in Streptococcus faecium was slightly nonrandom and did not vary with growth rate. Results were not significantly affected by strand exchange. In contrast, labeled cell wall segregated predominantly nonrandomly.

  20. Meiotic chromosome abnormalities in human spermatogenesis.

    PubMed

    Martin, Renée H

    2006-08-01

    The last few years have witnessed an explosion in the information about chromosome abnormalities in human sperm and the meiotic events that predispose to these abnormalities. We have determined that all chromosomes are susceptible to nondisjunction, but chromosomes 21 and 22 and, especially, the sex chromosomes have an increased frequency of aneuploidy. Studies are just beginning on the effects of potential mutagens on the chromosomal constitution of human sperm. The effects of pesticides and cancer therapeutic agents have been reviewed. In the last decade, there has been a great impetus to study chromosome abnormalities in sperm from infertile men because the advent of intracytoplasmic sperm injection (ICSI) made it possible for these men to father pregnancies. A large number of studies have demonstrated that infertile men have an increased frequency of chromosomally abnormal sperm and children, even when they have a normal somatic karyotype. Meiotic studies on the pachytene stage of spermatogenesis have demonstrated that infertile men have impaired chromosome synapsis, a significantly decreased frequency of recombination, and an increased frequency of chromosomes completely lacking a recombination site. Such errors make these cells susceptible to meiotic arrest and the production of aneuploid gametes.

  1. Advances in understanding paternally transmitted Chromosomal Abnormalities

    SciTech Connect

    Marchetti, F; Sloter, E; Wyrobek, A J

    2001-03-01

    Multicolor FISH has been adapted for detecting the major types of chromosomal abnormalities in human sperm including aneuploidies for clinically-relevant chromosomes, chromosomal aberrations including breaks and rearrangements, and other numerical abnormalities. The various sperm FISH assays have been used to evaluate healthy men, men of advanced age, and men who have received mutagenic cancer therapy. The mouse has also been used as a model to investigate the mechanism of paternally transmitted genetic damage. Sperm FISH for the mouse has been used to detect chromosomally abnormal mouse sperm, while the PAINT/DAPI analysis of mouse zygotes has been used to evaluate the types of chromosomal defects that can be paternally transmitted to the embryo and their effects on embryonic development.

  2. [Y chromosome structural abnormalities and Turner's syndrome].

    PubMed

    Ravel, C; Siffroi, J-P

    2009-06-01

    Although specifically male, the human Y chromosome may be observed in female karyotypes, mostly in women with Turner syndrome stigmata. In women with isolated gonadal dysgenesis but otherwise normal stature, the testis determining factor or SRY gene may have been removed from the Y chromosome or may be mutated. In other women with Turner syndrome, the karyotype is usually abnormal and shows a frequent 45,X/46,XY mosaicism. In these cases, the phenotype depends on the ratio between Y positive and 45,X cell lines in the body. When in mosaicism, Y chromosomes are likely to carry structural abnormalities which explain mitotic instability, such as the existence of two centromeres. Dicentric Y isochromosomes for the short arm (idic[Yp]) or ring Y chromosomes (r[Y]) are the most frequent abnormal Y chromosomes found in infertile patients and in Turner syndrome in mosaic with 45,X cells. Although monocentric, deleted Y chromosomes for the long arm and those carrying microdeletions in the AZF region are also instable and are frequently associated with a 45,X cell line. Management of infertile patients carrying such abnormal Y chromosomes must take into account the risk and the consequences of a mosaicism in the offspring.

  3. XYY chromosome abnormality in sexual homicide perpetrators.

    PubMed

    Briken, Peer; Habermann, Niels; Berner, Wolfgang; Hill, Andreas

    2006-03-05

    In a retrospective investigation of the court reports about sexual homicide perpetrators chromosome analysis had been carried out in 13 of 166 (7.8%) men. Three men (1.8%) with XYY chromosome abnormality were found. This rate is much higher than that found in unselected samples of prisoners (0.7-0.9%) or in the general population (0.01%). The three men had shown prepubescent abnormalities, school problems, and had suffered from physical abuse. The chromosome analysis in all cases had been carried out in connection with the forensic psychiatric court report due to the sexual homicide. However, two men had earlier psychiatric referrals. All were diagnosed as sexual sadistic, showed a psychopathic syndrome or psychopathy according to the Psychopathy Checklist-Revised [Hare RD, 1991, The Hare Psychopathy Checklist-Revised, Toronto, Ontario, Canada: Multi-Health Systems]. Two were multiple murderers. Especially forensic psychiatrists should be vigilant of the possibility of XYY chromosome abnormalities in sexual offenders.

  4. Tracking of chromosome dynamics in live Streptococcus pneumoniae reveals that transcription promotes chromosome segregation.

    PubMed

    Kjos, Morten; Veening, Jan-Willem

    2014-03-01

    Chromosome segregation is an essential part of the bacterial cell cycle but is poorly characterized in oval-shaped streptococci. Using time-lapse fluorescence microscopy and total internal reflection fluorescence microscopy, we have tracked the dynamics of chromosome segregation in live cells of the human pathogen Streptococcus pneumoniae. Our observations show that the chromosome segregation process last for two-thirds of the total cell cycle; the origin region segregates rapidly in the early stages of the cell cycle while nucleoid segregation finishes just before cell division. Previously we have demonstrated that the DNA-binding protein ParB and the condensin SMC promote efficient chromosome segregation, likely by an active mechanism. We now show that in the absence of SMC, cell division can occur over the unsegregated chromosomes. However, neither smc nor parB are essential in S. pneumoniae, suggesting the importance of additional mechanisms. Here we have identified the process of transcription as one of these mechanisms important for chromosome segregation in S. pneumoniae. Transcription inhibitors rifampicin and streptolydigin as well as mutants affected in transcription elongation cause chromosome segregation defects. Together, our results highlight the importance of passive (or indirect) processes such as transcription for chromosome segregation in oval-shaped bacteria.

  5. Recurrent chromosome 6 abnormalities in malignant mesothelioma.

    PubMed

    Ribotta, M; Roseo, F; Salvio, M; Castagneto, B; Carbone, M; Procopio, A; Giordano, A; Mutti, L

    1998-04-01

    The long latency period between asbestos exposure and the onset of malignant mesothelioma (MM) suggests that a multistep tumorigenesis process occurs whilst the capability of asbestos fibres to interfere directly with chromosomes focuses on the critical role of the chromosomal abnormalities in this neoplasm. The aim of our study was to identify any recurrent chromosomal changes in ten primary MM cell cultures derived from pleural effusions of patients with MM from the same geographic area and environmental and/or occupational exposure to asbestos fibers. Cytogenetic analysis was performed in accordance with International System for Human Cytogenetic Nomenclature. Our results confirmed a great number of cytogenetic abnormalities in MM cells. Recurrent loss of the long arms of chromosome 6 (6q-) was the most frequent abnormality detected (four epithelial and two mixed subtypes) while, on the whole, abnormalities of chromosome 6 were found in nine out of ten cases whereas chromosome 6 was normal only in the case with fibromatous subtype. Monosomy 13 and 17 was found in five cases, monosomy 14 in four cases and 22 in three cases. Since deletion of 6q- was detected even in relatively undisturbed karyotype, we hypothesize a multistep carcinogenic process in which deletion of 6q- is an early event in the development and progression of malignant mesothelioma.

  6. Chromosome abnormalities in acute lymphoblastic leukemia

    SciTech Connect

    Rowley, J.D.

    1980-01-01

    Less information is available on the cytogenetic abnormalities in marrow cells of patients with acute lymphoblastic leukemia (ALL) than on abnormalities in acute nonlymphocytic leukemia (ANLL); nonetheless, some patterns of karyotypic change in ALL are evident. Even with banding, about 50% of patients appear to have a normal karyotype. The modal chromosome number tends to be higher in ALL than in ANLL. Every patient with B-cell ALL has had an abnormality of one chromosome No. 14 that involved the translocation of material to the end of the long arm. Among seven reported cases, the translocation was from 8q in three patients and 11q in one. Cells with a haploid or near-haploid (24 to 35) chromosome number have been reported in five patients with ALL and in four patients in a lymphoid blast crisis of chronic myelogeneous leukemia. The karyotype in the four ALL patients whose cells were analyzed with banding was remarkably consistent. All patients had the haploid number, usually with both sex chromosomes, plus an additional No. 10, 18, and 21. Evolution of the karyotype, which occurs in the leukemic cells of about 50% of patients, involves cells of patients who had an initially normal or an initially abnormal karyotype. The evidence regarding a correlation between the presence of an abnormal clone prior to treatment and response to treatment is contradictory at present. Some chromosome abnormalities, such as the presence of a Philadelphia (Ph/sup 1/) chromosome, a 14q+chromosome, or a haploid clone, are associated with a relatively short survival.

  7. A stochastic model of kinetochore-microtubule attachment accurately describes fission yeast chromosome segregation.

    PubMed

    Gay, Guillaume; Courtheoux, Thibault; Reyes, Céline; Tournier, Sylvie; Gachet, Yannick

    2012-03-19

    In fission yeast, erroneous attachments of spindle microtubules to kinetochores are frequent in early mitosis. Most are corrected before anaphase onset by a mechanism involving the protein kinase Aurora B, which destabilizes kinetochore microtubules (ktMTs) in the absence of tension between sister chromatids. In this paper, we describe a minimal mathematical model of fission yeast chromosome segregation based on the stochastic attachment and detachment of ktMTs. The model accurately reproduces the timing of correct chromosome biorientation and segregation seen in fission yeast. Prevention of attachment defects requires both appropriate kinetochore orientation and an Aurora B-like activity. The model also reproduces abnormal chromosome segregation behavior (caused by, for example, inhibition of Aurora B). It predicts that, in metaphase, merotelic attachment is prevented by a kinetochore orientation effect and corrected by an Aurora B-like activity, whereas in anaphase, it is corrected through unbalanced forces applied to the kinetochore. These unbalanced forces are sufficient to prevent aneuploidy.

  8. Chromosomal abnormalities associated with cyclopia and synophthalmia.

    PubMed Central

    Howard, R O

    1977-01-01

    At the present time, essentially all known facts concerning cyclopia are consistent with some chromosomal disease, including clinical features of the pregnancy (fetal wastage, prematurity, intrauterine growth retardation, maternal age factor, complications of pregnancy), the generalized developmental abnormalities, specific ocular dysgenesis, by the high incidence of chromosomal abnormality already demonstrated, and the possibility of error in those cases of cyclopia with normal chromosomes. Even if chromosomal aberrations represent only one group of several different etiologic factors leading to cyclopia, at the present time chromosomal errors would seem to be the most common cause of cyclopia now recognized. Further studies will establish or disprove a chromosomal error in those instances which are now considered to be the result of an environmental factor alone or those with apparent familial patterns of inheritance. This apparent diverse origin of cyclopia can be clarified if future cyclopic specimens are carefully investigated. The evaluation should include a careful gross and microscopic examination of all organs, including the eye, and chromosome banding studies of all organs, including the eye, and chromosome banding studies of at least two cyclopic tissues. Then the presence or absence of multiple causative factors can be better evaluated. Images FIGURE 2 A FIGURE 2 B FIGURE 1 A FIGURE 1 B FIGURE 1 C FIGURE 1 D FIGURE 1 E FIGURE 1 F FIGURE 3 A FIGURE 3 B FIGURE 4 A FIGURE 4 B FIGURE 4 C FIGURE 4 D FIGURE 5 FIGURE 6 FIGURE 7 A FIGURE 7 B PMID:418547

  9. Escherichia coli Chromosomal Loci Segregate from Midcell with Universal Dynamics.

    PubMed

    Cass, Julie A; Kuwada, Nathan J; Traxler, Beth; Wiggins, Paul A

    2016-06-21

    The structure of the Escherichia coli chromosome is inherently dynamic over the duration of the cell cycle. Genetic loci undergo both stochastic motion around their initial positions and directed motion to opposite poles of the rod-shaped cell during segregation. We developed a quantitative method to characterize cell-cycle dynamics of the E. coli chromosome to probe the chromosomal steady-state mobility and segregation process. By tracking fluorescently labeled chromosomal loci in thousands of cells throughout the entire cell cycle, our method allows for the statistical analysis of locus position and motion, the step-size distribution for movement during segregation, and the locus drift velocity. The robust statistics of our detailed analysis of the wild-type E. coli nucleoid allow us to observe loci moving toward midcell before segregation occurs, consistent with a replication factory model. Then, as segregation initiates, we perform a detailed characterization of the average segregation velocity of loci. Contrary to origin-centric models of segregation, which predict distinct dynamics for oriC-proximal versus oriC-distal loci, we find that the dynamics of loci were universal and independent of genetic position.

  10. FtsK actively segregates sister chromosomes in Escherichia coli.

    PubMed

    Stouf, Mathieu; Meile, Jean-Christophe; Cornet, François

    2013-07-02

    Bacteria use the replication origin-to-terminus polarity of their circular chromosomes to control DNA transactions during the cell cycle. Segregation starts by active migration of the region of origin followed by progressive movement of the rest of the chromosomes. The last steps of segregation have been studied extensively in the case of dimeric sister chromosomes and when chromosome organization is impaired by mutations. In these special cases, the divisome-associated DNA translocase FtsK is required. FtsK pumps chromosomes toward the dif chromosome dimer resolution site using polarity of the FtsK-orienting polar sequence (KOPS) DNA motifs. Assays based on monitoring dif recombination have suggested that FtsK acts only in these special cases and does not act on monomeric chromosomes. Using a two-color system to visualize pairs of chromosome loci in living cells, we show that the spatial resolution of sister loci is accurately ordered from the point of origin to the dif site. Furthermore, ordered segregation in a region ∼200 kb long surrounding dif depended on the oriented translocation activity of FtsK but not on the formation of dimers or their resolution. FtsK-mediated segregation required the MatP protein, which delays segregation of the dif-surrounding region until cell division. We conclude that FtsK segregates the terminus region of sister chromosomes whether they are monomeric or dimeric and does so in an accurate and ordered manner. Our data are consistent with a model in which FtsK acts to release the MatP-mediated cohesion and/or interaction with the division apparatus of the terminus region in a KOPS-oriented manner.

  11. The spindle checkpoint and chromosome segregation in meiosis.

    PubMed

    Gorbsky, Gary J

    2015-07-01

    The spindle checkpoint is a key regulator of chromosome segregation in mitosis and meiosis. Its function is to prevent precocious anaphase onset before chromosomes have achieved bipolar attachment to the spindle. The spindle checkpoint comprises a complex set of signaling pathways that integrate microtubule dynamics, biomechanical forces at the kinetochores, and intricate regulation of protein interactions and post-translational modifications. Historically, many key observations that gave rise to the initial concepts of the spindle checkpoint were made in meiotic systems. In contrast with mitosis, the two distinct chromosome segregation events of meiosis present a special challenge for the regulation of checkpoint signaling. Preservation of fidelity in chromosome segregation in meiosis, controlled by the spindle checkpoint, also has a significant impact in human health. This review highlights the contributions from meiotic systems in understanding the spindle checkpoint as well as the role of checkpoint signaling in controlling the complex divisions of meiosis.

  12. Regional Control of Chromosome Segregation in Pseudomonas aeruginosa

    PubMed Central

    Lagage, Valentine

    2016-01-01

    Chromosome segregation in bacteria occurs concomitantly with DNA replication, and the duplicated regions containing the replication origin oriC are generally the first to separate and migrate to their final specific location inside the cell. In numerous bacterial species, a three-component partition machinery called the ParABS system is crucial for chromosome segregation. This is the case in the gammaproteobacterium Pseudomonas aeruginosa, where impairing the ParABS system is very detrimental for growth, as it increases the generation time and leads to the formation of anucleate cells and to oriC mispositioning inside the cell. In this study, we investigate in vivo the ParABS system in P. aeruginosa. Using chromatin immuno-precipitation coupled with high throughput sequencing, we show that ParB binds to four parS site located within 15 kb of oriC in vivo, and that this binding promotes the formation of a high order nucleoprotein complex. We show that one parS site is enough to prevent anucleate cell formation, therefore for correct chromosome segregation. By displacing the parS site from its native position on the chromosome, we demonstrate that parS is the first chromosomal locus to be separated upon DNA replication, which indicates that it is the site of force exertion of the segregation process. We identify a region of approximatively 650 kb surrounding oriC in which the parS site must be positioned for chromosome segregation to proceed correctly, and we called it “competence zone” of the parS site. Mutant strains that have undergone specific genetic rearrangements allow us to propose that the distance between oriC and parS defines this “competence zone”. Implications for the control of chromosome segregation in P. aeruginosa are discussed. PMID:27820816

  13. Chromosomal abnormalities in a psychiatric population

    SciTech Connect

    Lewis, K.E.; Lubetsky, M.J.; Wenger, S.L.; Steele, M.W.

    1995-02-27

    Over a 3.5 year period of time, 345 patients hospitalized for psychiatric problems were evaluated cytogenetically. The patient population included 76% males and 94% children with a mean age of 12 years. The criteria for testing was an undiagnosed etiology for mental retardation and/or autism. Cytogenetic studies identified 11, or 3%, with abnormal karyotypes, including 4 fragile X positive individuals (2 males, 2 females), and 8 with chromosomal aneuploidy, rearrangements, or deletions. While individuals with chromosomal abnormalities do not demonstrate specific behavioral, psychiatric, or developmental problems relative to other psychiatric patients, our results demonstrate the need for an increased awareness to order chromosomal analysis and fragile X testing in those individuals who have combinations of behavioral/psychiatric, learning, communication, or cognitive disturbance. 5 refs., 1 fig., 2 tabs.

  14. Chromosome segregation by the Escherichia coli Min system

    PubMed Central

    Di Ventura, Barbara; Knecht, Benoît; Andreas, Helena; Godinez, William J; Fritsche, Miriam; Rohr, Karl; Nickel, Walter; Heermann, Dieter W; Sourjik, Victor

    2013-01-01

    The mechanisms underlying chromosome segregation in prokaryotes remain a subject of debate and no unifying view has yet emerged. Given that the initial disentanglement of duplicated chromosomes could be achieved by purely entropic forces, even the requirement of an active prokaryotic segregation machinery has been questioned. Using computer simulations, we show that entropic forces alone are not sufficient to achieve and maintain full separation of chromosomes. This is, however, possible by assuming repeated binding of chromosomes along a gradient of membrane-associated tethering sites toward the poles. We propose that, in Escherichia coli, such a gradient of membrane tethering sites may be provided by the oscillatory Min system, otherwise known for its role in selecting the cell division site. Consistent with this hypothesis, we demonstrate that MinD binds to DNA and tethers it to the membrane in an ATP-dependent manner. Taken together, our combined theoretical and experimental results suggest the existence of a novel mechanism of chromosome segregation based on the Min system, further highlighting the importance of active segregation of chromosomes in prokaryotic cell biology. PMID:24022004

  15. Analysis of chromosome segregation during mammalian meiosis using combined immunofluorescence and fluorescence in situ hubridization

    SciTech Connect

    Hunt, P.A.; Embury, P.B.; Mroz, K.M.

    1994-09-01

    Meiotic non-disjunction is thought to occur in 10-20% of all human oocytes, making this the most common genetic abnormality in our species. Aberrant recombination has been implicated in the genesis of these errors; however, direct studies of the meiotic process have been hampered by the lack of material and appropriate technology. We have developed a technique for the evaluation of meiosis in intact mammalian oocytes that combines immunofluorescence and fluorescence in situ hybridization (FISH). This allows for simultaneous, 3-dimensional visualization of the meiotic spindle, the alignment of the chromosomes on the spindle, and the placement of specific chromosomes. We have used this technology to follow meiotic progression in oocytes from XO female mice to evaluate the behavior of an unsynapsed chromosome during mammalian meiosis. Perturbations in chromosome behavior are evident early in meiosis: during the formation of the first meiotic spindle, the univalent X chromosome is properly positioned. With the onset of anaphase, the single X chromosome most commonly segregates as an intact chromosome, although equational segregation of the X chromatids is seen in a significant minority (approximately 20%) of oocytes. These observations demonstrate that failure of pairing/recombination can result in segregation of sister chromatids at meiosis I. This has obvious implications for human non-disjunction, much of which is thought to be due to recombination deficiencies; accordingly, we are now extending our studies to include analyses of human oocytes.

  16. Nonrandom segregation of the mouse univalent X chromosome: evidence of spindle-mediated meiotic drive.

    PubMed Central

    LeMaire-Adkins, R; Hunt, P A

    2000-01-01

    A fundamental principle of Mendelian inheritance is random segregation of alleles to progeny; however, examples of distorted transmission either of specific alleles or of whole chromosomes have been described in a variety of species. In humans and mice, a distortion in chromosome transmission is often associated with a chromosome abnormality. One such example is the fertile XO female mouse. A transmission distortion effect that results in an excess of XX over XO daughters among the progeny of XO females has been recognized for nearly four decades. Utilizing contemporary methodology that combines immunofluorescence, FISH, and three-dimensional confocal microscopy, we have readdressed the meiotic segregation behavior of the single X chromosome in oocytes from XO females produced on two different inbred backgrounds. Our studies demonstrate that segregation of the univalent X chromosome at the first meiotic division is nonrandom, with preferential retention of the X chromosome in the oocyte in approximately 60% of cells. We propose that this deviation from Mendelian expectations is facilitated by a spindle-mediated mechanism. This mechanism, which appears to be a general feature of the female meiotic process, has implications for the frequency of nondisjunction in our species. PMID:11014823

  17. RNAi pathway participates in chromosome segregation in mammalian cells.

    PubMed

    Huang, Chuan; Wang, Xiaolin; Liu, Xu; Cao, Shuhuan; Shan, Ge

    2015-01-01

    The RNAi machinery is a mighty regulator in a myriad of life events. Despite lines of evidence that small RNAs and components of the RNAi pathway may be associated with structure and behavior of mitotic chromosomes in diverse organisms, a direct role of the RNAi pathway in mammalian mitotic chromosome segregation remains elusive. Here we report that Dicer and AGO2, two central components of the mammalian RNAi pathway, participate in the chromosome segregation. Knockdown of Dicer or AGO2 results in a higher incidence of chromosome lagging, and this effect is independent from microRNAs as examined with DGCR8 knockout cells. Further investigation has revealed that α-satellite RNA, a noncoding RNA derived from centromeric repeat region, is managed by AGO2 under the guidance of endogenous small interference RNAs (ASAT siRNAs) generated by Dicer. Furthermore, the slicer activity of AGO2 is essential for the chromosome segregation. Level and distribution of chromosome-associated α-satellite RNA have crucial regulatory effect on the localization of centromeric proteins such as centromere protein C1 (CENPC1). With these results, we also provide a paradigm in which the RNAi pathway participates in vital cellular events through the maintenance of level and distribution of noncoding RNAs in cells.

  18. Evolutionary cell biology of chromosome segregation: insights from trypanosomes

    PubMed Central

    Akiyoshi, Bungo; Gull, Keith

    2013-01-01

    Faithful transmission of genetic material is essential for the survival of all organisms. Eukaryotic chromosome segregation is driven by the kinetochore that assembles onto centromeric DNA to capture spindle microtubules and govern the movement of chromosomes. Its molecular mechanism has been actively studied in conventional model eukaryotes, such as yeasts, worms, flies and human. However, these organisms are closely related in the evolutionary time scale and it therefore remains unclear whether all eukaryotes use a similar mechanism. The evolutionary origins of the segregation apparatus also remain enigmatic. To gain insights into these questions, it is critical to perform comparative studies. Here, we review our current understanding of the mitotic mechanism in Trypanosoma brucei, an experimentally tractable kinetoplastid parasite that branched early in eukaryotic history. No canonical kinetochore component has been identified, and the design principle of kinetochores might be fundamentally different in kinetoplastids. Furthermore, these organisms do not appear to possess a functional spindle checkpoint that monitors kinetochore–microtubule attachments. With these unique features and the long evolutionary distance from other eukaryotes, understanding the mechanism of chromosome segregation in T. brucei should reveal fundamental requirements for the eukaryotic segregation machinery, and may also provide hints about the origin and evolution of the segregation apparatus. PMID:23635522

  19. Chromosome abnormalities in primary ovarian cancer

    SciTech Connect

    Yonescu, R.; Currie, J.; Griffin, C.A.

    1994-09-01

    Chromosome abnormalities that are specific and recurrent may occur in regions of the genome that are involved in the conversion of normal cells to those with tumorigenic potential. Ovarian cancer is the primary cause of death among patients with gynecological malignancies. We have performed cytogenetic analysis of 16 ovarian tumors from women age 28-82. Three tumors of low malignant potential and three granulosa cell tumors had normal karyotypes. To look for the presence of trisomy 12, which has been suggested to be a common aberration in this group of tumors, interphase fluorescence in situ hybridization was performed on direct preparations from three of these tumors using a probe for alpha satellite sequences of chromosome 12. In the 3 preparations, 92-98 percent of the cells contained two copies of chromosome 12, indicating that trisomy 12 is not a universal finding in low grade ovarian tumors. Endometrioid carcinoma of the ovary is histologically indistinguishable from endometial carcinoma of the uterus. We studied 10 endometrioid tumors to determine the degree of genetic similarity between these two carcinomas. Six out of ten endometrioid tumors showed a near-triploid modal number, and one presented with a tetraploid modal number. Eight of the ten contained structural chromosome abnormalities, of which the most frequent were 1p- (5 tumors), 19q+ (3 tumors), 6q- or ins(6) (4 tumors), 3q- or 3q+ (4 tumors). These cytogenetic results resemble those reported for papillary ovarian tumors and differ from those of endometrial carcinoma of the uterus. We conclude that despite the histologic similarities between the endometrioid and endometrial carcinomas, the genetic abnormalities in the genesis of these tumors differ significantly.

  20. A novel chromosome segregation mechanism during female meiosis

    PubMed Central

    McNally, Karen Perry; Panzica, Michelle T.; Kim, Taekyung; Cortes, Daniel B.; McNally, Francis J.

    2016-01-01

    In a wide range of eukaryotes, chromosome segregation occurs through anaphase A, in which chromosomes move toward stationary spindle poles, anaphase B, in which chromosomes move at the same velocity as outwardly moving spindle poles, or both. In contrast, Caenorhabditis elegans female meiotic spindles initially shorten in the pole-to-pole axis such that spindle poles contact the outer kinetochore before the start of anaphase chromosome separation. Once the spindle pole-to-kinetochore contact has been made, the homologues of a 4-μm-long bivalent begin to separate. The spindle shortens an additional 0.5 μm until the chromosomes are embedded in the spindle poles. Chromosomes then separate at the same velocity as the spindle poles in an anaphase B–like movement. We conclude that the majority of meiotic chromosome movement is caused by shortening of the spindle to bring poles in contact with the chromosomes, followed by separation of chromosome-bound poles by outward sliding. PMID:27335123

  1. The cohesion stabilizer sororin favors DNA repair and chromosome segregation during mouse oocyte meiosis.

    PubMed

    Huang, Chun-Jie; Yuan, Yi-Feng; Wu, Di; Khan, Faheem Ahmed; Jiao, Xiao-Fei; Huo, Li-Jun

    2017-03-01

    Maintenance and timely termination of cohesion on chromosomes ensures accurate chromosome segregation to guard against aneuploidy in mammalian oocytes and subsequent chromosomally abnormal pregnancies. Sororin, a cohesion stabilizer whose relevance in antagonizing the anti-cohesive property of Wings-apart like protein (Wapl), has been characterized in mitosis; however, the role of Sororin remains unclear during mammalian oocyte meiosis. Here, we show that Sororin is required for DNA damage repair and cohesion maintenance on chromosomes, and consequently, for mouse oocyte meiotic program. Sororin is constantly expressed throughout meiosis and accumulates on chromatins at germinal vesicle (GV) stage/G2 phase. It localizes onto centromeres from germinal vesicle breakdown (GVBD) to metaphase II stage. Inactivation of Sororin compromises the GVBD and first polar body extrusion (PBE). Furthermore, Sororin inactivation induces DNA damage indicated by positive γH2AX foci in GV oocytes and precocious chromatin segregation in MII oocytes. Finally, our data indicate that PlK1 and MPF dissociate Sororin from chromosome arms without affecting its centromeric localization. Our results define Sororin as a determinant during mouse oocyte meiotic maturation by favoring DNA damage repair and chromosome separation, and thereby, maintaining the genome stability and generating haploid gametes.

  2. Acentrosomal spindle assembly and chromosome segregation during oocyte meiosis.

    PubMed

    Dumont, Julien; Desai, Arshad

    2012-05-01

    The ability to reproduce relies in most eukaryotes on specialized cells called gametes. Gametes are formed by the process of meiosis in which, after a single round of replication, two successive cell divisions reduce the ploidy of the genome. Fusion of gametes at fertilization reconstitutes diploidy. In most animal species, chromosome segregation during female meiosis occurs on spindles assembled in the absence of the major microtubule-organizing center, the centrosome. In mammals, oocyte meiosis is error prone and underlies most birth aneuploidies. Here, we review recent work on acentrosomal spindle formation and chromosome alignment/separation during oocyte meiosis in different animal models.

  3. Autosomal Chromosome Abnormality: A Cause of Birth Defects.

    ERIC Educational Resources Information Center

    Plumridge, Diane

    Intended for parents and professionals, the book explains chromosome abnormalities in lay terms and discusses the relationship of specific conditions to birth defects. Chromosomal abnormalities are defined and factors in diagnosis and recurrence are discussed. Normal chromosome reproduction processes are covered while such numerical abnormalities…

  4. The multiple roles of Bub1 in chromosome segregation during mitosis and meiosis

    SciTech Connect

    Marchetti, Francesco; Venkatachalam, Sundaresan

    2009-06-19

    Aneuploidy, any deviation from an exact multiple of the haploid number of chromosomes, is a common occurrence in cancer and represents the most frequent chromosomal disorder in newborns. Eukaryotes have evolved mechanisms to assure the fidelity of chromosome segregation during cell division that include a multiplicity of checks and controls. One of the main cell division control mechanisms is the spindle assembly checkpoint (SAC) that monitors the proper attachment of chromosomes to spindle fibers and prevents anaphase until all kinetochores are properly attached. The mammalian SAC is composed by at least 14 evolutionary-conserved proteins that work in a coordinated fashion to monitor the establishment of amphitelic attachment of all chromosomes before allowing cell division to occur. Among the SAC proteins, the budding uninhibited by benzimidazole protein 1 (Bub1), is a highly conserved protein of prominent importance for the proper functioning of the SAC. Studies have revealed many roles for Bub1 in both mitosis and meiosis, including the localization of other SAC proteins to the kinetochore, SAC signaling, metaphase congression and the protection of the sister chromatid cohesion. Recent data show striking sex specific differences in the response to alterations in Bub1 activity. Proper Bub1 functioning is particularly important during oogenesis in preventing the generation of aneuploid gametes that can have detrimental effects on the health status of the fetus and the newborn. These data suggest that Bub1 is a master regulator of SAC and chromosomal segregation in both mitosis and meiosis. Elucidating its many essential functions in regulating proper chromosome segregation can have important consequences for preventing tumorigenesis and developmental abnormalities.

  5. Cytogenetic Analysis for Suspected Chromosomal Abnormalities; A Five Years Experience

    PubMed Central

    Karra, Vijay Kumar; Jindal, Ankur; Puppala, Madhavi; Singh, Pratiksha; Rawat, Kanchan; Kapoor, Seema

    2016-01-01

    Introduction Chromosomal abnormalities are the results of alterations in the number or structure of chromosomes causing significant human morbidity and mortality. They are responsible for a large proportion of miscarriages, developmental delay, disorders of sexual development, congenital malformations and mental retardation. Aim The aim of this study was to describe the prevalence of different chromosomal abnormalities in North Indian patients referred for cytogenetic analysis. Materials and Methods Total of 859 patients ranging from newborn to 37 years of age were referred to the division of genetics, Department of Paediatrics between 2010 and 2015, with a variety of clinical disorders; Down syndrome (DS), Turner’s syndrome (TS) and Klinefelter syndrome; amenorrhea; ambiguous sex and multiple congenital malformations. Chromosomal analysis was performed on lymphocyte culture according to standard methods. Results Of the 859 cases studied, 371 (43.1%) had chromosomal abnormalities. The most common autosomal abnormalities were DS 302 (81.4%) and sex chromosomal abnormalities were TS 51 (13.7%). Numerical abnormalities were accounted for 353 (41.0%) and structural abnormalities 18 (2.0%), respectively. Various other chromosomal anomalies were also reported. Conclusion We have reviewed the incidence and distribution of chromosomal abnormalities and found higher rate of chromosomal abnormalities 43.1% in the referred cases. Our data suggest that chromosomal analysis is important tool in the evaluation of genetic disorders and helps clinicians to provide accurate diagnosis and proper genetic counselling. PMID:27790464

  6. Asymmetric chromosome segregation in Xanthomonas citri ssp. citri

    PubMed Central

    Ucci, Amanda P; Martins, Paula M M; Lau, Ivy F; Bacci, Maurício; Belasque, José; Ferreira, Henrique

    2014-01-01

    This study was intended to characterize the chromosome segregation process of Xanthomonas citri ssp. citri (Xac) by investigating the functionality of the ParB factor encoded on its chromosome, and its requirement for cell viability and virulence. Using TAP tagging we show that ParB is expressed in Xac. Disruption of parB increased the cell doubling time and precluded the ability of Xac to colonize the host citrus. Moreover, Xac mutant cells expressing only truncated forms of ParB exhibited the classical phenotype of aberrant chromosome organization, and seemed affected in cell division judged by their reduced growth rate and the propensity to form filaments. The ParB-GFP localization pattern in Xac was suggestive of an asymmetric mode of replicon partitioning, which together with the filamentation phenotype support the idea that Xac may control septum placement using mechanisms probably analogous to Caulobacter crescentus, and perhaps Vibrio cholerae, and Corynebacterium glutamicum. Xac exhibits asymmetric chromosome segregation, and the perturbation of this process leads to an inability to colonize the host plant. PMID:24339434

  7. Neocentromeres Provide Chromosome Segregation Accuracy and Centromere Clustering to Multiple Loci along a Candida albicans Chromosome

    PubMed Central

    Burrack, Laura S.; Hutton, Hannah F.; Clancey, Shelly Applen; Plemmons, Alexandra E.; Saha, Amrita; Turman, Breanna; Berman, Judith

    2016-01-01

    Assembly of kinetochore complexes, involving greater than one hundred proteins, is essential for chromosome segregation and genome stability. Neocentromeres, or new centromeres, occur when kinetochores assemble de novo, at DNA loci not previously associated with kinetochore proteins, and they restore chromosome segregation to chromosomes lacking a functional centromere. Neocentromeres have been observed in a number of diseases and may play an evolutionary role in adaptation or speciation. However, the consequences of neocentromere formation on chromosome missegregation rates, gene expression, and three-dimensional (3D) nuclear structure are not well understood. Here, we used Candida albicans, an organism with small, epigenetically-inherited centromeres, as a model system to study the functions of twenty different neocentromere loci along a single chromosome, chromosome 5. Comparison of neocentromere properties relative to native centromere functions revealed that all twenty neocentromeres mediated chromosome segregation, albeit to different degrees. Some neocentromeres also caused reduced levels of transcription from genes found within the neocentromere region. Furthermore, like native centromeres, neocentromeres clustered in 3D with active/functional centromeres, indicating that formation of a new centromere mediates the reorganization of 3D nuclear architecture. This demonstrates that centromere clustering depends on epigenetically defined function and not on the primary DNA sequence, and that neocentromere function is independent of its distance from the native centromere position. Together, the results show that a neocentromere can form at many loci along a chromosome and can support the assembly of a functional kinetochore that exhibits native centromere functions including chromosome segregation accuracy and centromere clustering within the nucleus. PMID:27662467

  8. Tumor-Specific Chromosome Mis-Segregation Controls Cancer Plasticity by Maintaining Tumor Heterogeneity

    PubMed Central

    Hu, Yuanjie; Ru, Ning; Xiao, Huasheng; Chaturbedi, Abhishek; Hoa, Neil T.; Tian, Xiao-Jun; Zhang, Hang; Ke, Chao; Yan, Fengrong; Nelson, Jodi; Li, Zhenzhi; Gramer, Robert; Yu, Liping; Siegel, Eric; Zhang, Xiaona; Jia, Zhenyu; Jadus, Martin R.; Limoli, Charles L.; Linskey, Mark E.; Xing, Jianhua; Zhou, Yi-Hong

    2013-01-01

    Aneuploidy with chromosome instability is a cancer hallmark. We studied chromosome 7 (Chr7) copy number variation (CNV) in gliomas and in primary cultures derived from them. We found tumor heterogeneity with cells having Chr7-CNV commonly occurs in gliomas, with a higher percentage of cells in high-grade gliomas carrying more than 2 copies of Chr7, as compared to low-grade gliomas. Interestingly, all Chr7-aneuploid cell types in the parental culture of established glioma cell lines reappeared in single-cell-derived subcultures. We then characterized the biology of three syngeneic glioma cultures dominated by different Chr7-aneuploid cell types. We found phenotypic divergence for cells following Chr7 mis-segregation, which benefited overall tumor growth in vitro and in vivo. Mathematical modeling suggested the involvement of chromosome instability and interactions among cell subpopulations in restoring the optimal equilibrium of tumor cell types. Both our experimental data and mathematical modeling demonstrated that the complexity of tumor heterogeneity could be enhanced by the existence of chromosomes with structural abnormality, in addition to their mis-segregations. Overall, our findings show, for the first time, the involvement of chromosome instability in maintaining tumor heterogeneity, which underlies the enhanced growth, persistence and treatment resistance of cancers. PMID:24282558

  9. Down's Syndrome and Leukemia: Mechanism of Additional Chromosomal Abnormalities

    ERIC Educational Resources Information Center

    And Others; Goh, Kong-oo

    1978-01-01

    Chromosomal abnormalities, some appearing in a stepwise clonal evoluation, were found in five Down's syndrome patients (35 weeks to 12 years old), four with acute leukemia and one with abnormal regulation of leukopoiesis. (Author/SBH)

  10. Back to the roots: segregation of univalent sex chromosomes in meiosis.

    PubMed

    Fabig, Gunar; Müller-Reichert, Thomas; Paliulis, Leocadia V

    2016-06-01

    In males of many taxa, univalent sex chromosomes normally segregate during the first meiotic division, and analysis of sex chromosome segregation was foundational for the chromosome theory of inheritance. Correct segregation of single or multiple univalent sex chromosomes occurs in a cellular environment where every other chromosome is a bivalent that is being partitioned into homologous chromosomes at anaphase I. The mechanics of univalent chromosome segregation vary among animal taxa. In some, univalents establish syntelic attachment of sister kinetochores to the spindle. In others, amphitelic attachment is established. Here, we review how this problem of segregation of unpaired chromosomes is solved in different animal systems. In addition, we give a short outlook of how mechanistic insights into this process could be gained by explicitly studying model organisms, such as Caenorhabditis elegans.

  11. A Case of ADHD and a Major Y Chromosome Abnormality

    ERIC Educational Resources Information Center

    Mulligan, Aisling; Gill, Michael; Fitzgerald, Michael

    2008-01-01

    Background: ADHD is a common, heritable disorder of childhood. Sex chromosome abnormalities are relatively rare conditions that are sometimes associated with behavioral disorders. Method: The authors present a male child with ADHD and a major de-novo Y chromosome abnormality consisting of deletion of the long arm and duplication of the short arm.…

  12. Visualizing how cancer chromosome abnormalities form in living cells

    Cancer.gov

    For the first time, scientists have directly observed events that lead to the formation of a chromosome abnormality that is often found in cancer cells. The abnormality, called a translocation, occurs when part of a chromosome breaks off and becomes attac

  13. Directly transmitted unbalanced chromosome abnormalities and euchromatic variants

    PubMed Central

    Barber, J

    2005-01-01

    In total, 200 families were reviewed with directly transmitted, cytogenetically visible unbalanced chromosome abnormalities (UBCAs) or euchromatic variants (EVs). Both the 130 UBCA and 70 EV families were divided into three groups depending on the presence or absence of an abnormal phenotype in parents and offspring. No detectable phenotypic effect was evident in 23/130 (18%) UBCA families ascertained mostly through prenatal diagnosis (group 1). In 30/130 (23%) families, the affected proband had the same UBCA as other phenotypically normal family members (group 2). In the remaining 77/130 (59%) families, UBCAs had consistently mild consequences (group 3). In the 70 families with established EVs of 8p23.1, 9p12, 9q12, 15q11.2, and 16p11.2, no phenotypic effect was apparent in 38/70 (54%). The same EV was found in affected probands and phenotypically normal family members in 30/70 families (43%) (group 2), and an EV co-segregated with mild phenotypic anomalies in only 2/70 (3%) families (group 3). Recent evidence indicates that EVs involve copy number variation of common paralogous gene and pseudogene sequences that are polymorphic in the normal population and only become visible at the cytogenetic level when copy number is high. The average size of the deletions and duplications in all three groups of UBCAs was close to 10 Mb, and these UBCAs and EVs form the "Chromosome Anomaly Collection" at http://www.ngrl.org.uk/Wessex/collection. The continuum of severity associated with UBCAs and the variability of the genome at the sub-cytogenetic level make further close collaboration between medical and laboratory staff essential to distinguish clinically silent variation from pathogenic rearrangement. PMID:16061560

  14. Prevalence of chromosomal abnormalities in infertile couples in romania

    PubMed Central

    Mierla, D; Malageanu, M; Tulin, R; Albu, D

    2015-01-01

    The purpose of this study was to establish a correlation between the presence of chromosomal abnormalities in one of the partners and infertility. This retrospective study was performed at the Department of Reproductive Medicine, Life Memorial Hospital, Bucharest, Romania, between August 2007 to December 2011. Two thousand, one hundred and ninety-five patients with reproductive problems were investigated, and the frequency of chromosomal abnormalities was calculated. The control group consisting of 87 fertile persons who had two or more children, was investigated in this retrospective study. All the patients of this study were investigated by cytogenetic techniques and the results of the two groups were compared by a two-tailed Fisher’s exact test. In this study, 94.99% patients had a normal karyotype and 5.01% had chromosomal abnormalities (numerical and structural chromosomal abnormalities). In the study group, numerical chromosomal abnormalities were detected in 1.14% of infertile men and 0.62% of infertile women, and structural chromosomal abnormalities were detected in 1.38% of infertile men and 1.87% of infertile women, respectively. The correlation between the incidence of chromosomal anomalies in the two sexes in couple with reproductive problems was not statistically significant. Recently, a possible association between infertility and chromosomal abnormalities with a significant statistical association has been reported. Our study shows that there is no association between chromosomal abnormalities and infertility, but this study needs to be confirmed with further investigations and a larger control group to establish the role of chromosomal abnormalities in the etiology of infertility. PMID:26929902

  15. Psychiatric syndromes in individuals with chromosome 18 abnormalities.

    PubMed

    Zavala, Juan; Ramirez, Mercedes; Medina, Rolando; Heard, Patricia; Carter, Erika; Crandall, AnaLisa; Hale, Daniel; Cody, Jannine; Escamilla, Michael

    2010-04-05

    Chromosome 18 abnormalities are associated with a range of physical abnormalities such as short stature and hearing impairments. Psychiatric manifestations have also been observed. This study focuses on the presentations of psychiatric syndromes as they relate to specific chromosomal abnormalities of chromosome 18. Twenty-five subjects (13 with an 18q deletion, 9 with 18p tetrasomy, and 3 with an 18p deletion), were interviewed by psychiatrists (blind to specific chromosomal abnormality) using the DIGS (subjects 18 and older) or KSADS-PL (subjects under 18). A consensus best estimation diagnostic process was employed to determine psychiatric syndromes. Oligonucleotide Array Comparative Genomic Hybridization (Agilent Technologies) was utilized to define specific regions of chromosome 18 that were deleted or duplicated. These data were further analyzed to determine critical regions of the chromosome as they relate to phenotypic manifestations in these subjects. 58.3% of the chromosome 18q- deletion subjects had depressive symptoms, 58.3% had anxiety symptoms, 25% had manic symptoms, and 25% had psychotic symptoms. 66.6% of the chromosome 18p- deletion subjects had anxiety symptoms, and none had depressive, manic, or psychotic symptoms. Fifty percent of the chromosome 18p tetrasomy subjects had anxiety symptoms, 12.5% had psychotic symptoms, and 12.5% had a mood disorder. All three chromosomal disorders were associated with high anxiety rates. Psychotic, manic and depressive disorders were seen mostly in 18q- subjects and this may be helpful in narrowing regions for candidate genes for these psychiatric conditions.

  16. Segregation of the AML t(7;11)(p15;p15) translocation chromosomes in somatic cell hybrids

    SciTech Connect

    Borrow, J.; Munroe, D.; Housman, D.E.

    1994-09-01

    The t(7;11)(p15;p15) translocation is a recurrent chromosomal abnormality associated predominately with acute myeloid leukemia (AML) FAB M2 and occasionally with other types of AML or CML blast crisis. High resolution banding techniques have previously localized the breakpoints to 7q15.1 and 11p15.5. We have fused t(7;11)(p15;p15) blast cells from an AML patient to CHTG (hamster) cells in order to segregate the translocated chromosomes from their normal counterparts in somatic cell hybrids. Fusion events containing the derivative chromosomes or the normal chromosome 11 were enriched by panning with the antibodies M1C1 and MER2. These antibodies recognize cell surface markers which are expressed from genes which map to opposite sides of the breakpoint on chromosome 11 (11p13 and 11p15.5, respectively). Individual hybrids were expanded and typed with a series of ordered STSs from chromosomes 7 and 11, and hybrids containing the der(7) and der(11) chromosomes were identified. The segregation of the STSs between the two derivatives is in full agreement with the consensus breakpoint positions as determined cytogenetically. These hybrids may prove useful in further delineation of the breakpoint regions on chromosomes 7 and 11.

  17. Variation in Y chromosome segregation in natural populations of Drosophila melanogaster

    SciTech Connect

    Clark, A.G.

    1987-01-01

    Functional variation among Y chromosomes in natural populations of Drosophila melanogaster was assayed by a segregation study. A total of 36 Y chromosomes was extracted and ten generations of replacement backcrossing yielded stocks with Y chromosomes in two different genetic backgrounds. Eleven of the Y chromosomes were from diverse geographic origins, and the remaining 25 were from locally captured flies. Segregation of sexes in adult offspring was scored for the four possible crosses among the two backgrounds with each Y chromosome. Although the design confounds meiotic drive and effects on viability, statistical partitioning of these effects reveals significant variation among lines in Y chromosome segregation. Results are discussed in regards to models of Y-linked segregation and viability effects, which suggest that Y-linked adaptive polymorphism is unlikely.

  18. Variation in Y Chromosome Segregation in Natural Populations of Drosophila melanogaster

    PubMed Central

    Clark, Andrew G.

    1987-01-01

    Functional variation among Y chromosomes in natural populations of Drosophila melanogaster was assayed by a segregation study. A total of 36 Y chromosomes was extracted and ten generations of replacement backcrossing yielded stocks with Y chromosomes in two different genetic backgrounds. Eleven of the Y chromosomes were from diverse geographic origins, and the remaining 25 were from locally captured flies. Segregation of sexes in adult offspring was scored for the four possible crosses among the two backgrounds with each Y chromosome. Although the design confounds meiotic drive and effects on viability, statistical partitioning of these effects reveals significant variation among lines in Y chromosome segregation. Results are discussed in regards to models of Y-linked segregation and viability effects, which suggest that Y-linked adaptive polymorphism is unlikely. PMID:3104134

  19. Physical Model of Segregation of E.coli Chromosomes using Molecular Dynamics

    NASA Astrophysics Data System (ADS)

    Alnahhas, Faisal; Kharel, Savan

    2016-03-01

    Chromosome segregation is one of the most interesting physical processes during a bacterial cell cycle. We will use molecular dynamics simulations which will help us understand how strongly confined polymer segregates. In the presentation, we will discuss how segregation of initially overlapping circular chromosome occurs during a cell cycle. In particular, we will describe the role played by entropic mechanism in the demixing of overlapping circular polymer confined in a cylindrical boundary. We discuss how our polymer chains modeled as an E-coli chromosome experiences an effective repulsion, which ultimately leads to partition driven by the entropic forces. Also, we will also discuss how the segregation of circular chromosome in cylindrical confinement differs from a spherical confinement. Finally, we will discuss the role played by proteins and supercoiling in during the segregation process.

  20. Genomic imprinting as a probable explanation for variable intrafamilial phenotypic expression of an unusual chromosome 3 abnormality

    SciTech Connect

    Fryburg, J.S.; Shashi, V.; Kelly, T.E.

    1994-09-01

    We present a 4 generation family in which an abnormal chromosome 3 with dup(3)(q25) segregated from great-grandmother to grandmother to son without phenotypic effect. The son`s 2 daughters have dysmorphic features, mild developmental delays and congenital heart disease. Both girls have the abnormal chr. 3 but are the only family members with the abnormality to have phenotypic effects. An unaffected son of the father has normal chromosomes. FISH with whole chromosome paints for chromosomes 1, 2, 6, 7, 8, 14, 18, and 22 excluded these as the origin of the extra material. Chromosome 3-specific paint revealed a uniform pattern, suggesting that the extra material is from chromosome 3. Comparative genomic hybridization and DNA studies are pending. Possible explanations for the discordance in phenotypes between the 4th generation offspring and the first 3 generations include: an undetected rearrangement in the previous generations that is unbalanced in the two affected individuals; the chromosome abnormality may be a benign variant and unrelated to the phenotype; or, most likely, genomic imprinting. Genomic imprinting is suggested by the observation that a phenotypic effect was only seen after the chromosome was inherited from the father. The mothers in the first two generations appear to have passed the abnormal chr. 3 on without effect. This is an opportunity to delineate a region of the human genome affected by paternal imprinting.

  1. Chromosomal abnormalities, meiotic behavior and fertility in domestic animals.

    PubMed

    Villagómez, D A F; Pinton, A

    2008-01-01

    Since the advent of the surface microspreading technique for synaptonemal complex analysis, increasing interest in describing the synapsis patterns of chromosome abnormalities associated with fertility of domestic animals has been noticed during the past three decades. In spite of the number of scientific reports describing the occurrence of structural chromosome abnormalities, their meiotic behavior and gametic products, little is known in domestic animal species about the functional effects of such chromosome aberrations in the germ cell line of carriers. However, some interesting facts gained from recent and previous studies on the meiotic behavior of chromosome abnormalities of domestic animals permit us to discuss, in the frame of recent knowledge emerging from mouse and human investigations, the possible mechanism implicated in the well known association between meiotic disruption and chromosome pairing failure. New cytogenetic techniques, based on molecular and immunofluorescent analyses, are allowing a better description of meiotic processes, including gamete production. The present communication reviews the knowledge of the meiotic consequences of chromosome abnormalities in domestic animals.

  2. Drosophila male germline stem cells do not asymmetrically segregate chromosome strands.

    PubMed

    Yadlapalli, Swathi; Cheng, Jun; Yamashita, Yukiko M

    2011-03-15

    Adult stem cells continuously supply differentiated cells throughout the life of organisms. This increases the risk of replicative senescence or neoplastic transformation due to mutations that accumulate over many rounds of DNA replication. The immortal strand hypothesis proposes that stem cells reduce the accumulation of replication-induced mutations by retaining the older template DNA strands. Other models have also been proposed in which stem cells asymmetrically segregate chromosome strands for other reasons, such as retention of epigenetic memories. Recently, the idea has emerged that the mother centrosome, which is stereotypically retained within some asymmetrically dividing stem cells, might be utilized as a means of asymmetrically segregating chromosome strands. We have tested this hypothesis in germline stem cells (GSCs) from Drosophila melanogaster testis, which undergo asymmetric divisions marked by the asymmetric segregation of centrosomes and the acquisition of distinct daughter cell fates (stem cell self-renewal versus differentiation). Using 5-bromo-2-deoxyuridine labeling combined with direct visualization of GSC-gonialblast (differentiating daughter) pairs, we directly scored the outcome of chromosome strand segregation. Our data show that, in male GSCs in the Drosophila testis, chromosome strands are not asymmetrically segregated, despite asymmetrically segregating centrosomes. Our data demonstrate that asymmetric centrosome segregation in stem cells does not necessarily lead to asymmetric chromosome strand segregation.

  3. HP1-Assisted Aurora B Kinase Activity Prevents Chromosome Segregation Errors.

    PubMed

    Abe, Yusuke; Sako, Kosuke; Takagaki, Kentaro; Hirayama, Youko; Uchida, Kazuhiko S K; Herman, Jacob A; DeLuca, Jennifer G; Hirota, Toru

    2016-03-07

    Incorrect attachment of kinetochore microtubules is the leading cause of chromosome missegregation in cancers. The highly conserved chromosomal passenger complex (CPC), containing mitotic kinase Aurora B as a catalytic subunit, ensures faithful chromosome segregation through destabilizing incorrect microtubule attachments and promoting biorientation of chromosomes on the mitotic spindle. It is unknown whether CPC dysfunction affects chromosome segregation fidelity in cancers and, if so, how. Here, we show that heterochromatin protein 1 (HP1) is an essential CPC component required for full Aurora B activity. HP1 binding to the CPC becomes particularly important when Aurora B phosphorylates kinetochore targets to eliminate erroneous microtubule attachments. Remarkably, a reduced proportion of HP1 bound to CPC is widespread in cancers, which causes an impairment in Aurora B activity. These results indicate that HP1 is an essential modulator for CPC function and identify a molecular basis for chromosome segregation errors in cancer cells.

  4. Molecular cloaking of H2A.Z on mortal DNA chromosomes during nonrandom segregation.

    PubMed

    Huh, Yang Hoon; Sherley, James L

    2011-10-01

    Although nonrandom sister chromatid segregation is a singular property of distributed stem cells (DSCs) that are responsible for renewing and repairing mature vertebrate tissues, both its cellular function and its molecular mechanism remain unknown. This situation persists in part because of the lack of facile methods for detecting and quantifying nonrandom segregating cells and for identifying chromosomes with immortal DNA strands, the cellular molecules that signify nonrandom segregation. During nonrandom segregation, at each mitosis, asymmetrically self-renewing DSCs continuously cosegregate to themselves the set of chromosomes that contain immortal DNA strands, which are the oldest DNA strands. Here, we report the discovery of a molecular asymmetry between segregating sets of immortal chromosomes and opposed mortal chromosomes (i.e., containing the younger set of DNA template strands) that constitutes a new convenient biomarker for detection of cells undergoing nonrandom segregation and direct delineation of chromosomes that bear immortal DNA strands. In both cells engineered with DSC-specific properties and ex vivo-expanded mouse hair follicle stem cells, the histone H2A variant H2A.Z shows specific immunodetection on immortal DNA chromosomes. Cell fixation analyses indicate that H2A.Z is present on mortal chromosomes as well but is cloaked from immunodetection, and the cloaking entity is acid labile. The H2A.Z chromosomal asymmetry produced by molecular cloaking provides a first direct assay for nonrandom segregation and for chromosomes with immortal DNA strands. It also seems likely to manifest an important aspect of the underlying mechanism(s) responsible for nonrandom sister chromatid segregation in DSCs.

  5. Molecular cytogenetic studies in structural abnormalities of chromosome 13

    SciTech Connect

    Lozzio, C.B.; Bamberger, E.; Anderson, I.

    1994-09-01

    A partial trisomy 13 was detected prenatally in an amniocentesis performed due to the following ultrasound abnormalities: open sacral neural tube defect (NTD), a flattened cerebellum, and lumbar/thoracic hemivertebrae. Elevated AFP and positive acetylcholinesterase in amniotic fluid confirmed the open NTD. Chromosome analysis showed an extra acrocentric chromosome marker. FISH analysis with the painting probe 13 showed that most of the marker was derived from this chromosome. Chromosomes on the parents revealed that the mother had a balanced reciprocal translocation t(2;13)(q23;q21). Dual labeling with painting chromosomes 2 and 13 on cells from the mother and from the amniotic fluid identified the marker as a der(13)t(2;13)(p23;q21). Thus, the fetus had a partial trisomy 13 and a small partial trisomy 2p. The maternal grandfather was found to be a carrier for this translocation. Fetal demise occurred a 29 weeks of gestation. The fetus had open lumbar NTD and showed dysmorphic features, overlapping fingers and imperforate anus. This woman had a subsequent pregnancy and chorionic villi sample showed that this fetus was normal. Another case with an abnormal chromosome 13 was a newborn with partial monosomy 13 due to the presence of a ring chromosome 13. This infant had severe intrauterine growth retardation, oligohydramnios, dysmorphic features and multiple congenital microphthalmia, congenital heart disease, absent thumbs and toes and cervical vertebral anomalies. Chromosome studies in blood and skin fibroblast cultures showed that one chromosome 3 was replaced by a ring chromosome of various sizes. This ring was confirmed to be derived from chromosome 13 using the centromeric 21/13 probe.

  6. Chromosomal Abnormalities in Infertile Men from Southern India

    PubMed Central

    Suganya, Jaganathan; Kujur, Smita B; Selvaraj, Kamala; Suruli, Muthiah S.; Haripriya, Geetha

    2015-01-01

    Background and Objective Male infertility has been associated with aneuploidies and structural chromosomal abnormalities, Yq microdeletions and specific gene mutations and/or polymorphisms. Besides genetic factors, any block in sperm delivery, endocrine disorders, testicular tumours, infectious diseases, medications, lifestyle factors and environmental toxins can also play a causative role. This study aimed to determine the constitutional karyotype in infertile males having normal female partners in a south Indian population. Materials and Methods A total of 180 men with a complaint of primary infertility ranging from 1 to 25 years were screened for chromosomal abnormalities through conventional analysis of GTG-banded metaphases from cultured lymphocytes. Results Four individuals were diagnosed to have Klinefelter syndrome. Two cases exhibited reciprocal translocations and one showed a maternally inherited insertion. Polymorphisms were seen in sixty-seven patients (37.2%). Conclusion The occurrence of chromosomal abnormalities in 4.6% and variants involving the heterochromatic regions of Y, chromosome 9 and the acrocentric chromosomes in 38.2% of the infertile men with an abnormal seminogram strongly reiterates the inclusion of routine cytogenetic testing and counselling in the diagnostic work-up prior to the use of assisted reproduction technologies. PMID:26393143

  7. Chromosomal abnormalities in fetuses with ultrasonographically detected neural tube defects.

    PubMed

    Kanit, Hakan; Özkan, Azra Arici; Öner, Soner Recai; Ispahi, Ciğdem; Endrikat, Jan Siegfried; Ertan, Kubilay

    2011-10-01

    We analyzed the karyotype of fetuses with ultrasonographically detected neural tube defects (NTDs). In our study, we included a total of 194 fetuses with NTDs. We analyzed the type of NTD, the karyotype, maternal age, fetal gestational age at diagnosis, and fetal sex. Of the 194 fetuses with NTDs, 87 were anencephalic and 107 had other, nonanencephalic, NTDs. A total of 12 fetuses were shown to have chromosomal abnormalities. Three of 87 anencephalic fetuses (3.45%) had chromosomal abnormalities. The sex ratio for anencephalic fetuses was 65.5% : 34.5% for female and male fetuses. Nine of 107 fetuses with other NTDs (8.41%) had chromosomal abnormalities. Seven fetuses had isolated NTDs and a further seven fetuses had additional ultrasonographic anomalies. Two of the latter had abnormal karyotypes. The sex ratio of all other NTD cases was 67.3% : 32.7% for female and male fetuses. The high number of chromosomal abnormalities justifies prenatal karyotyping in all fetuses with ultrasonographically diagnosed NTDs.

  8. Clonal chromosome abnormalities in 54 cases of ovarian carcinoma.

    PubMed

    Thompson, F H; Emerson, J; Alberts, D; Liu, Y; Guan, X Y; Burgess, A; Fox, S; Taetle, R; Weinstein, R; Makar, R

    1994-03-01

    As a prelude to assessing the relationship of chromosome alterations to clinical outcome in ovarian carcinoma, we report on the cytogenetic analysis on short-term cultures from 54 patients. All patients had histopathologically confirmed malignancy, with the majority of cases demonstrating serous ovarian adenocarcinomas. Structural alterations were evident in 52 cases, whereas numeric changes were identified in 13 cases. The most notable numeric abnormalities were loss of the X-chromosome (9/13 total cases) and +7 (3/9 diploid cases). Structural alterations most frequently involved chromosomes 1, 3, 6, 7, 11, and 12. Chromosomal breakpoints were shown to cluster in several chromosomal banding regions, including 1p36, 1p11-q21, 3p23-p10, 7p (especially 7p22), 11p, 11q, 12p13-q12, and 12q24. The frequency of structural alterations involving the following chromosome arms was found to be significantly increased: 1p (p < 0.01), 7p (p < 0.01), 11p (p < 0.01), 11q (p < 0.05), and 12p (p < 0.05). An analysis of the net gain or loss of chromosome segments was also performed, with the most consistent tendency observed being over-representation of 1q and chromosome 7, deletion of 1p, and loss of the X chromosome.

  9. Cognitive and Academic Skills in Children with Sex Chromosome Abnormalities.

    ERIC Educational Resources Information Center

    Bender, Bruce G.; And Others

    1991-01-01

    Follows 46 unselected children with various sex chromosome abnormalities using intellectual, language, and achievement testing. Notes that, although most children were not mentally retarded, most received special education help. Finds support for the inference that learning disorders were genetically mediated in this group. (RS)

  10. Chromosomal abnormalities are associated with aging and cancer

    Cancer.gov

    Two new studies have found that large structural abnormalities in chromosomes, some of which have been associated with increased risk of cancer, can be detected in a small fraction of people without a prior history of cancer. The studies found that these

  11. Dbl2 Regulates Rad51 and DNA Joint Molecule Metabolism to Ensure Proper Meiotic Chromosome Segregation

    PubMed Central

    Hyppa, Randy W.; Benko, Zsigmond; Misova, Ivana; Schleiffer, Alexander; Smith, Gerald R.; Gregan, Juraj

    2016-01-01

    To identify new proteins required for faithful meiotic chromosome segregation, we screened a Schizosaccharomyces pombe deletion mutant library and found that deletion of the dbl2 gene led to missegregation of chromosomes during meiosis. Analyses of both live and fixed cells showed that dbl2Δ mutant cells frequently failed to segregate homologous chromosomes to opposite poles during meiosis I. Removing Rec12 (Spo11 homolog) to eliminate meiotic DNA double-strand breaks (DSBs) suppressed the segregation defect in dbl2Δ cells, indicating that Dbl2 acts after the initiation of meiotic recombination. Analyses of DSBs and Holliday junctions revealed no significant defect in their formation or processing in dbl2Δ mutant cells, although some Rec12-dependent DNA joint molecules persisted late in meiosis. Failure to segregate chromosomes in the absence of Dbl2 correlated with persistent Rad51 foci, and deletion of rad51 or genes encoding Rad51 mediators also suppressed the segregation defect of dbl2Δ. Formation of foci of Fbh1, an F-box helicase that efficiently dismantles Rad51-DNA filaments, was impaired in dbl2Δ cells. Our results suggest that Dbl2 is a novel regulator of Fbh1 and thereby Rad51-dependent DSB repair required for proper meiotic chromosome segregation and viable sex cell formation. The wide conservation of these proteins suggests that our results apply to many species. PMID:27304859

  12. Mechanisms and consequences of paternally transmitted chromosomal abnormalities

    SciTech Connect

    Marchetti, F; Wyrobek, A J

    2005-04-05

    Paternally transmitted chromosomal damage has been associated with pregnancy loss, developmental and morphological defects, infant mortality, infertility, and genetic diseases in the offspring including cancer. There is epidemiological evidence linking paternal exposure to occupational or environmental agents with an increased risk of abnormal reproductive outcomes. There is also a large body of literature on germ cell mutagenesis in rodents showing that treatment of male germ cells with mutagens has dramatic consequences on reproduction producing effects such as those observed in human epidemiological studies. However, we know very little about the etiology, transmission and early embryonic consequences of paternally-derived chromosomal abnormalities. The available evidence suggests that: (1) there are distinct patterns of germ cell-stage differences in the sensitivity of induction of transmissible genetic damage with male postmeiotic cells being the most sensitive; (2) cytogenetic abnormalities at first metaphase after fertilization are critical intermediates between paternal exposure and abnormal reproductive outcomes; and, (3) there are maternally susceptibility factors that may have profound effects on the amount of sperm DNA damage that is converted into chromosomal aberrations in the zygote and directly affect the risk for abnormal reproductive outcomes.

  13. Addiction toxin Fst has unique effects on chromosome segregation and cell division in Enterococcus faecalis and Bacillus subtilis.

    PubMed

    Patel, S; Weaver, K E

    2006-08-01

    The Fst toxin of the Enterococcus faecalis pAD1-encoded par addiction module functions intracellularly to kill plasmid-free segregants. Previous results had shown that Fst induction results in membrane permeabilization and cessation of macromolecular synthesis, but only after 45 min. Electron micrographs of toxin-induced cells showed no obvious membrane abnormalities but did reveal defects in nucleoid segregation and cell division, begging the question of which is the primary effect of Fst. To distinguish the possibilities, division septae and nucleoids were visualized simultaneously with fluorescent vancomycin and a variety of DNA stains. Results showed that division and segregation defects occurred in some cells within 15 min after induction. At these early time points, affected cells remained resistant to membrane-impermeant DNA stains, suggesting that loss of membrane integrity is a secondary effect caused by ongoing division and/or segregation defects. Fst-resistant mutants showed greater variability in cell length and formed multiple septal rings even in the absence of Fst. Fst induction was also toxic to Bacillus subtilis. In this species, Fst induction caused only minor division abnormalities, but all cells showed a condensation of the nucleoid, suggesting that effects on the structure of the chromosomal DNA might be paramount.

  14. The dynamics of signal amplification by macromolecular assemblies for the control of chromosome segregation

    PubMed Central

    Lee, Semin; Bolanos-Garcia, Victor M.

    2014-01-01

    The control of chromosome segregation relies on the spindle assembly checkpoint (SAC), a complex regulatory system that ensures the high fidelity of chromosome segregation in higher organisms by delaying the onset of anaphase until each chromosome is properly bi-oriented on the mitotic spindle. Central to this process is the establishment of multiple yet specific protein-protein interactions in a narrow time-space window. Here we discuss the highly dynamic nature of multi-protein complexes that control chromosome segregation in which an intricate network of weak but cooperative interactions modulate signal amplification to ensure a proper SAC response. We also discuss the current structural understanding of the communication between the SAC and the kinetochore; how transient interactions can regulate the assembly and disassembly of the SAC as well as the challenges and opportunities for the definition and the manipulation of the flow of information in SAC signaling. PMID:25324779

  15. Insensitivity of Chromosome I and the Cell Cycle to Blockage of Replication and Segregation of Vibrio cholerae Chromosome II

    PubMed Central

    Kadoya, Ryosuke; Chattoraj, Dhruba K.

    2012-01-01

    ABSTRACT Vibrio cholerae has two chromosomes (chrI and chrII) whose replication and segregation are under different genetic controls. The region covering the replication origin of chrI resembles that of the Escherichia coli chromosome, and both origins are under control of the highly conserved initiator, DnaA. The origin region of chrII resembles that of plasmids that have iterated initiator-binding sites (iterons) and is under control of the chrII-specific initiator, RctB. Both chrI and chrII encode chromosome-specific orthologs of plasmid partitioning proteins, ParA and ParB. Here, we have interfered with chrII replication, segregation, or both, using extra copies of sites that titrate RctB or ParB. Under these conditions, replication and segregation of chrI remain unaffected for at least 1 cell cycle. In this respect, chrI behaves similarly to the E. coli chromosome when plasmid maintenance is disturbed in the same cell. Apparently, no checkpoint exists to block cell division before the crippled chromosome is lost by a failure to replicate or to segregate. Whether blocking chrI replication can affect chrII replication remains to be tested. PMID:22570276

  16. Multiple congenital abnormalities in a newborn with two supernumerary marker chromosomes derived from chromosome 14.

    PubMed

    Faas, B H W; Van Der Deure, J; Wunderink, M I; Merkx, G; Brunner, H G

    2006-01-01

    Pure partial duplication or triplication of the proximal part of chromosome 14 has been reported in only 4 patients. Other individuals with a duplication or triplication of this region have additional chromosome imbalances. We present a new case with a supernumerary marker chromosome in all blood cells and in 35% of the cells an additional smaller marker chromosome. Both markers appeared to be derived from chromosome 14 (del(14)(q21.2) in all cells and del(14)(q11.2) in 35% of the cells). This results in a partial duplication of the proximal region of chromosome 14, combined with a mosaic partial triplication of a smaller segment of the same region. In this paper, we compare the clinical features of this case to those of cases from the literature. Although most of the patients from literature were unbalanced translocation carriers, their clinical features were comparable, except from renal abnormalities.

  17. Nuclear envelope expansion is crucial for proper chromosomal segregation during a closed mitosis.

    PubMed

    Takemoto, Ai; Kawashima, Shigehiro A; Li, Juan-Juan; Jeffery, Linda; Yamatsugu, Kenzo; Elemento, Olivier; Nurse, Paul

    2016-03-15

    Here, we screened a 10,371 library of diverse molecules using a drug-sensitive fission yeast strain to identify compounds which cause defects in chromosome segregation during mitosis. We identified a phosphorium-ylide-based compound Cutin-1 which inhibits nuclear envelope expansion and nuclear elongation during the closed mitosis of fission yeast, and showed that its target is the β-subunit of fatty acid synthase. A point mutation in the dehydratase domain of Fas1 conferred in vivo and in vitro resistance to Cutin-1. Time-lapse photomicrography showed that the bulk of the chromosomes were only transiently separated during mitosis, and nucleoli separation was defective. Subsequently sister chromatids re-associated leading to chromosomal mis-segregation. These segregation defects were reduced when the nuclear volume was increased and were increased when the nuclear volume was reduced. We propose that there needs to be sufficient nuclear volume to allow the nuclear elongation necessary during a closed mitosis to take place for proper chromosome segregation, and that inhibition of fatty acid synthase compromises nuclear elongation and leads to defects in chromosomal segregation.

  18. Short- and long-term effects of chromosome mis-segregation and aneuploidy.

    PubMed

    Santaguida, Stefano; Amon, Angelika

    2015-08-01

    Dividing cells that experience chromosome mis-segregation generate aneuploid daughter cells, which contain an incorrect number of chromosomes. Although aneuploidy interferes with the proliferation of untransformed cells, it is also, paradoxically, a hallmark of cancer, a disease defined by increased proliferative potential. These contradictory effects are also observed in mouse models of chromosome instability (CIN). CIN can inhibit and promote tumorigenesis. Recent work has provided insights into the cellular consequences of CIN and aneuploidy. Chromosome mis-segregation per se can alter the genome in many more ways than just causing the gain or loss of chromosomes. The short- and long-term effects of aneuploidy are caused by gene-specific effects and a stereotypic aneuploidy stress response. Importantly, these recent findings provide insights into the role of aneuploidy in tumorigenesis.

  19. Chromosome mis-segregation and cytokinesis failure in trisomic human cells.

    PubMed

    Nicholson, Joshua M; Macedo, Joana C; Mattingly, Aaron J; Wangsa, Darawalee; Camps, Jordi; Lima, Vera; Gomes, Ana M; Dória, Sofia; Ried, Thomas; Logarinho, Elsa; Cimini, Daniela

    2015-05-05

    Cancer cells display aneuploid karyotypes and typically mis-segregate chromosomes at high rates, a phenotype referred to as chromosomal instability (CIN). To test the effects of aneuploidy on chromosome segregation and other mitotic phenotypes we used the colorectal cancer cell line DLD1 (2n = 46) and two variants with trisomy 7 or 13 (DLD1+7 and DLD1+13), as well as euploid and trisomy 13 amniocytes (AF and AF+13). We found that trisomic cells displayed higher rates of chromosome mis-segregation compared to their euploid counterparts. Furthermore, cells with trisomy 13 displayed a distinctive cytokinesis failure phenotype. We showed that up-regulation of SPG20 expression, brought about by trisomy 13 in DLD1+13 and AF+13 cells, is sufficient for the cytokinesis failure phenotype. Overall, our study shows that aneuploidy can induce chromosome mis-segregation. Moreover, we identified a trisomy 13-specific mitotic phenotype that is driven by up-regulation of a gene encoded on the aneuploid chromosome.

  20. The negatively charged carboxy-terminal tail of β-tubulin promotes proper chromosome segregation

    PubMed Central

    Fees, Colby P.; Aiken, Jayne; O’Toole, Eileen T.; Giddings, Thomas H.; Moore, Jeffrey K.

    2016-01-01

    Despite the broadly conserved role of microtubules in chromosome segregation, we have a limited understanding of how molecular features of tubulin proteins contribute to the underlying mechanisms. Here we investigate the negatively charged carboxy-terminal tail domains (CTTs) of α- and β-tubulins, using a series of mutants that alter or ablate CTTs in budding yeast. We find that ablating β-CTT causes elevated rates of chromosome loss and cell cycle delay. Complementary live-cell imaging and electron tomography show that β-CTT is necessary to properly position kinetochores and organize microtubules within the assembling spindle. We identify a minimal region of negatively charged amino acids that is necessary and sufficient for proper chromosome segregation and provide evidence that this function may be conserved across species. Our results provide the first in vivo evidence of a specific role for tubulin CTTs in chromosome segregation. We propose that β-CTT promotes the ordered segregation of chromosomes by stabilizing the spindle and contributing to forces that move chromosomes toward the spindle poles. PMID:27053662

  1. Comprehensive meiotic segregation analysis of a 4-breakpoint t(1;3;6) complex chromosome rearrangement using single sperm array comparative genomic hybridization and FISH.

    PubMed

    Hornak, Miroslav; Vozdova, Miluse; Musilova, Petra; Prinosilova, Petra; Oracova, Eva; Linkova, Vlasta; Vesela, Katerina; Rubes, Jiri

    2014-10-01

    Complex chromosomal rearrangements (CCR) represent rare structural chromosome abnormalities frequently associated with infertility. In this study, meiotic segregation in spermatozoa of an infertile normospermic carrier of a 4-breakpoint t(1;3;6) CCR was analysed. A newly developed array comparative genomic hybridization protocol was used, and all chromosomes in 50 single sperm cells were simultaneously examined. Three-colour FISH was used to analyse chromosome segregation in 1557 other single sperm cells. It was also used to measure an interchromosomal effect; sperm chromatin structure assay was used to measure chromatin integrity. A high-frequency of unbalanced spermatozoa (84%) was observed, mostly arising from the 3:3 symmetrical segregation mode. Array comparative genomic hybridization was used to detect additional aneuploidies in two out of 50 spermatozoa (4%) in chromosomes not involved in the complex chromosome rearrangement. Significantly increased rates of diploidy and XY disomy were found in the CCR carrier compared with the control group (P < 0.001). Defective condensation of sperm chromatin was also found in 22.7% of spermatozoa by sperm chromatin structure assay. The results indicate that the infertility in the man with CCR and normal spermatozoa was caused by a production of chromosomally unbalanced, XY disomic and diploid spermatozoa and spermatozoa with defective chromatin condensation.

  2. Chromosome Segregation in Budding Yeast: Sister Chromatid Cohesion and Related Mechanisms

    PubMed Central

    2014-01-01

    Studies on budding yeast have exposed the highly conserved mechanisms by which duplicated chromosomes are evenly distributed to daughter cells at the metaphase–anaphase transition. The establishment of proteinaceous bridges between sister chromatids, a function provided by a ring-shaped complex known as cohesin, is central to accurate segregation. It is the destruction of this cohesin that triggers the segregation of chromosomes following their proper attachment to microtubules. Since it is irreversible, this process must be tightly controlled and driven to completion. Furthermore, during meiosis, modifications must be put in place to allow the segregation of maternal and paternal chromosomes in the first division for gamete formation. Here, I review the pioneering work from budding yeast that has led to a molecular understanding of the establishment and destruction of cohesion. PMID:24395824

  3. Spindle Assembly and Chromosome Segregation Requires Central Spindle Proteins in Drosophila Oocytes

    PubMed Central

    Das, Arunika; Shah, Shital J.; Fan, Bensen; Paik, Daniel; DiSanto, Daniel J.; Hinman, Anna Maria; Cesario, Jeffry M.; Battaglia, Rachel A.; Demos, Nicole; McKim, Kim S.

    2016-01-01

    Oocytes segregate chromosomes in the absence of centrosomes. In this situation, the chromosomes direct spindle assembly. It is still unclear in this system which factors are required for homologous chromosome bi-orientation and spindle assembly. The Drosophila kinesin-6 protein Subito, although nonessential for mitotic spindle assembly, is required to organize a bipolar meiotic spindle and chromosome bi-orientation in oocytes. Along with the chromosomal passenger complex (CPC), Subito is an important part of the metaphase I central spindle. In this study we have conducted genetic screens to identify genes that interact with subito or the CPC component Incenp. In addition, the meiotic mutant phenotype for some of the genes identified in these screens were characterized. We show, in part through the use of a heat-shock-inducible system, that the Centralspindlin component RacGAP50C and downstream regulators of cytokinesis Rho1, Sticky, and RhoGEF2 are required for homologous chromosome bi-orientation in metaphase I oocytes. This suggests a novel function for proteins normally involved in mitotic cell division in the regulation of microtubule–chromosome interactions. We also show that the kinetochore protein, Polo kinase, is required for maintaining chromosome alignment and spindle organization in metaphase I oocytes. In combination our results support a model where the meiotic central spindle and associated proteins are essential for acentrosomal chromosome segregation. PMID:26564158

  4. Cytomixis and meiotic abnormalities during microsporogenesis are responsible for male sterility and chromosome variations in Houttuynia cordata.

    PubMed

    Guan, J-Z; Wang, J-J; Cheng, Z-H; Liu, Y; Li, Z-Y

    2012-01-17

    Houttuynia cordata (Saururaceae) is a leaf vegetable and a medicinal herb througout much of Asia. Cytomixis and meiotic abnormalities during microsporogenesis were found in two populations of H. cordata with different ploidy levels (2n = 38, 96). Cytomixis occurred in pollen mother cells during meiosis at high frequencies and with variable degrees of chromatin/chromosome transfer. Meiotic abnormalities, such as chromosome laggards, asymmetric segregation and polyads, also prevailed in pollen mother cells at metaphase of the first division and later stages. They were caused by cytomixis and resulted in very low pollen viability and male sterility. Pollen mother cells from the population with 2n = 38 showed only simultaneous cytokinesis, but most pollen mother cells from the population with 2n = 96 showed successive cytokinesis; a minority underwent simultaneous cytokinesis. Cytomixis and irregular meiotic divisions appear to be the origin of the intraspecific polyploidy in this species, which has large variations in chromosome numbers.

  5. Meiosis I chromosome segregation is established through regulation of microtubule-kinetochore interactions.

    PubMed

    Miller, Matthew P; Unal, Elçin; Brar, Gloria A; Amon, Angelika

    2012-12-18

    During meiosis, a single round of DNA replication is followed by two consecutive rounds of nuclear divisions called meiosis I and meiosis II. In meiosis I, homologous chromosomes segregate, while sister chromatids remain together. Determining how this unusual chromosome segregation behavior is established is central to understanding germ cell development. Here we show that preventing microtubule-kinetochore interactions during premeiotic S phase and prophase I is essential for establishing the meiosis I chromosome segregation pattern. Premature interactions of kinetochores with microtubules transform meiosis I into a mitosis-like division by disrupting two key meiosis I events: coorientation of sister kinetochores and protection of centromeric cohesin removal from chromosomes. Furthermore we find that restricting outer kinetochore assembly contributes to preventing premature engagement of microtubules with kinetochores. We propose that inhibition of microtubule-kinetochore interactions during premeiotic S phase and prophase I is central to establishing the unique meiosis I chromosome segregation pattern.DOI:http://dx.doi.org/10.7554/eLife.00117.001.

  6. Co-segregation of sex chromosomes in the male black widow spider Latrodectus mactans (Araneae, Theridiidae).

    PubMed

    Ault, Jeffrey G; Felt, Kristen D; Doan, Ryan N; Nedo, Alexander O; Ellison, Cassondra A; Paliulis, Leocadia V

    2017-02-23

    During meiosis I, homologous chromosomes join together to form bivalents. Through trial and error, bivalents achieve stable bipolar orientations (attachments) on the spindle that eventually allow the segregation of homologous chromosomes to opposite poles. Bipolar orientations are stable through tension generated by poleward forces to opposite poles. Unipolar orientations lack tension and are stereotypically not stable. The behavior of sex chromosomes during meiosis I in the male black widow spider Latrodectus mactans (Araneae, Theridiidae) challenges the principles governing such a scenario. We found that male L. mactans has two distinct X chromosomes, X1 and X2. The X chromosomes join together to form a connection that is present in prometaphase I but is lost during metaphase I, before the autosomes disjoin at anaphase I. We found that both X chromosomes form stable unipolar orientations to the same pole that assure their co-segregation at anaphase I. Using micromanipulation, immunofluorescence microscopy, and electron microscopy, we studied this unusual chromosome behavior to explain how it may fit the current dogma of chromosome distribution during cell division.

  7. Oxidative stress in oocytes during midprophase induces premature loss of cohesion and chromosome segregation errors

    PubMed Central

    Perkins, Adrienne T.; Das, Thomas M.; Panzera, Lauren C.; Bickel, Sharon E.

    2016-01-01

    In humans, errors in meiotic chromosome segregation that produce aneuploid gametes increase dramatically as women age, a phenomenon termed the “maternal age effect.” During meiosis, cohesion between sister chromatids keeps recombinant homologs physically attached and premature loss of cohesion can lead to missegregation of homologs during meiosis I. A growing body of evidence suggests that meiotic cohesion deteriorates as oocytes age and contributes to the maternal age effect. One hallmark of aging cells is an increase in oxidative damage caused by reactive oxygen species (ROS). Therefore, increased oxidative damage in older oocytes may be one of the factors that leads to premature loss of cohesion and segregation errors. To test this hypothesis, we used an RNAi strategy to induce oxidative stress in Drosophila oocytes and measured the fidelity of chromosome segregation during meiosis. Knockdown of either the cytoplasmic or mitochondrial ROS scavenger superoxide dismutase (SOD) caused a significant increase in segregation errors, and heterozygosity for an smc1 deletion enhanced this phenotype. FISH analysis indicated that SOD knockdown moderately increased the percentage of oocytes with arm cohesion defects. Consistent with premature loss of arm cohesion and destabilization of chiasmata, the frequency at which recombinant homologs missegregate during meiosis I is significantly greater in SOD knockdown oocytes than in controls. Together these results provide an in vivo demonstration that oxidative stress during meiotic prophase induces chromosome segregation errors and support the model that accelerated loss of cohesion in aging human oocytes is caused, at least in part, by oxidative damage. PMID:27791141

  8. Oxidative stress in oocytes during midprophase induces premature loss of cohesion and chromosome segregation errors.

    PubMed

    Perkins, Adrienne T; Das, Thomas M; Panzera, Lauren C; Bickel, Sharon E

    2016-11-01

    In humans, errors in meiotic chromosome segregation that produce aneuploid gametes increase dramatically as women age, a phenomenon termed the "maternal age effect." During meiosis, cohesion between sister chromatids keeps recombinant homologs physically attached and premature loss of cohesion can lead to missegregation of homologs during meiosis I. A growing body of evidence suggests that meiotic cohesion deteriorates as oocytes age and contributes to the maternal age effect. One hallmark of aging cells is an increase in oxidative damage caused by reactive oxygen species (ROS). Therefore, increased oxidative damage in older oocytes may be one of the factors that leads to premature loss of cohesion and segregation errors. To test this hypothesis, we used an RNAi strategy to induce oxidative stress in Drosophila oocytes and measured the fidelity of chromosome segregation during meiosis. Knockdown of either the cytoplasmic or mitochondrial ROS scavenger superoxide dismutase (SOD) caused a significant increase in segregation errors, and heterozygosity for an smc1 deletion enhanced this phenotype. FISH analysis indicated that SOD knockdown moderately increased the percentage of oocytes with arm cohesion defects. Consistent with premature loss of arm cohesion and destabilization of chiasmata, the frequency at which recombinant homologs missegregate during meiosis I is significantly greater in SOD knockdown oocytes than in controls. Together these results provide an in vivo demonstration that oxidative stress during meiotic prophase induces chromosome segregation errors and support the model that accelerated loss of cohesion in aging human oocytes is caused, at least in part, by oxidative damage.

  9. ETOPOSIDE INDUCES CHROMOSOMAL ABNORMALITIES IN SPERMATOCYTES AND SPERMATOGONIAL STEM CELLS

    SciTech Connect

    Marchetti, F; Pearson, F S; Bishop, J B; Wyrobek, A J

    2005-07-15

    Etoposide (ET) is a chemotherapeutic agent widely used in the treatment of leukemia, lymphomas and many solid tumors, such as testicular and ovarian cancers, that affect patients in their reproductive years. The purpose of the study was to use sperm FISH analyses to characterize the long-term effects of ET on male germ cells. We used a mouse model to characterize the induction of chromosomal aberrations (partial duplications and deletions) and whole chromosomal aneuploidies in sperm of mice treated with a clinical dose of ET. Semen samples were collected at 25 and 49 days after dosing to investigate the effects of ET on meiotic pachytene cells and spermatogonial stem-cells, respectively. ET treatment resulted in major increases in the frequencies of sperm carrying chromosomal aberrations in both meiotic pachytene (27- to 578-fold) and spermatogonial stem-cells (8- to 16-fold), but aneuploid sperm were induced only after treatment of meiotic cells (27-fold) with no persistent effects in stem cells. These results demonstrate that male meiotic germ cells are considerably more sensitive to ET than spermatogonial stem-cell and that increased frequencies of sperm with structural aberrations persist after spermatogonial stem-cell treatment. These findings predict that patients who undergo chemotherapy with ET may have transient elevations in the frequencies of aneuploid sperm, but more importantly, may have persistent elevations in the frequencies of sperm with chromosomal aberrations, placing them at higher risk for abnormal reproductive outcomes long after the end of their chemotherapy.

  10. Diagnosis of four chromosome abnormalities of unknown origin by chromosome microdissection and subsequent reverse and forward painting

    SciTech Connect

    Coelho, K.E.F.A. de; Egashira, M.; Kato, R.

    1996-06-14

    A molecular cytogenetic method consisting of chromosome microdissection and subsequent reverse/forward chromosome painting is a powerful tool to identify chromosome abnormalities of unknown origin. We present 4 cases of chromosome structural abnormalities whose origins were ascertained by this method. In one MCA/MR patient with an add(5q)chromosome, fluorescence in situ hybridization (FISH), using probes generated from a microdissected additional segment of the add(5q) chromosome and then from a distal region of normal chromosome 5, confirmed that the patient had a tandem duplication for a 5q35-qter segment. Similarly, we ascertained that an additional segment of an add(3p) chromosome in another MCA/MR patient had been derived from a 7q32-qter segment. In a woman with a history of successive spontaneous abortions and with a minute marker chromosome, painting using microdissected probes from the whole marker chromosome revealed that it was i(15)(p10) or psu dic(15;15)(q11;q11). Likewise, a marker observed in a fetus was a ring chromosome derived from the paracentromeric region of chromosome 19. We emphasize the value of the microdissection-based chromosome painting method in the identification of unknown chromosomes, especially for marker chromosomes. The method may contribute to a collection of data among patients with similar or identical chromosome abnormalities, which may lead to a better clinical syndrome delineation. 15 refs., 2 figs.

  11. “Genome-wide recombination and chromosome segregation in human oocytes and embryos reveal selection for maternal recombination rates”

    PubMed Central

    Natesan, Senthilkumar A.; Joshi, Hrishikesh A.; Cimadomo, Danilo; Griffin, Darren K.; Sage, Karen; Summers, Michael C.; Thornhill, Alan R.; Housworth, Elizabeth; Herbert, Alex D.; Rienzi, Laura; Ubaldi, Filippo M.; Handyside, Alan H.; Hoffmann, Eva R.

    2015-01-01

    Crossover recombination reshuffles genes and prevents errors in segregation that lead to extra or missing chromosomes (aneuploidy) in human eggs, a major cause of pregnancy failure and congenital disorders. Here, we generate genome-wide maps of crossovers and chromosome segregation patterns by recovering all three products of single female meioses. Genotyping > 4 million informative single-nucleotide polymorphisms (SNPs) from 23 complete meioses allowed us to map 2,032 maternal and 1,342 paternal crossovers and to infer the segregation patterns of 529 chromosome pairs. We uncover a novel reverse chromosome segregation pattern in which both homologs separate their sister chromatids at meiosis I; detect selection for higher recombination rates in the female germline by the elimination of aneuploid embryos; and report chromosomal drive against non-recombinant chromatids at meiosis II. Collectively, our findings reveal that recombination not only affects homolog segregation at meiosis I but also the fate of sister chromatids at meiosis II. PMID:25985139

  12. Different chromosome Y abnormalities in a case with short stature.

    PubMed

    Balkan, Mahmut; Fidanboy, Mehmet; Özbek, M Nuri; Alp, M Nail; Budak, Turgay

    2012-12-01

    We report a case with different chromosome Y abnormalities. Case was an 11-year-old boy, who was diagnosed with short stature, referred to laboratory of human medical genetics laboratory for genetic evaluation. Chromosomal analysis of the case was carried out on peripheral blood lymphocyte culture. Classic cytogenetic analysis (G and C banding) was confirmed by using fluorescence in situ hybridization analysis (FISH) technique. Cytogenetic and FISH analysis showed a mosaic 46,X,i(Yq)/45,X/47,X,i(Yq)x2/47,XYY karyotype. Case, which was found interesting due to its rarity, is discussed with its clinical features and cytogenetic results, in the light of relevant source information. This case underlines the importance of karyotyping patients with unexplained short stature. This clinical report also will be helpful in defining the phenotypic range associated with these karyotypes.

  13. Prevalence of chromosomal abnormalities and Y chromosome microdeletion among men with severe semen abnormalities and its correlation with successful sperm retrieval

    PubMed Central

    Mascarenhas, Mariano; Thomas, Sumi; Kamath, Mohan S.; Ramalingam, Ramya; Kongari, Ann Marie; Yuvarani, S; Srivastava, Vivi M.; George, Korula

    2016-01-01

    AIM: To estimate the prevalence of chromosomal abnormalities and Y chromosome microdeletion among men with azoospermia and severe oligozoospermia and its correlation with successful surgical sperm retrieval. SETTING AND DESIGN: A prospective study in a tertiary level infertility unit. MATERIALS AND METHODS: In a prospective observation study, men with azoospermia and severe oligozoospermia (concentration <5 million/ml) attending the infertility center underwent genetic screening. Peripheral blood karyotype was done by Giemsa banding. Y chromosome microdeletion study was performed by a multiplex polymerase chain reaction. RESULTS: The study group consisted of 220 men, 133 of whom had azoospermia and 87 had severe oligozoospermia. Overall, 21/220 (9.5%) men had chromosomal abnormalities and 13/220 (5.9%) men had Y chromosome microdeletions. Chromosomal abnormalities were seen in 14.3% (19/133) of azoospermic men and Y chromosome microdeletions in 8.3% (11/133). Of the 87 men with severe oligozoospermia, chromosomal abnormalities and Y chromosome microdeletions were each seen in 2.3% (2/87). Testicular sperm aspiration was done in 13 men and was successful in only one, who had a deletion of azoospermia factor c. CONCLUSIONS: Our study found a fairly high prevalence of genetic abnormality in men with severe semen abnormalities and a correlation of genetic abnormalities with surgical sperm retrieval outcomes. These findings support the need for genetic screening of these men prior to embarking on surgical sperm retrieval and assisted reproductive technology intracytoplasmic sperm injection. PMID:27803587

  14. Meiotic segregation of sex chromosomes in mosaic and non-mosaic XYY males: case reports and review of the literature.

    PubMed

    Rives, N; Siméon, N; Milazzo, J P; Barthélémy, C; Macé, B

    2003-08-01

    The aim of this study was to determine the incidence of sex chromosome aneuploidy in spermatozoa of two males with a 47,XYY karyotype and one male with a 46,XY/47,XYY constitution. Spermatozoa obtained from two oligospermic patients and one volunteer semen donor were studied by multicolour fluorescence in situ hybridization. In the XY/XYY male, the frequencies of X-bearing to Y-bearing sperm were significantly different from the 1 : 1 expected ratio. Significantly increased frequencies were found in the mosaic and non-mosaic males for 24,XX and 24,YY sperm when compared with control donors. The number of 24,XY sperm was significantly different from the controls in the XYY males, but not in the mosaic male. The incidence of disomy 18 and the rate of diploidy also increased in the three patients. However, the mosaic male had the lowest cumulative rate of disomic and diploid spermatozoa when compared with the two XYY patients. Our data suggest that: (i) chromosome abnormalities observed in spermatozoa of the two XYY oligoasthenoteratospermic (OAT) males arise through segregation errors in XY germ cells rather than normal meiosis of XYY germ cells, (ii) mosaic XYY males with normal semen parameters have a lower risk of producing offspring with a sex chromosomal abnormality than OAT males with XYY karyotype.

  15. Nonrandom sister chromatid segregation of sex chromosomes in Drosophila male germline stem cells.

    PubMed

    Yamashita, Yukiko M

    2013-05-01

    Sister chromatids are the product of DNA replication, which is assumed to be a very precise process. Therefore, sister chromatids should be exact copies of each other. However, reports have indicated that sister chromatids are segregated nonrandomly during cell division, suggesting that sister chromatids are not the same, although their DNA sequences are the same. Researchers have speculated that stem cells may retain template strands to avoid replication-induced mutations. An alternative proposal is that cells may segregate distinct epigenetic information carried on sister chromatids. Recently, we found that Drosophila male germline stem cells segregate sister chromatids of X and Y chromosomes with a strong bias. We discuss this finding in relation to existing models for nonrandom sister chromatid segregation.

  16. Autophagy is required for efficient meiosis progression and proper meiotic chromosome segregation in fission yeast.

    PubMed

    Matsuhara, Hirotada; Yamamoto, Ayumu

    2016-01-01

    Autophagy is a conserved intracellular degradation system, which contributes to development and differentiation of various organisms. Yeast cells undergo meiosis under nitrogen-starved conditions and require autophagy for meiosis initiation. However, the precise roles of autophagy in meiosis remain unclear. Here, we show that autophagy is required for efficient meiosis progression and proper meiotic chromosome segregation in fission yeast. Autophagy-defective strains bearing a mutation in the autophagy core factor gene atg1, atg7, or atg14 exhibit deformed nuclear structures during meiosis. These mutant cells require an extracellular nitrogen supply for meiosis progression following their entry into meiosis and show delayed meiosis progression even with a nitrogen supply. In addition, they show frequent chromosome dissociation from the spindle together with spindle overextension, forming extra nuclei. Furthermore, Aurora kinase, which regulates chromosome segregation and spindle elongation, is significantly increased at the centromere and spindle in the mutant cells. Aurora kinase down-regulation eliminated delayed initiation of meiosis I and II, chromosome dissociation, and spindle overextension, indicating that increased Aurora kinase activity may cause these aberrances in the mutant cells. Our findings show a hitherto unrecognized relationship of autophagy with the nuclear structure, regulation of cell cycle progression, and chromosome segregation in meiosis.

  17. [Diagnosis of MDS: morphology, chromosome abnormalities and genetic mutations].

    PubMed

    Hata, Tomoko

    2015-10-01

    Myelodysplastic syndromes (MDS) are a group of hematological neoplasms associated with ineffective hematopoiesis and that can transform into acute leukemia. The clinical classification of MDS which is defined by cytopenia, the rate of blasts in peripheral blood and bone marrow, dysplasia, and chromosomal abnormalities, has undergone continuous revision. To increase the accuracy of dysplastic evaluation, IWGM-MDS and the Research Committee for Idiopathic Hematopoietic Disorders, Ministry of Health, Labour and Welfare, Japan have proposed a quantitative and qualitative definition of dysplasia. Recently, refining the definition of dysgranulopoiesis was proposed by IWGM-MDS. Neutrophils with abnormal clumping of chromatin, and harboring more than 4 nuclear projections, were recognized as dysplastic features. At present, karyotypic abnormalities are detected in approximately 50% of de novo MDS and these remain the most critical prognostic factor. In the new cytogenetic scoring system, cytogenetic abnormalities were classified into five prognostic subgroups. This new classification was adopted by the revised IPSS. Approximately 80% to 90% of MDS patients have detectable mutations by whole-exon sequencing or whole genome sequencing. Many genetic mutations had biological and prognostic significance. It is important to further understand the utility of this factor in determining prognosis and in selecting among therapeutic options.

  18. KDM4C Activity Modulates Cell Proliferation and Chromosome Segregation in Triple-Negative Breast Cancer

    PubMed Central

    Garcia, Jeison; Lizcano, Fernando

    2016-01-01

    The Jumonji-containing domain protein, KDM4C, is a histone demethylase associated with the development of several forms of human cancer. However, its specific function in the viability of tumoral lineages is yet to be determined. This work investigates the importance of KDM4C activity in cell proliferation and chromosome segregation of three triple-negative breast cancer cell lines using a specific demethylase inhibitor. Immunofluorescence assays show that KDM4C is recruited to mitotic chromosomes and that the modulation of its activity increases the number of mitotic segregation errors. However, 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) cell proliferation assays demonstrate that the demethylase activity is required for cell viability. These results suggest that the histone demethylase activity of KDM4C is essential for breast cancer progression given its role in the maintenance of chromosomal stability and cell growth, thus highlighting it as a potential therapeutic target. PMID:27840577

  19. Connecting the dots of the bacterial cell cycle: Coordinating chromosome replication and segregation with cell division.

    PubMed

    Hajduk, Isabella V; Rodrigues, Christopher D A; Harry, Elizabeth J

    2016-05-01

    Proper division site selection is crucial for the survival of all organisms. What still eludes us is how bacteria position their division site with high precision, and in tight coordination with chromosome replication and segregation. Until recently, the general belief, at least in the model organisms Bacillus subtilis and Escherichia coli, was that spatial regulation of division comes about by the combined negative regulatory mechanisms of the Min system and nucleoid occlusion. However, as we review here, these two systems cannot be solely responsible for division site selection and we highlight additional regulatory mechanisms that are at play. In this review, we put forward evidence of how chromosome replication and segregation may have direct links with cell division in these bacteria and the benefit of recent advances in chromosome conformation capture techniques in providing important information about how these three processes mechanistically work together to achieve accurate generation of progenitor cells.

  20. Chromosome abnormalities in human arrested preimplantation embryos: A multiple-probe FISH study

    SciTech Connect

    Munne, S.; Grifo, J.; Cohen, J. ); Weier, H.U.G. )

    1994-07-01

    Numerical chromosome abnormalities were studied in single blastomeres from arrested or otherwise morphologically abnormal human preimplantation embryos. A 6-h FISH procedure with fluorochrome-labeled DNA probes was developed to determine numerical abnormalities of chromosomes X, Y, and 18. The three chromosomes were stained and detected simultaneously in 571 blastomeres from 131 embryos. Successful analysis including biopsy, fixation, and FISH analysis was achieved in 86.5% of all blastomeres. The procedure described here offers a reliable alternative to sexing of embryos by PCR and allows simultaneous ploidy assessment. For the three chromosomes tested, numerical aberrations were found in 56.5% of the embroys. Most abnormal embryos were polyploid or mosaics, and 6.1% were aneuploid for gonosomes or chromosome 18. Extrapolation of these results to all human chromosomes suggests that the majority of abnormally developing and arrested human embryos carry numerical chromosome abnormalities. 44 refs., 1 fig., 4 tabs.

  1. A septal chromosome segregator protein evolved into a conjugative DNA-translocator protein

    PubMed Central

    Sepulveda, Edgardo; Vogelmann, Jutta

    2011-01-01

    Streptomycetes, Gram-positive soil bacteria well known for the production of antibiotics feature a unique conjugative DNA transfer system. In contrast to classical conjugation which is characterized by the secretion of a pilot protein covalently linked to a single-stranded DNA molecule, in Streptomyces a double-stranded DNA molecule is translocated during conjugative transfer. This transfer involves a single plasmid encoded protein, TraB. A detailed biochemical and biophysical characterization of TraB, revealed a close relationship to FtsK, mediating chromosome segregation during bacterial cell division. TraB translocates plasmid DNA by recognizing 8-bp direct repeats located in a specific plasmid region clt. Similar sequences accidentally also occur on chromosomes and have been shown to be bound by TraB. We suggest that TraB mobilizes chromosomal genes by the interaction with these chromosomal clt-like sequences not relying on the integration of the conjugative plasmid into the chromosome. PMID:22479692

  2. The Drosophila l(1)zw10 gene product, required for accurate mitotic chromosome segregation, is redistributed at anaphase onset

    PubMed Central

    1992-01-01

    Mutations in the gene l(1)zw10 disrupt the accuracy of chromosome segregation in a variety of cell types during the course of Drosophila development. Cytological analysis of mutant larval brain neuroblasts shows very high levels of aneuploid cells. Many anaphase figures are aberrant, the most frequent abnormality being the presence of lagging chromosomes that remain in the vicinity of the metaphase plate when the other chromosomes have migrated toward the spindle poles. Finally, the centromeric connection between sister chromatids in mutant neuroblasts treated with colchicine often appears to be broken, in contrast with similarly treated control neuroblasts. The 85-kD protein encoded by the l(1)zw10 locus displays a dynamic pattern of localization in the course of the embryonic cell cycle. It is excluded from the nuclei during interphase, but migrates into the nuclear zone during prometaphase. At metaphase, the zw10 antigen is found in a novel filamentous structure that may be specifically associated with kinetochore microtubules. Upon anaphase onset, there is an extremely rapid redistribution of the zw10 protein to a location at or near the kinetochores of the separating chromosomes. PMID:1339459

  3. Robin sequence associated with karyotypic mosaicism involving chromosome 22 abnormalities

    SciTech Connect

    Salinas, C.F.; Jastrzab, J.M.; Centu, E.S.

    1994-09-01

    Robin sequence is characterized by cleft palate, hypoplastic mandible, glossoptosis and respiratory difficulties. The Robin sequence may be observed as an isolated defect or as part of about 33 syndromes; however, to our knowledge, it has never been reported associated with chromosome 22 abnormalities. We examined a two-month-old black boy with a severe case of Robin sequence. Exam revealed a small child with hypoplastic mandible, glossoptosis, high palate and respiratory difficulty with continuous apnea episodes resulting in cyanotic lips and nails. In order to relieve the upper airway obstruction, his tongue was attached to the lower lip. Later a tracheostomy was performed. On follow-up exam, this patient was found to have developmental delay. Cytogenetic studies of both peripheral blood and fibroblast cells showed mosaicism involving chromosome 22 abnormalities which were designated as follows: 45,XY,-22/46,XY,-22,+r(22)/46,XY. Fluorescence in situ hybridization (FISH) studies confirmed the identity of the r(22) and showed the presence of the DiGeorge locus (D22575) but the absence of the D22539 locus which maps to 22q13.3. Reported cases of r(22) show no association with Robin sequence. However, r(22) has been associated with flat bridge of the nose, bulbous tip of the nose, epicanthus and high palate, all characteristics that we also observed in this case. These unusual cytogenetic findings may be causally related to the dysmorphology found in the patient we report.

  4. Complex polar machinery required for proper chromosome segregation in vegetative and sporulating cells of Bacillus subtilis

    PubMed Central

    Kloosterman, Tomas G.; Lenarcic, Rok; Willis, Clare R.; Roberts, David M.; Hamoen, Leendert W.; Errington, Jeff

    2016-01-01

    Summary Chromosome segregation is an essential process of cell multiplication. In prokaryotes, segregation starts with the newly replicated sister origins of replication, oriCs, which move apart to defined positions in the cell. We have developed a genetic screen to identify mutants defective in placement of oriC during spore development in the Gram‐positive bacterium Bacillus subtilis. In addition to the previously identified proteins Soj and DivIVA, our screen identified several new factors involved in polar recruitment of oriC: a reported regulator of competence ComN, and the regulators of division site selection MinD and MinJ. Previous work implicated Soj as an important regulator of oriC positioning in the cell. Our results suggest a model in which the DivIVA‐interacting proteins ComN and MinJ recruit MinD to the cell pole, and that these proteins work upstream of Soj to enable oriC placement. We show that these proteins form a polar complex, which acts in parallel with but distinct from the sporulation‐specific RacA pathway of oriC placement, and also functions during vegetative growth. Our study further shows that MinD has two distinct cell cycle roles, in cell division and chromosome segregation, and highlights that cell probably use multiple parallel mechanisms to ensure accurate chromosome segregation. PMID:27059541

  5. Phosphorylation of PP1 Regulator Sds22 by PLK1 Ensures Accurate Chromosome Segregation.

    PubMed

    Duan, Hequan; Wang, Chunli; Wang, Ming; Gao, Xinjiao; Yan, Maomao; Akram, Saima; Peng, Wei; Zou, Hanfa; Wang, Dong; Zhou, Jiajia; Chu, Youjun; Dou, Zhen; Barrett, Gregory; Green, Hadiyah-Nichole; Wang, Fangjun; Tian, Ruijun; He, Ping; Wang, Wenwen; Liu, Xing; Yao, Xuebiao

    2016-09-30

    During cell division, accurate chromosome segregation is tightly regulated by Polo-like kinase 1 (PLK1) and opposing activities of Aurora B kinase and protein phosphatase 1 (PP1). However, the regulatory mechanisms underlying the aforementioned hierarchical signaling cascade during mitotic chromosome segregation have remained elusive. Sds22 is a conserved regulator of PP1 activity, but how it regulates PP1 activity in space and time during mitosis remains elusive. Here we show that Sds22 is a novel and cognate substrate of PLK1 in mitosis, and the phosphorylation of Sds22 by PLK1 elicited an inhibition of PP1-mediated dephosphorylation of Aurora B at threonine 232 (Thr(232)) in a dose-dependent manner. Overexpression of a phosphomimetic mutant of Sds22 causes a dramatic increase in mitotic delay, whereas overexpression of a non-phosphorylatable mutant of Sds22 results in mitotic arrest. Mechanistically, the phosphorylation of Sds22 by PLK1 strengthens the binding of Sds22 to PP1 and inhibits the dephosphorylation of Thr(232) of Aurora B to ensure a robust, error-free metaphase-anaphase transition. These findings delineate a conserved signaling hierarchy that orchestrates dynamic protein phosphorylation and dephosphorylation of critical mitotic regulators during chromosome segregation to guard chromosome stability.

  6. Large-Scale Selective Sweep among Segregation Distorter Chromosomes in African Populations of Drosophila melanogaster

    PubMed Central

    Presgraves, Daven C.; Gérard, Pierre R.; Cherukuri, Anjuli; Lyttle, Terrence W.

    2009-01-01

    Segregation Distorter (SD) is a selfish, coadapted gene complex on chromosome 2 of Drosophila melanogaster that strongly distorts Mendelian transmission; heterozygous SD/SD + males sire almost exclusively SD-bearing progeny. Fifty years of genetic, molecular, and theory work have made SD one of the best-characterized meiotic drive systems, but surprisingly the details of its evolutionary origins and population dynamics remain unclear. Earlier analyses suggested that the SD system arose recently in the Mediterranean basin and then spread to a low, stable equilibrium frequency (1–5%) in most natural populations worldwide. In this report, we show, first, that SD chromosomes occur in populations in sub-Saharan Africa, the ancestral range of D. melanogaster, at a similarly low frequency (∼2%), providing evidence for the robustness of its equilibrium frequency but raising doubts about the Mediterranean-origins hypothesis. Second, our genetic analyses reveal two kinds of SD chromosomes in Africa: inversion-free SD chromosomes with little or no transmission advantage; and an African-endemic inversion-bearing SD chromosome, SD-Mal, with a perfect transmission advantage. Third, our population genetic analyses show that SD-Mal chromosomes swept across the African continent very recently, causing linkage disequilibrium and an absence of variability over 39% of the length of the second chromosome. Thus, despite a seemingly stable equilibrium frequency, SD chromosomes continue to evolve, to compete with one another, or evade suppressors in the genome. PMID:19412335

  7. Unique Function of the Bacterial Chromosome Segregation Machinery in Apically Growing Streptomyces - Targeting the Chromosome to New Hyphal Tubes and its Anchorage at the Tips

    PubMed Central

    Lipietta, Natalia; Tilley, Emma; Zakrzewska-Czerwińska, Jolanta; Herron, Paul

    2016-01-01

    The coordination of chromosome segregation with cell growth is fundamental to the proliferation of any organism. In most unicellular bacteria, chromosome segregation is strictly coordinated with cell division and involves ParA that moves the ParB nucleoprotein complexes bi- or unidirectionally toward the cell pole(s). However, the chromosome organization in multiploid, apically extending and branching Streptomyces hyphae challenges the known mechanisms of bacterial chromosome segregation. The complex Streptomyces life cycle involves two stages: vegetative growth and sporulation. In the latter stage, multiple cell divisions accompanied by chromosome compaction and ParAB assisted segregation turn multigenomic hyphal cell into a chain of unigenomic spores. However, the requirement for active chromosome segregation is unclear in the absence of canonical cell division during vegetative growth except in the process of branch formation. The mechanism by which chromosomes are targeted to new hyphae in streptomycete vegetative growth has remained unknown until now. Here, we address the question of whether active chromosome segregation occurs at this stage. Applied for the first time in Streptomyces, labelling of the chromosomal replication initiation region (oriC) and time-lapse microscopy, revealed that in vegetative hyphae every copy of the chromosome is complexed with ParB, whereas ParA, through interaction with the apical protein complex (polarisome), tightly anchors only one chromosome at the hyphal tip. The anchor is maintained during replication, when ParA captures one of the daughter oriCs. During spore germination and branching, ParA targets one of the multiple chromosomal copies to the new hyphal tip, enabling efficient elongation of hyphal tube. Thus, our studies reveal a novel role for ParAB proteins during hyphal tip establishment and extension. PMID:27977672

  8. Mitotic Spindle Disruption by Alternating Electric Fields Leads to Improper Chromosome Segregation and Mitotic Catastrophe in Cancer Cells

    PubMed Central

    Giladi, Moshe; Schneiderman, Rosa S; Voloshin, Tali; Porat, Yaara; Munster, Mijal; Blat, Roni; Sherbo, Shay; Bomzon, Zeev; Urman, Noa; Itzhaki, Aviran; Cahal, Shay; Shteingauz, Anna; Chaudhry, Aafia; Kirson, Eilon D; Weinberg, Uri; Palti, Yoram

    2015-01-01

    Tumor Treating Fields (TTFields) are low intensity, intermediate frequency, alternating electric fields. TTFields are a unique anti-mitotic treatment modality delivered in a continuous, noninvasive manner to the region of a tumor. It was previously postulated that by exerting directional forces on highly polar intracellular elements during mitosis, TTFields could disrupt the normal assembly of spindle microtubules. However there is limited evidence directly linking TTFields to an effect on microtubules. Here we report that TTFields decrease the ratio between polymerized and total tubulin, and prevent proper mitotic spindle assembly. The aberrant mitotic events induced by TTFields lead to abnormal chromosome segregation, cellular multinucleation, and caspase dependent apoptosis of daughter cells. The effect of TTFields on cell viability and clonogenic survival substantially depends upon the cell division rate. We show that by extending the duration of exposure to TTFields, slowly dividing cells can be affected to a similar extent as rapidly dividing cells. PMID:26658786

  9. Chromosome abnormalities and the genetics of congenital corneal opacification

    PubMed Central

    Mataftsi, A.; Islam, L.; Kelberman, D.; Sowden, J.C.

    2011-01-01

    Congenital corneal opacification (CCO) encompasses a broad spectrum of disorders that have different etiologies, including genetic and environmental. Terminology used in clinical phenotyping is commonly not specific enough to describe separate entities, for example both the terms Peters anomaly and sclerocornea have been ascribed to a clinical picture of total CCO, without investigating the presence or absence of iridocorneal adhesions. This is not only confusing but also unhelpful in determining valid genotype-phenotype correlations, and thereby revealing clues for pathogenesis. We undertook a systematic review of the literature focusing on CCO as part of anterior segment developmental anomalies (ASDA), and analyzed its association specifically with chromosomal abnormalities. Genes previously identified as being associated with CCO are also summarized. All reports were critically appraised to classify phenotypes according to described features, rather than the given diagnosis. Some interesting associations were found, and are discussed. PMID:21738392

  10. Chromosome abnormalities and the genetics of congenital corneal opacification.

    PubMed

    Mataftsi, A; Islam, L; Kelberman, D; Sowden, J C; Nischal, K K

    2011-01-01

    Congenital corneal opacification (CCO) encompasses a broad spectrum of disorders that have different etiologies, including genetic and environmental. Terminology used in clinical phenotyping is commonly not specific enough to describe separate entities, for example both the terms Peters anomaly and sclerocornea have been ascribed to a clinical picture of total CCO, without investigating the presence or absence of iridocorneal adhesions. This is not only confusing but also unhelpful in determining valid genotype-phenotype correlations, and thereby revealing clues for pathogenesis. We undertook a systematic review of the literature focusing on CCO as part of anterior segment developmental anomalies (ASDA), and analyzed its association specifically with chromosomal abnormalities. Genes previously identified as being associated with CCO are also summarized. All reports were critically appraised to classify phenotypes according to described features, rather than the given diagnosis. Some interesting associations were found, and are discussed.

  11. Functional Characterization of CENP-A Post-Translational Modifications in Chromosome Segregation

    DTIC Science & Technology

    2014-07-01

    merits further studies . We established that CENP-A α-amino tri-methylation is required for ensuring high fidelity of chromosome segregation, and hence...showed loss of centromeric staining indicating it is specific to methylated CENP-A (included in the proposal) (Fig.1A). We also depleted CENP-A...results indicating that the newly raised antibody recognize methylated CENP-A. Our previous results show that CENP-A N-terminal methionine is

  12. Chromosome segregation impacts on cell growth and division site selection in Corynebacterium glutamicum.

    PubMed

    Donovan, Catriona; Schauss, Astrid; Krämer, Reinhard; Bramkamp, Marc

    2013-01-01

    Spatial and temporal regulation of bacterial cell division is imperative for the production of viable offspring. In many rod-shaped bacteria, regulatory systems such as the Min system and nucleoid occlusion ensure the high fidelity of midcell divisome positioning. However, regulation of division site selection in bacteria lacking recognizable Min and nucleoid occlusion remains less well understood. Here, we describe one such rod-shaped organism, Corynebacterium glutamicum, which does not always place the division septum precisely at midcell. Here we now show at single cell level that cell growth and division site selection are spatially and temporally regulated by chromosome segregation. Mutants defective in chromosome segregation have more variable cell growth and aberrant placement of the division site. In these mutants, division septa constrict over and often guillotine the nucleoid, leading to nonviable, DNA-free cells. Our results suggest that chromosome segregation or some nucleoid associated factor influences growth and division site selection in C. glutamicum. Understanding growth and regulation of C. glutamicum cells will also be of importance to develop strains for industrial production of biomolecules, such as amino acids.

  13. Chromosome Segregation Impacts on Cell Growth and Division Site Selection in Corynebacterium glutamicum

    PubMed Central

    Donovan, Catriona; Schauss, Astrid; Krämer, Reinhard; Bramkamp, Marc

    2013-01-01

    Spatial and temporal regulation of bacterial cell division is imperative for the production of viable offspring. In many rod-shaped bacteria, regulatory systems such as the Min system and nucleoid occlusion ensure the high fidelity of midcell divisome positioning. However, regulation of division site selection in bacteria lacking recognizable Min and nucleoid occlusion remains less well understood. Here, we describe one such rod-shaped organism, Corynebacterium glutamicum, which does not always place the division septum precisely at midcell. Here we now show at single cell level that cell growth and division site selection are spatially and temporally regulated by chromosome segregation. Mutants defective in chromosome segregation have more variable cell growth and aberrant placement of the division site. In these mutants, division septa constrict over and often guillotine the nucleoid, leading to nonviable, DNA-free cells. Our results suggest that chromosome segregation or some nucleoid associated factor influences growth and division site selection in C. glutamicum. Understanding growth and regulation of C. glutamicum cells will also be of importance to develop strains for industrial production of biomolecules, such as amino acids. PMID:23405112

  14. Identification of Conserved MEL-28/ELYS Domains with Essential Roles in Nuclear Assembly and Chromosome Segregation

    PubMed Central

    Hirano, Yasuhiro; Mauro, Michael; Lai, Allison; Ayuso, Cristina; Haraguchi, Tokuko; Hiraoka, Yasushi; Piano, Fabio

    2016-01-01

    Nucleoporins are the constituents of nuclear pore complexes (NPCs) and are essential regulators of nucleocytoplasmic transport, gene expression and genome stability. The nucleoporin MEL-28/ELYS plays a critical role in post-mitotic NPC reassembly through recruitment of the NUP107-160 subcomplex, and is required for correct segregation of mitotic chromosomes. Here we present a systematic functional and structural analysis of MEL-28 in C. elegans early development and human ELYS in cultured cells. We have identified functional domains responsible for nuclear envelope and kinetochore localization, chromatin binding, mitotic spindle matrix association and chromosome segregation. Surprisingly, we found that perturbations to MEL-28’s conserved AT-hook domain do not affect MEL-28 localization although they disrupt MEL-28 function and delay cell cycle progression in a DNA damage checkpoint-dependent manner. Our analyses also uncover a novel meiotic role of MEL-28. Together, these results show that MEL-28 has conserved structural domains that are essential for its fundamental roles in NPC assembly and chromosome segregation. PMID:27341616

  15. Identification of Conserved MEL-28/ELYS Domains with Essential Roles in Nuclear Assembly and Chromosome Segregation.

    PubMed

    Gómez-Saldivar, Georgina; Fernandez, Anita; Hirano, Yasuhiro; Mauro, Michael; Lai, Allison; Ayuso, Cristina; Haraguchi, Tokuko; Hiraoka, Yasushi; Piano, Fabio; Askjaer, Peter

    2016-06-01

    Nucleoporins are the constituents of nuclear pore complexes (NPCs) and are essential regulators of nucleocytoplasmic transport, gene expression and genome stability. The nucleoporin MEL-28/ELYS plays a critical role in post-mitotic NPC reassembly through recruitment of the NUP107-160 subcomplex, and is required for correct segregation of mitotic chromosomes. Here we present a systematic functional and structural analysis of MEL-28 in C. elegans early development and human ELYS in cultured cells. We have identified functional domains responsible for nuclear envelope and kinetochore localization, chromatin binding, mitotic spindle matrix association and chromosome segregation. Surprisingly, we found that perturbations to MEL-28's conserved AT-hook domain do not affect MEL-28 localization although they disrupt MEL-28 function and delay cell cycle progression in a DNA damage checkpoint-dependent manner. Our analyses also uncover a novel meiotic role of MEL-28. Together, these results show that MEL-28 has conserved structural domains that are essential for its fundamental roles in NPC assembly and chromosome segregation.

  16. Mad2, Bub3, and Mps1 regulate chromosome segregation and mitotic synchrony in Giardia intestinalis, a binucleate protist lacking an anaphase-promoting complex

    PubMed Central

    Vicente, Juan-Jesus; Cande, W. Zacheus

    2014-01-01

    The binucleate pathogen Giardia intestinalis is a highly divergent eukaryote with a semiopen mitosis, lacking an anaphase-promoting complex/cyclosome (APC/C) and many of the mitotic checkpoint complex (MCC) proteins. However, Giardia has some MCC components (Bub3, Mad2, and Mps1) and proteins from the cohesin system (Smc1 and Smc3). Mad2 localizes to the cytoplasm, but Bub3 and Mps1 are either located on chromosomes or in the cytoplasm, depending on the cell cycle stage. Depletion of Bub3, Mad2, or Mps1 resulted in a lowered mitotic index, errors in chromosome segregation (including lagging chromosomes), and abnormalities in spindle morphology. During interphase, MCC knockdown cells have an abnormal number of nuclei, either one nucleus usually on the left-hand side of the cell or two nuclei with one mislocalized. These results suggest that the minimal set of MCC proteins in Giardia play a major role in regulating many aspects of mitosis, including chromosome segregation, coordination of mitosis between the two nuclei, and subsequent nuclear positioning. The critical importance of MCC proteins in an organism that lacks their canonical target, the APC/C, suggests a broader role for these proteins and hints at new pathways to be discovered. PMID:25057014

  17. The contribution of chromosomal abnormalities to congenital heart defects: a population-based study.

    PubMed

    Hartman, Robert J; Rasmussen, Sonja A; Botto, Lorenzo D; Riehle-Colarusso, Tiffany; Martin, Christa L; Cragan, Janet D; Shin, Mikyong; Correa, Adolfo

    2011-12-01

    We aimed to assess the frequency of chromosomal abnormalities among infants with congenital heart defects (CHDs) in an analysis of population-based surveillance data. We reviewed data from the Metropolitan Atlanta Congenital Defects Program, a population-based birth-defects surveillance system, to assess the frequency of chromosomal abnormalities among live-born infants and fetal deaths with CHDs delivered from January 1, 1994, to December 31, 2005. Among 4430 infants with CHDs, 547 (12.3%) had a chromosomal abnormality. CHDs most likely to be associated with a chromosomal abnormality were interrupted aortic arch (type B and not otherwise specified; 69.2%), atrioventricular septal defect (67.2%), and double-outlet right ventricle (33.3%). The most common chromosomal abnormalities observed were trisomy 21 (52.8%), trisomy 18 (12.8%), 22q11.2 deletion (12.2%), and trisomy 13 (5.7%). In conclusion, in our study, approximately 1 in 8 infants with a CHD had a chromosomal abnormality. Clinicians should have a low threshold at which to obtain testing for chromosomal abnormalities in infants with CHDs, especially those with certain types of CHDs. Use of new technologies that have become recently available (e.g., chromosomal microarray) may increase the identified contribution of chromosomal abnormalities even further.

  18. [The relationship between clinical outcomes of reproduc-tive abnormalities and chromosome polymorphism].

    PubMed

    Wang, Xiao-Rong; Deng, Jian-Xia; Li, Jin-Jin

    2007-11-01

    To study the relationship between chromosome polymorphism and clinical effect of reproductive abnormalities, we prepared chromosomes from peripheral blood lymphocytes and carried out G/C banding and karyotype analyses. Out of 1 414 cases who came in for genetic counseling, 273 had chromosome abnormalities. Among these 273 cases, 180 cases (65.93%) were karyotype variations, with the remaining 93 cases (34.07%) being non-polymorphic chromosomal abnormalities. Karyotype variations included 10 cases of satellite increases in the D/G group, 35 cases of secondary constriction increases, 99 cases of big or small Y chromosome, 6 cases of pericentric inversion of chromosome Y and 30 cases of pericentric inversion of chromosome 9. These results indicated that clinical effect such as abortion, sterility, stillbirth and congenital malformation are mainly related to chromosome polymorphisms.

  19. Sex ratio in normal and disomic sperm: Evidence that the extra chromosome 21 preferentially segregates with the Y chromosome

    SciTech Connect

    Griffin, D.K.; Millie, E.A.; Hassold, T.J. |

    1996-11-01

    In humans, deviations from a 1:1 male:female ratio have been identified in both chromosomally normal and trisomic live births: among normal newborns there is a slight excess of males, among trisomy 18 live borns a large excess of females, and among trisomy 21 live borns an excess of males. These differences could arise from differential production of or fertilization by Y- or X-bearing sperm or from selection against male or female conceptions. To examine the proportion of Y- and X- bearing sperm in normal sperm and in sperm disomic for chromosomes 18 or 21, we used three-color FISH (to the X and Y and either chromosome 18 or chromosome 21) to analyze > 300,000 sperm from 24 men. In apparently normal sperm, the sex ratio was nearly 1:1 (148,074 Y-bearing to 148,657 X-bearing sperm), and the value was not affected by the age of the donor. Certain of the donors, however, had significant excesses of Y- or X-bearing sperm. In disomy 18 sperm, there were virtually identical numbers of Y- and X-bearing sperm; thus, the excess of females in trisomy 18 presumably is due to selection against male trisomic conceptions. In contrast, we observed 69 Y-bearing and 44 X-bearing sperm disomic for chromosome 21. This is consistent with previous molecular studies, which have identified an excess of males among paternally derived cases of trisomy 21, and suggests that some of the excess of males among Down syndrome individuals is attributable to a nondisjunctional mechanism in which the extra chromosome 21 preferentially segregates with the Y chromosome. 17 refs., 2 tabs.

  20. CDE-1 affects chromosome segregation through uridylation of CSR-1-bound siRNAs.

    PubMed

    van Wolfswinkel, Josien C; Claycomb, Julie M; Batista, Pedro J; Mello, Craig C; Berezikov, Eugene; Ketting, René F

    2009-10-02

    We have studied the function of a conserved germline-specific nucleotidyltransferase protein, CDE-1, in RNAi and chromosome segregation in C. elegans. CDE-1 localizes specifically to mitotic chromosomes in embryos. This localization requires the RdRP EGO-1, which physically interacts with CDE-1, and the Argonaute protein CSR-1. We found that CDE-1 is required for the uridylation of CSR-1 bound siRNAs, and that in the absence of CDE-1 these siRNAs accumulate to inappropriate levels, accompanied by defects in both meiotic and mitotic chromosome segregation. Elevated siRNA levels are associated with erroneous gene silencing, most likely through the inappropriate loading of CSR-1 siRNAs into other Argonaute proteins. We propose a model in which CDE-1 restricts specific EGO-1-generated siRNAs to the CSR-1 mediated, chromosome associated RNAi pathway, thus separating it from other endogenous RNAi pathways. The conserved nature of CDE-1 suggests that similar sorting mechanisms may operate in other animals, including mammals.

  1. Fission yeast Pot1 and RecQ helicase are required for efficient chromosome segregation.

    PubMed

    Takahashi, Katsunori; Imano, Ryota; Kibe, Tatsuya; Seimiya, Hiroyuki; Muramatsu, Yukiko; Kawabata, Naoki; Tanaka, Genki; Matsumoto, Yoshitake; Hiromoto, Taisuke; Koizumi, Yuka; Nakazawa, Norihiko; Yanagida, Mitsuhiro; Yukawa, Masashi; Tsuchiya, Eiko; Ueno, Masaru

    2011-02-01

    Pot1 is a single-stranded telomere-binding protein that is conserved from fission yeast to mammals. Deletion of Schizosaccharomyces pombe pot1(+) causes immediate telomere loss. S. pombe Rqh1 is a homolog of the human RecQ helicase WRN, which plays essential roles in the maintenance of genomic stability. Here, we demonstrate that a pot1Δ rqh1-hd (helicase-dead) double mutant maintains telomeres that are dependent on Rad51-mediated homologous recombination. Interestingly, the pot1Δ rqh1-hd double mutant displays a "cut" (cell untimely torn) phenotype and is sensitive to the antimicrotubule drug thiabendazole (TBZ). Moreover, the chromosome ends of the double mutant do not enter the pulsed-field electrophoresis gel. These results suggest that the entangled chromosome ends in the pot1Δ rqh1-hd double mutant inhibit chromosome segregation, signifying that Pot1 and Rqh1 are required for efficient chromosome segregation. We also found that POT1 knockdown, WRN-deficient human cells are sensitive to the antimicrotubule drug vinblastine, implying that some of the functions of S. pombe Pot1 and Rqh1 may be conserved in their respective human counterparts POT1 and WRN.

  2. Meiosis in holocentric chromosomes: orientation and segregation of an autosome and sex chromosomes in Triatoma infestans (Heteroptera).

    PubMed

    Pérez, R; Rufas, J S; Suja, J A; Page, J; Panzera, F

    2000-01-01

    The meiotic behaviour of the X chromosome and one autosomal pair of the heteropteran Triatoma infestans was analysed by means of C-banding plus DAPI staining. At first metaphase, the X univalent is oriented with its long axis parallel to the equatorial plate, which suggests a holocentric interaction with the spindle fibres. After this initial orientation, kinetic activity is restricted to one of both chromatid ends. The election of the active chromatid end is random and it is independent of the end selected in the sister chromatid. At second metaphase, the X and Y chromatids associate side by side forming a pseudobivalent. After that, the kinetic activity is again restricted to either of both chromosomal ends in a random fashion. At first metaphase, the fourth autosomal bivalent shows two alternative random orientations depending on the chromosome end showing kinetic activity (DAPI positive or opposite). At second metaphase, half bivalents are oriented with their long axis parallel to the equatorial plate. Three different segregation patterns are observed. The kinetic activity can be localised: (i) in the end with the DAPI signal (46.9%), (ii) in the opposite end (44.6%) or (iii) in one DAPI-positive end in one chromatid and in the opposite end in the other one (8.5%). The existence of the last pattern indicates that the same end can show kinetic activity during both meiotic divisions. Our results provide new information on the comparative meiotic behaviour of autosomes and sex chromosomes in holocentric systems.

  3. Clinical implications of chromosomal abnormalities in gastric adenocarcinomas

    SciTech Connect

    Wu, Chew-Wun; Chen, Gen-Der; Fann, Cathy S.-J.; Lee, Anna F.-Y.; Chi, Chin-Wen; Liu, Jacqueline M.; Weier, Ulli; Chen, Jeou-Yuan

    2003-06-23

    Gastric carcinoma (GC) is one of the most common malignancies worldwide and has a very poor prognosis. Genetic imbalances in 62 primary gastric adenocarcinomas of various histopathologic types and pathologic stages and six gastric cancer-derived cell lines were analyzed by comparative genomic hybridization, and the relationship of genomic abnormalities to clinical features in primary GC was evaluated at a genome-wide level. Eighty-four percent of the tumors and all six cell lines showed DNA copy number changes. The recurrent chromosomal abnormalities including gains at 15 regions and losses at 8 regions were identified. Statistical analyses revealed that gains at 17q24-qter (53 percent), 20q13-qter (48 percent), 1p32-p36 (42 percent), 22q12-qter (27 percent), 17p13-pter (24 percent), 16p13-pter (21 percent), 6p21-pter (19 percent), 20p12-pter (19 percent), 7p21-pter (18 percent), 3q28-qter (8 percent), and 13q13-q14 (8 percent), and losses at 18q12-qter (11 percent), 3p12 (8 percent), 3p25-pter (8 percent), 5q14-q23 (8 percent), and 9p21-p23 (5 percent), are associated with unique patient or tumor-related features. GCs of differing histopathologic features were shown to be associated with distinct patterns of genetic alterations, supporting the notion that they evolve through distinct genetic pathways. Metastatic tumors were also associated with specific genetic changes. These regions may harbor candidate genes involved in the pathogenesis of this malignancy.

  4. Identification and Characterization of Segregation Distortion Loci on Cotton Chromosome 18

    PubMed Central

    Dai, Baosheng; Guo, Huanle; Huang, Cong; Ahmed, Muhammad M.; Lin, Zhongxu

    2017-01-01

    Segregation distortion is commonly detected via genetic mapping and this phenomenon has been reported in many species. However, the genetic causes of the segregation distortion regions in a majority of species are still unclear. To genetically dissect the SD on chromosome 18 in cotton, eight reciprocal backcross populations and two F2 populations were developed. Eleven segregation distortion loci (SDL) were detected in these ten populations. Comparative analyses among populations revealed that SDL18.1 and SDL18.9 were consistent with male gametic competition; whereas SDL18.4 and SDL18.11 reflected female gametic selection. Similarly, other SDL could reflect zygotic selection. The surprising finding was that SDL18.8 was detected in all populations, and the direction was skewed towards heterozygotes. Consequently, zygotic selection or heterosis could represent the underlying genetic mechanism for SDL18.8. Among developed introgression lines, SDL18.8 was introgressed as a heterozygote, further substantiating that a heterozygote state was preferred under competition. Six out of 11 SDL on chromosome 18 were dependent on the cytoplasmic environment. These results indicated that different SDL showed varying responses to the cytoplasmic environment. Overall, the results provided a novel strategy to analyze the molecular mechanisms, which could be further exploited in cotton interspecific breeding programs. PMID:28149299

  5. Different segregation patterns in five carriers due to a pericentric inversion of chromosome 1.

    PubMed

    Luo, Yuqin; Xu, Chenming; Sun, Yixi; Wang, Liya; Chen, Songchang; Jin, Fan

    2014-12-01

    Pericentric inversion can produce recombinant gametes; however, meiotic segregation studies on the relationship between the frequency of recombinants and the inverted segment size are rare. Triple-color fluorescence in situ hybridization (FISH) was performed to analyze the meiotic behavior in five inv(1) carriers with different breakpoints. Recombination gametes were absent in Patient 1, whereas the percentages of the recombinants in Patients 2, 3, 4, and 5 were of 9.2%, 15.3%, 17.3%, and 40.9%, respectively. A significant difference was present for the frequencies of the recombinant spermatozoa among the five patients (p < 0.001). For each patient, the frequency of the two types of recombinant gametes (dup(1p)/del(1q) or del(1p)/dup(1q)) did not exhibit a significant difference in comparison with the expected 1:1 ratio (p > 0.05). The meiotic segregation of nine inv(1) carriers (including those presented in this paper) is now available. A significant correlation was discovered between the rate of recombination and the proportion of the chromosome implicated in the inversion (R = 0.9435, p < 0.001). The frequency of the recombinant gametes was directly related to the proportion of the chromosome that was inverted. Sperm-FISH allowed an additional comprehension of the patterns of meiotic segregation and provided accurate genetic counseling.

  6. Chromosomal Abnormalities in Patients with Congenital Heart Disease

    PubMed Central

    Trevisan, Patrícia; Zen, Tatiana Diehl; Rosa, Rafael Fabiano Machado; da Silva, Juliane Nascimento; Koshiyama, Dayane Bohn; Paskulin, Giorgio Adriano; Zen, Paulo Ricardo Gazzola

    2013-01-01

    Background Chromosomal abnormalities (CAs) are an important cause of congenital heart disease (CHD). Objective Determine the frequency, types and clinical characteristics of CAs identified in a sample of prospective and consecutive patients with CHD. Method Our sample consisted of patients with CHD evaluated during their first hospitalization in a cardiac intensive care unit of a pediatric referral hospital in Southern Brazil. All patients underwent clinical and cytogenetic assessment through high-resolution karyotype. CHDs were classified according to Botto et al. Chi-square, Fisher exact test and odds ratio were used in the statistical analysis (p < 0.05). Results Our sample consisted of 298 patients, 53.4% males, with age ranging from 1 day to 14 years. CAs were observed in 50 patients (16.8%), and 49 of them were syndromic. As for the CAs, 44 (88%) were numeric (40 patients with +21, 2 with +18, 1 with triple X and one with 45,X) and 6 (12%) structural [2 patients with der(14,21), +21, 1 with i(21q), 1 with dup(17p), 1 with del(6p) and 1 with add(18p)]. The group of CHDs more often associated with CAs was atrioventricular septal defect. Conclusions CAs detected through karyotyping are frequent in patients with CHD. Thus, professionals, especially those working in Pediatric Cardiology Services, must be aware of the implications that performing the karyotype can bring to the diagnosis, treatment and prognosis and for genetic counseling of patients and families. PMID:24145389

  7. [A case of Werner syndrome with chromosomal abnormality].

    PubMed

    Ochi, Masayuki; Igase, Michiya; Nagai, Ayako; Nakamura, Syunpei; Nagai, Tokihisa; Kawajiri, Masakazu; Nakura, Jun; Kohara, Katsuhiko; Miki, Tetsurou

    2006-09-01

    A 52-year-old woman with diabetes mellitus (DM) complained of weakness of the arms and legs. She was referred to our hospital in November 2002 because of anemia, thyroid tumor and meningioma including DM. She was short in stature, juvenile bilateral cataract, intractable skin ulcers, clavus on the sole of her foot, a bird-like face and high-pitched voice. Typical physical features led to the final diagnosis of Werner's syndrome. Although the myelogram revealed no abnormal findings except erythroid hypoplasia, cytogenetic analysis of bone marrow cells showed deletion of chromosome 20 in 10% of the analyzed cells, which suggested the possibility of that myelodysplastic syndrome (MDS) or acute myeloblastic leukemia (AML) could occur. She had a thyroidectomy because both lobes of the thyroid gland were enlarged and caused hoarseness, In addition, it is common knowledge that the goiter could become malignant. We need to follow her carefully because she might be vulnerable to malignant disease, including leukemia and malignant meningioma.

  8. Parental decisions of prenatally detected sex chromosome abnormality.

    PubMed Central

    Kim, Yon-Ju; Park, So-Yeon; Han, Jung-Heol; Kim, Moon-Young; Yang, Jae-Hyug; Choi, Kyu-Hong; Kim, Young-Mi; Kim, Jin-Mee; Ryu, Hyun-Mee

    2002-01-01

    Because of the widespread use of amniocentesis, the prenatal recognition of sex chromosome abnormality (SCA) has become increasingly common. Recent literature provided an insight into the understanding of the natural history and prognosis for individuals with SCA. Our study was designed to review the parental decision on pregnancy with SCA. Over the last 10 yr, we diagnosed 38 cases (0.50%) with SCA out of 7,498 prenatal cases. We reviewed the records and the results of the pregnancies. We included the cases (n=25) of apparently normal anatomic fetus to analyze the factors influencing parental decision. We excluded 13 cases with obvious anomaly or presumably bad outcome. Fifteen (60%) couples continued their pregnancies and ten (40%) terminated theirs. Nine couples (64%) out of fourteen mosaicism cases continued their pregnancies. All five pregnancies assisted by reproductive technique continued their pregnancies. More pregnancies were continued when counseling was done by an MD geneticist rather than by an obstetrician. A significant trend was observed with a higher rate of pregnancy continuation in recent years. The genetic counseling is important to give appropriate information to the parents. Establishing guidelines and protocols will help both obstetricians and parents to make a decision. PMID:11850589

  9. Chromosome orientation fluorescence in situ hybridization (CO-FISH) to study sister chromatid segregation in vivo

    PubMed Central

    Falconer, Ester; Chavez, Elizabeth; Henderson, Alexander; Lansdorp, Peter M.

    2013-01-01

    Previously, assays for sister chromatid segregation patterns relied on incorporation of BrdU and indirect methods to infer segregation patterns after two cell divisions. Here we describe a method to differentially label sister chromatids of murine cells and directly assay sister chromatid segregation patterns following one cell division in vitro and in vivo by adaptation of the well-established CO-FISH (chromosome orientation fluorescent in situ hybridization) technique. 5-bromo-2′-deoxyuridine (BrdU) is incorporated into newly-formed DNA strands, followed by photolysis and exonuclease digestion to create single-stranded sister chromatids containing parental template DNA only. Such single-stranded sister chromatids are differentially labeled using unidirectional probes to major satellite sequences coupled to fluorescent markers. Differentially-labeled sister chromatids in post-mitotic cells are visualized using fluorescence microscopy and sister chromatid segregation patterns can be directly assayed after one cell division. This procedure requires four days for in vivo mouse tissues, and two days for in vitro cultured cells. PMID:20595964

  10. Cell division patterns and chromosomal segregation defects in oral cancer stem cells.

    PubMed

    Kaseb, Hatem O; Lewis, Dale W; Saunders, William S; Gollin, Susanne M

    2016-09-01

    Oral squamous cell carcinoma (OSCC) is a serious public health problem caused primarily by smoking and alcohol consumption or human papillomavirus. The cancer stem cell (CSC) theory posits that CSCs show unique characteristics, including self-renewal and therapeutic resistance. Examining biomarkers and other features of CSCs is critical to better understanding their biology. To this end, the results show that cellular SOX2 immunostaining correlates with other CSC biomarkers in OSCC cell lines and marks the rare CSC population. To assess whether CSC division patterns are symmetrical, resulting in two CSC, or asymmetrical, leading to one CSC and one cancer cell, cell size and fluorescence intensity of mitotic cells stained with SOX2 were analyzed. Asymmetrical SOX2 distribution in ≈25% of the mitoses analyzed was detected. Chromosomal instability, some of which is caused by chromosome segregation defects (CSDs), is a feature of cancer cells that leads to altered gene copy numbers. We compare chromosomal instability (as measured by CSDs) between CSCs (SOX2+) and non-CSCs (SOX2-) from the same OSCC cell lines. CSDs were more common in non-CSCs (SOX2-) than CSCs (SOX2+) and in symmetrical CSC (SOX2+) mitotic pairs than asymmetrical CSC (SOX2+/SOX2-) mitotic pairs. CSCs showed fewer and different types of CSDs after ionizing radiation treatment than non-CSCs. Overall, these data are the first to demonstrate both symmetrical and asymmetrical cell divisions with CSDs in OSCC CSC. Further, the results suggest that CSCs may undergo altered behavior, including therapeutic resistance as a result of chromosomal instability due to chromosome segregation defects. © 2016 Wiley Periodicals, Inc.

  11. Huntingtin-interacting protein 1-related is required for accurate congression and segregation of chromosomes.

    PubMed

    Park, Sun Joo

    2010-12-01

    Huntingtin-interacting protein 1-related (HIP1r) is known to function in clathrin-mediated endocytosis and regulation of the actin cytoskeleton, which occurs continuously in non-dividing cells. This study reports a new function for HIP1r in mitosis. Green fluorescent protein-fused HIP1r localizes to the mitotic spindles. Depletion of HIP1r by RNA interference induces misalignment of chromosomes and prolonged mitosis, which is associated with decreased proliferation of HIP1r-deficeint cells. Chromosome misalignment leads to missegregation and ultimately production of multinucleated cells. Depletion of HIP1r causes persistent activation of the spindle checkpoint in misaligned chromosomes. These findings suggest that HIP1r plays an important role in regulating the attachment of spindle microtubules to chromosomes during mitosis, an event that is required for accurate congression and segregation of chromosomes. This finding may provide new insights that improve the understanding of various human diseases involving HIP1r as well as its fusion genes.

  12. Dialkyl Phosphate Urinary Metabolites and Chromosomal Abnormalities in Human Sperm

    PubMed Central

    Figueroa, Zaida I.; Young, Heather A.; Meeker, John D.; Martenies, Sheena E.; Barr, Dana Boyd; Gray, George; Perry, Melissa J.

    2015-01-01

    Background The past decade has seen numerous human health studies seeking to characterize the impacts of environmental exposures, such as organophosphate (OP) insecticides, on male reproduction. Despite an extensive literature on OP toxicology, many hormone-mediated effects on the testes are not well understood. Objectives This study investigated environmental exposures to OPs and their association with the frequency of sperm chromosomal abnormalities (i.e., disomy) among adult men. Methods Men (n=159) from a study assessing the impact of environmental exposures on male reproductive health were included in this investigation. Multi-probe fluorescence in situ hybridization (FISH) for chromosomes X, Y, and 18 was used to determine XX18, YY18, XY18 and total disomy in sperm nuclei. Urine was analyzed using gas chromatography coupled with mass spectrometry for concentrations of dialkyl phosphate (DAP) metabolites of OPs [dimethylphosphate (DMP); dimethylthiophosphate (DMTP); dimethyldithiophosphate (DMDTP); diethylphosphate (DEP); diethylthiophosphate (DETP); and diethyldithiophosphate (DEDTP)]. Poisson regression was used to model the association between OP exposures and disomy measures. Incidence rate ratios (IRRs) were calculated for each disomy type by exposure quartiles for most metabolites, controlling for age, race, BMI, smoking, specific gravity, total sperm concentration, motility, and morphology. Results A significant positive trend was seen for increasing IRRs by exposure quartiles of DMTP, DMDTP, DEP and DETP in XX18, YY18, XY18 and total disomy. A significant inverse association was observed between DMP and total disomy. Findings for total sum of DAP metabolites concealed individual associations as those results differed from the patterns observed for each individual metabolite. Dose-response relationships appeared nonmonotonic, with most of the increase in disomy rates occurring between the second and third exposure quartiles and without additional

  13. Hormad1 mutation disrupts synaptonemal complex formation, recombination, and chromosome segregation in mammalian meiosis.

    PubMed

    Shin, Yong-Hyun; Choi, Youngsok; Erdin, Serpil Uckac; Yatsenko, Svetlana A; Kloc, Malgorzata; Yang, Fang; Wang, P Jeremy; Meistrich, Marvin L; Rajkovic, Aleksandar

    2010-11-04

    Meiosis is unique to germ cells and essential for reproduction. During the first meiotic division, homologous chromosomes pair, recombine, and form chiasmata. The homologues connect via axial elements and numerous transverse filaments to form the synaptonemal complex. The synaptonemal complex is a critical component for chromosome pairing, segregation, and recombination. We previously identified a novel germ cell-specific HORMA domain encoding gene, Hormad1, a member of the synaptonemal complex and a mammalian counterpart to the yeast meiotic HORMA domain protein Hop1. Hormad1 is essential for mammalian gametogenesis as knockout male and female mice are infertile. Hormad1 deficient (Hormad1(-/) (-)) testes exhibit meiotic arrest in the early pachytene stage, and synaptonemal complexes cannot be visualized by electron microscopy. Hormad1 deficiency does not affect localization of other synaptonemal complex proteins, SYCP2 and SYCP3, but disrupts homologous chromosome pairing. Double stranded break formation and early recombination events are disrupted in Hormad1(-/) (-) testes and ovaries as shown by the drastic decrease in the γH2AX, DMC1, RAD51, and RPA foci. HORMAD1 co-localizes with γH2AX to the sex body during pachytene. BRCA1, ATR, and γH2AX co-localize to the sex body and participate in meiotic sex chromosome inactivation and transcriptional silencing. Hormad1 deficiency abolishes γH2AX, ATR, and BRCA1 localization to the sex chromosomes and causes transcriptional de-repression on the X chromosome. Unlike testes, Hormad1(-/) (-) ovaries have seemingly normal ovarian folliculogenesis after puberty. However, embryos generated from Hormad1(-/) (-) oocytes are hyper- and hypodiploid at the 2 cell and 8 cell stage, and they arrest at the blastocyst stage. HORMAD1 is therefore a critical component of the synaptonemal complex that affects synapsis, recombination, and meiotic sex chromosome inactivation and transcriptional silencing.

  14. Fifty probands with extra structurally abnormal chromosomes characterized by fluorescence in situ hybridization

    SciTech Connect

    Blennow, E.; Telenius, H.; Nordenskjoeld, M.

    1995-01-02

    Extra structurally abnormal chromosomes (ESACs) are small supernumerary chromosomes often associated with developmental abnormalities and malformations. We present 50 probands with ESACs characterized by fluorescence in situ hybridization using centromere-specific probes and chromosome-specific libraries. ESAC-specific libraries were constructed by flow sorting and subsequent amplification by DOP-PCR. Using such ESAC-specific libraries we were able to outline the chromosome regions involved. Twenty-three of the 50 ESACs were inverted duplications of chromosome 15 (inv dup(15)), including patients with normal phenotypes and others with similar clinical symptoms. These 2 groups differed in size and shape of the inv dup(15). Patients with a large inv dup(15), which included the Prader-Willi region, had a high risk of abnormality, whereas patients with a small inv dup(15), not including the Prader-Willi region, were normal. ESACs derived from chromosomes 13 or 21 appeared to have a low risk of abnormality, while one out of 3 patients with an ESAC derived from chromosome 14 had discrete symptoms. One out of 3 patients with an ESAC derived from chromosome 22 had severe anomalies, corresponding to some of the manifestations of the cat eye syndrome. Small extra ring chromosomes of autosomal origin and ESACs identified as i(12p) or i(18p) were all associated with a high risk of abnormality. 42 refs., 2 figs., 2 tabs.

  15. Non-random autosome segregation: a stepping stone for the evolution of sex chromosome complexes? Sex-biased transmission of autosomes could facilitate the spread of antagonistic alleles, and generate sex-chromosome systems with multiple X or Y chromosomes.

    PubMed

    Schwander, Tanja; Beukeboom, Leo W

    2011-02-01

    A new study in Caenorhabditis elegans shows that homologous autosomes segregate non-randomly with the sex chromosome in the heterogametic sex. Segregation occurs according to size, small autosomes segregating with, and large autosomes segregating away from the X-chromosome. Such sex-biased transmission of autosomes could facilitate the spread of sexually antagonistic alleles whose effects favor the fitness of one sex at the expense of the other. This may provide a first step toward the evolution of new sex determination systems.

  16. Angelman syndrome protein UBE3A interacts with primary microcephaly protein ASPM, localizes to centrosomes and regulates chromosome segregation.

    PubMed

    Singhmar, Pooja; Kumar, Arun

    2011-01-01

    Many proteins associated with the phenotype microcephaly have been localized to the centrosome or linked to it functionally. All the seven autosomal recessive primary microcephaly (MCPH) proteins localize at the centrosome. Microcephalic osteodysplastic primordial dwarfism type II protein PCNT and Seckel syndrome (also characterized by severe microcephaly) protein ATR are also centrosomal proteins. All of the above findings show the importance of centrosomal proteins as the key players in neurogenesis and brain development. However, the exact mechanism as to how the loss-of-function of these proteins leads to microcephaly remains to be elucidated. To gain insight into the function of the most commonly mutated MCPH gene ASPM, we used the yeast two-hybrid technique to screen a human fetal brain cDNA library with an ASPM bait. The analysis identified Angelman syndrome gene product UBE3A as an ASPM interactor. Like ASPM, UBE3A also localizes to the centrosome. The identification of UBE3A as an ASPM interactor is not surprising as more than 80% of Angelman syndrome patients have microcephaly. However, unlike in MCPH, microcephaly is postnatal in Angelman syndrome patients. Our results show that UBE3A is a cell cycle regulated protein and its level peaks in mitosis. The shRNA knockdown of UBE3A in HEK293 cells led to many mitotic abnormalities including chromosome missegregation, abnormal cytokinesis and apoptosis. Thus our study links Angelman syndrome protein UBE3A to ASPM, centrosome and mitosis for the first time. We suggest that a defective chromosome segregation mechanism is responsible for the development of microcephaly in Angelman syndrome.

  17. Angelman Syndrome Protein UBE3A Interacts with Primary Microcephaly Protein ASPM, Localizes to Centrosomes and Regulates Chromosome Segregation

    PubMed Central

    Singhmar, Pooja; Kumar, Arun

    2011-01-01

    Many proteins associated with the phenotype microcephaly have been localized to the centrosome or linked to it functionally. All the seven autosomal recessive primary microcephaly (MCPH) proteins localize at the centrosome. Microcephalic osteodysplastic primordial dwarfism type II protein PCNT and Seckel syndrome (also characterized by severe microcephaly) protein ATR are also centrosomal proteins. All of the above findings show the importance of centrosomal proteins as the key players in neurogenesis and brain development. However, the exact mechanism as to how the loss-of-function of these proteins leads to microcephaly remains to be elucidated. To gain insight into the function of the most commonly mutated MCPH gene ASPM, we used the yeast two-hybrid technique to screen a human fetal brain cDNA library with an ASPM bait. The analysis identified Angelman syndrome gene product UBE3A as an ASPM interactor. Like ASPM, UBE3A also localizes to the centrosome. The identification of UBE3A as an ASPM interactor is not surprising as more than 80% of Angelman syndrome patients have microcephaly. However, unlike in MCPH, microcephaly is postnatal in Angelman syndrome patients. Our results show that UBE3A is a cell cycle regulated protein and its level peaks in mitosis. The shRNA knockdown of UBE3A in HEK293 cells led to many mitotic abnormalities including chromosome missegregation, abnormal cytokinesis and apoptosis. Thus our study links Angelman syndrome protein UBE3A to ASPM, centrosome and mitosis for the first time. We suggest that a defective chromosome segregation mechanism is responsible for the development of microcephaly in Angelman syndrome. PMID:21633703

  18. Impact of excluding cases with known chromosomal abnormalities on the prevalence of structural birth defects, Hawaii, 1986-1999.

    PubMed

    Forrester, Mathias B; Merz, Ruth D

    2004-08-01

    Chromosomal abnormalities are more common in the presence of structural birth defects. However, much of the literature have only provided chromosomal abnormality rates for one or a few structural birth defects at a time. This study calculated the chromosomal abnormality rates for a number of structural birth defects using data from the Hawaii Birth Defects Program (HBDP) for deliveries during 1986-1999 and evaluated the impact of exclusion of cases with chromosomal abnormalities when calculating birth prevalence. The chromosomal abnormality rates were highest for endocardial cushion defect (40%) and omphalocele (27%), while no chromosomal abnormalities were reported for pyloric stenosis, persistent cloaca, and deficiency of lower limbs. The majority of chromosomal abnormality rates fell within a certain range, with 32 (63%) of the birth defect categories having chromosomal abnormality rates of 5-15%. The chromosomal abnormality rates also tended to be higher for multiple than for isolated cases. For three of the structural birth defects (ventricular septal defect, atrial septal defect, endocardial cushion defect), the birth prevalence of the defect, when cases with a chromosomal abnormality were excluded, was significantly lower than the birth prevalence that included those cases. Chromosomal abnormality rates varied by type of structural birth defect and presence of other major structural birth defects. For at least several structural birth defects, exclusion of cases with chromosomal abnormalities significantly underestimated the birth prevalence. This underestimation may be important, depending on the purpose of the analysis.

  19. Synchronizing chromosome segregation by flux-dependent force equalization at kinetochores

    PubMed Central

    Matos, Irina; Pereira, António J.; Lince-Faria, Mariana; Cameron, Lisa A.; Salmon, Edward D.

    2009-01-01

    The synchronous movement of chromosomes during anaphase ensures their correct inheritance in every cell division. This reflects the uniformity of spindle forces acting on chromosomes and their simultaneous entry into anaphase. Although anaphase onset is controlled by the spindle assembly checkpoint, it remains unknown how spindle forces are uniformly distributed among different chromosomes. In this paper, we show that tension uniformity at metaphase kinetochores and subsequent anaphase synchrony in Drosophila S2 cells are promoted by spindle microtubule flux. These results can be explained by a mechanical model of the spindle where microtubule poleward translocation events associated with flux reflect relaxation of the kinetochore–microtubule interface, which accounts for the redistribution and convergence of kinetochore tensions in a timescale comparable to typical metaphase duration. As predicted by the model, experimental acceleration of mitosis precludes tension equalization and anaphase synchrony. We propose that flux-dependent equalization of kinetochore tensions ensures a timely and uniform maturation of kinetochore–microtubule interfaces necessary for error-free and coordinated segregation of chromosomes in anaphase. PMID:19581410

  20. Risk of Chromosomal Abnormalities in Early Spontaneous Abortion after Assisted Reproductive Technology: A Meta-Analysis

    PubMed Central

    Qin, Jun-Zhen; Pang, Li-Hong; Li, Min-Qing; Xu, Jing; Zhou, Xing

    2013-01-01

    Background Studies on the risk of chromosomal abnormalities in early spontaneous abortion after assisted reproductive technology (ART) are relatively controversial and insufficient. Thus, to obtain a more precise evaluation of the risk of embryonic chromosomal abnormalities in first-trimester miscarriage after ART, we performed a meta-analysis of all available case–control studies relating to the cytogenetic analysis of chromosomal abnormalities in first-trimester miscarriage after ART. Methods Literature search in the electronic databases MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) based on the established strategy. Meta-regression, subgroup analysis, and Galbraith plots were conducted to explore the sources of heterogeneity. Results A total of 15 studies with 1,896 cases and 1,186 controls relevant to the risk of chromosomal abnormalities in first- trimester miscarriage after ART, and 8 studies with 601 cases and 602 controls evaluating frequency of chromosome anomaly for maternal age≥35 versus <35 were eligible for the meta-analysis. No statistical difference was found in risk of chromosomally abnormal miscarriage compared to natural conception and the different types of ART utilized, whereas the risk of fetal aneuploidy significantly increased with maternal age≥35 (OR 2.88, 95% CI: 1.74–4.77). Conclusions ART treatment does not present an increased risk for chromosomal abnormalities occurring in a first trimester miscarriage, but incidence of fetal aneuploidy could increase significantly with advancing maternal age. PMID:24130752

  1. Chromosome segregation and organization are targets of 5′-Fluorouracil in eukaryotic cells

    PubMed Central

    Mojardín, Laura; Botet, Javier; Moreno, Sergio; Salas, Margarita

    2015-01-01

    The antimetabolite 5′-Fluorouracil (5FU) is an analog of uracil commonly employed as a chemotherapeutic agent in the treatment of a range of cancers including colorectal tumors. To assess the cellular effects of 5FU, we performed a genome-wide screening of the haploid deletion library of the eukaryotic model Schizosaccharomyces pombe. Our analysis validated previously characterized drug targets including RNA metabolism, but it also revealed unexpected mechanisms of action associated with chromosome segregation and organization (post-translational histone modification, histone exchange, heterochromatin). Further analysis showed that 5FU affects the heterochromatin structure (decreased levels of histone H3 lysine 9 methylation) and silencing (down-regulation of heterochromatic dg/dh transcripts). To our knowledge, this is the first time that defects in heterochromatin have been correlated with increased cytotoxicity to an anticancer drug. Moreover, the segregation of chromosomes, a process that requires an intact heterochromatin at centromeres, was impaired after drug exposure. These defects could be related to the induction of genes involved in chromatid cohesion and kinetochore assembly. Interestingly, we also observed that thiabendazole, a microtubule-destabilizing agent, synergistically enhanced the cytotoxic effects of 5FU. These findings point to new targets and drug combinations that could potentiate the effectiveness of 5FU-based treatments. PMID:25483073

  2. Chromosome segregation and organization are targets of 5'-Fluorouracil in eukaryotic cells.

    PubMed

    Mojardín, Laura; Botet, Javier; Moreno, Sergio; Salas, Margarita

    2015-01-01

    The antimetabolite 5'-Fluorouracil (5FU) is an analog of uracil commonly employed as a chemotherapeutic agent in the treatment of a range of cancers including colorectal tumors. To assess the cellular effects of 5FU, we performed a genome-wide screening of the haploid deletion library of the eukaryotic model Schizosaccharomyces pombe. Our analysis validated previously characterized drug targets including RNA metabolism, but it also revealed unexpected mechanisms of action associated with chromosome segregation and organization (post-translational histone modification, histone exchange, heterochromatin). Further analysis showed that 5FU affects the heterochromatin structure (decreased levels of histone H3 lysine 9 methylation) and silencing (down-regulation of heterochromatic dg/dh transcripts). To our knowledge, this is the first time that defects in heterochromatin have been correlated with increased cytotoxicity to an anticancer drug. Moreover, the segregation of chromosomes, a process that requires an intact heterochromatin at centromeres, was impaired after drug exposure. These defects could be related to the induction of genes involved in chromatid cohesion and kinetochore assembly. Interestingly, we also observed that thiabendazole, a microtubule-destabilizing agent, synergistically enhanced the cytotoxic effects of 5FU. These findings point to new targets and drug combinations that could potentiate the effectiveness of 5FU-based treatments.

  3. Specific and non-specific interactions of ParB with DNA: implications for chromosome segregation

    PubMed Central

    Taylor, James A.; Pastrana, Cesar L.; Butterer, Annika; Pernstich, Christian; Gwynn, Emma J.; Sobott, Frank; Moreno-Herrero, Fernando; Dillingham, Mark S.

    2015-01-01

    The segregation of many bacterial chromosomes is dependent on the interactions of ParB proteins with centromere-like DNA sequences called parS that are located close to the origin of replication. In this work, we have investigated the binding of Bacillus subtilis ParB to DNA in vitro using a variety of biochemical and biophysical techniques. We observe tight and specific binding of a ParB homodimer to the parS sequence. Binding of ParB to non-specific DNA is more complex and displays apparent positive co-operativity that is associated with the formation of larger, poorly defined, nucleoprotein complexes. Experiments with magnetic tweezers demonstrate that non-specific binding leads to DNA condensation that is reversible by protein unbinding or force. The condensed DNA structure is not well ordered and we infer that it is formed by many looping interactions between neighbouring DNA segments. Consistent with this view, ParB is also able to stabilize writhe in single supercoiled DNA molecules and to bridge segments from two different DNA molecules in trans. The experiments provide no evidence for the promotion of non-specific DNA binding and/or condensation events by the presence of parS sequences. The implications of these observations for chromosome segregation are discussed. PMID:25572315

  4. A developmentally regulated translational control pathway establishes the meiotic chromosome segregation pattern

    PubMed Central

    Berchowitz, Luke E.; Gajadhar, Aaron S.; van Werven, Folkert J.; De Rosa, Alexandra A.; Samoylova, Mariya L.; Brar, Gloria A.; Xu, Yifeng; Xiao, Che; Futcher, Bruce; Weissman, Jonathan S.; White, Forest M.; Amon, Angelika

    2013-01-01

    Production of haploid gametes from diploid progenitor cells is mediated by a specialized cell division, meiosis, where two divisions, meiosis I and II, follow a single S phase. Errors in progression from meiosis I to meiosis II lead to aneuploid and polyploid gametes, but the regulatory mechanisms controlling this transition are poorly understood. Here, we demonstrate that the conserved kinase Ime2 regulates the timing and order of the meiotic divisions by controlling translation. Ime2 coordinates translational activation of a cluster of genes at the meiosis I–meiosis II transition, including the critical determinant of the meiotic chromosome segregation pattern CLB3. We further show that Ime2 mediates translational control through the meiosis-specific RNA-binding protein Rim4. Rim4 inhibits translation of CLB3 during meiosis I by interacting with the 5′ untranslated region (UTR) of CLB3. At the onset of meiosis II, Ime2 kinase activity rises and triggers a decrease in Rim4 protein levels, thereby alleviating translational repression. Our results elucidate a novel developmentally regulated translational control pathway that establishes the meiotic chromosome segregation pattern. PMID:24115771

  5. Long G2 accumulates recombination intermediates and disturbs chromosome segregation at dysfunction telomere in Schizosaccharomyces pombe

    SciTech Connect

    Habib, Ahmed G.K.; Masuda, Kenta; Yukawa, Masashi; Tsuchiya, Eiko; Ueno, Masaru

    2015-08-14

    Protection of telomere (Pot1) is a single-stranded telomere binding protein which is essential for chromosome ends protection. Fission yeast Rqh1 is a member of RecQ helicases family which has essential roles in the maintenance of genomic stability and regulation of homologous recombination. Double mutant between fission yeast pot1Δ and rqh1 helicase dead (rqh1-hd) maintains telomere by homologous recombination. In pot1Δ rqh1-hd double mutant, recombination intermediates accumulate near telomere which disturb chromosome segregation and make cells sensitive to microtubule inhibitors thiabendazole (TBZ). Deletion of chk1{sup +} or mutation of its kinase domain shortens the G2 of pot1Δ rqh1-hd double mutant and suppresses both the accumulation of recombination intermediates and the TBZ sensitivity of that double mutant. In this study, we asked whether the long G2 is the reason for the TBZ sensitivity of pot1Δ rqh1-hd double mutant. We found that shortening the G2 of pot1Δ rqh1-hd double mutant by additional mutations of wee1 and mik1 or gain of function mutation of Cdc2 suppresses both the accumulation of recombination intermediates and the TBZ sensitivity of pot1Δ rqh1-hd double mutant. Our results suggest that long G2 of pot1Δ rqh1-hd double mutant may allow time for the accumulation of recombination intermediates which disturb chromosome segregation and make cells sensitive to TBZ. - Ηighlights: • We show link between long G2 and accumulation of toxic recombination intermediates. • Accumulation of recombination intermediates at telomere results in TBZ sensitivity. • Activation of DNA damage checkpoint worsens cells' viability in presence of TBZ.

  6. Assessment of chromosomal abnormalities in sperm of infertile men using sperm karyotyping and multicolour fluorescence in situ hybridization (FISH)

    SciTech Connect

    Moosani, N.; Martin, R.H.

    1994-09-01

    Individuals with male factor infertility resulting from idiopathic oligo-, astheno- or teratozoospermia are frequently offered IVF in an attempt to increase their chances of having a child. A concern remains whether these infertile males have an elevated risk of transmitting chromosomal abnormalities to their offspring. Sperm chromosomal complements from these men were assayed using the human sperm/hamster oocyte fusion system and fluorescence in situ hybridization (FISH) on sperm nuclei. For each of 5 infertile patients, 100 sperm karyotypes were analyzed and multicolour FISH analysis was performed on a minimum of 10,000 sperm nuclei for each chromosome-specific DNA probe for chromosomes 1 (pUC1.77), 12 (D12Z3), X (XC) and Y (DYZ3). As a group, the infertile patients showed increased frequencies of both numerical ({chi}{sup 2}=17.26, {proportional_to} <0.001) and total abnormalities ({chi}{sup 2}=7.78, {proportional_to} <0.01) relative to control donors when assessed by sperm karyotypes. Analysis of sperm nuclei by FISH indicated a significant increase in the frequency of disomy for chromosome 1 in three of the five patients as compared to control donors ({chi}{sup 2}>8.35, {proportional_to} <0.005). In addition, the frequency of XY disomy was significantly higher in four of the five patients studied by FISH ({chi}{sup 2}>10.58, {proportional_to}<0.005), suggesting that mis-segregation caused by the failure of the XY bivalent to pair may play a role in idiopathic male infertility.

  7. X Chromosome Abnormalities and Cognitive Development: Implications for Understanding Normal Human Development.

    ERIC Educational Resources Information Center

    Walzer, Stanley

    1985-01-01

    Argues that knowledge from studies of individuals with sex chromosome abnormalities can further understanding of aspects of normal human development. Studies of XO girls, XXY boys, XXX girls, and males with a fragile X chromosome are summarized to demonstrate how results contribute to knowledge about normal cognitive development and about…

  8. Chromosome replication and segregation govern the biogenesis and inheritance of inorganic polyphosphate granules.

    PubMed

    Henry, Jonathan T; Crosson, Sean

    2013-10-01

    Prokaryotes and eukaryotes synthesize long chains of orthophosphate, known as polyphosphate (polyP), which form dense granules within the cell. PolyP regulates myriad cellular functions and is often localized to specific subcellular addresses through mechanisms that remain undefined. In this study, we present a molecular-level analysis of polyP subcellular localization in the model bacterium Caulobacter crescentus. We demonstrate that biogenesis and localization of polyP is controlled as a function of the cell cycle, which ensures regular partitioning of granules between mother and daughter. The enzyme polyphosphate kinase 1 (Ppk1) is required for granule production, colocalizes with granules, and dynamically localizes to the sites of new granule synthesis in nascent daughter cells. Localization of Ppk1 within the cell requires an intact catalytic active site and a short, positively charged tail at the C-terminus of the protein. The processes of chromosome replication and segregation govern both the number and position of Ppk1/polyP complexes within the cell. We propose a multistep model in which the chromosome establishes sites of polyP coalescence, which recruit Ppk1 to promote the in situ synthesis of large granules. These findings underscore the importance of both chromosome dynamics and discrete protein localization as organizing factors in bacterial cell biology.

  9. Evidence for a DNA-relay mechanism in ParABS-mediated chromosome segregation.

    PubMed

    Lim, Hoong Chuin; Surovtsev, Ivan Vladimirovich; Beltran, Bruno Gabriel; Huang, Fang; Bewersdorf, Jörg; Jacobs-Wagner, Christine

    2014-05-23

    The widely conserved ParABS system plays a major role in bacterial chromosome segregation. How the components of this system work together to generate translocation force and directional motion remains uncertain. Here, we combine biochemical approaches, quantitative imaging and mathematical modeling to examine the mechanism by which ParA drives the translocation of the ParB/parS partition complex in Caulobacter crescentus. Our experiments, together with simulations grounded on experimentally-determined biochemical and cellular parameters, suggest a novel 'DNA-relay' mechanism in which the chromosome plays a mechanical function. In this model, DNA-bound ParA-ATP dimers serve as transient tethers that harness the elastic dynamics of the chromosome to relay the partition complex from one DNA region to another across a ParA-ATP dimer gradient. Since ParA-like proteins are implicated in the partitioning of various cytoplasmic cargos, the conservation of their DNA-binding activity suggests that the DNA-relay mechanism may be a general form of intracellular transport in bacteria.DOI: http://dx.doi.org/10.7554/eLife.02758.001.

  10. Chromosome replication and segregation govern the biogenesis and inheritance of inorganic polyphosphate granules

    PubMed Central

    Henry, Jonathan T.; Crosson, Sean

    2013-01-01

    Prokaryotes and eukaryotes synthesize long chains of orthophosphate, known as polyphosphate (polyP), which form dense granules within the cell. PolyP regulates myriad cellular functions and is often localized to specific subcellular addresses through mechanisms that remain undefined. In this study, we present a molecular-level analysis of polyP subcellular localization in the model bacterium Caulobacter crescentus. We demonstrate that biogenesis and localization of polyP is controlled as a function of the cell cycle, which ensures regular partitioning of granules between mother and daughter. The enzyme polyphosphate kinase 1 (Ppk1) is required for granule production, colocalizes with granules, and dynamically localizes to the sites of new granule synthesis in nascent daughter cells. Localization of Ppk1 within the cell requires an intact catalytic active site and a short, positively charged tail at the C-terminus of the protein. The processes of chromosome replication and segregation govern both the number and position of Ppk1/polyP complexes within the cell. We propose a multistep model in which the chromosome establishes sites of polyP coalescence, which recruit Ppk1 to promote the in situ synthesis of large granules. These findings underscore the importance of both chromosome dynamics and discrete protein localization as organizing factors in bacterial cell biology. PMID:23985321

  11. Aurora B–mediated localized delays in nuclear envelope formation facilitate inclusion of late-segregating chromosome fragments

    PubMed Central

    Karg, Travis; Warecki, Brandt; Sullivan, William

    2015-01-01

    To determine how chromosome segregation is coordinated with nuclear envelope formation (NEF), we examined the dynamics of NEF in the presence of lagging acentric chromosomes in Drosophila neuroblasts. Acentric chromosomes often exhibit delayed but ultimately successful segregation and incorporation into daughter nuclei. However, it is unknown whether these late-segregating acentric fragments influence NEF to ensure their inclusion in daughter nuclei. Through live analysis, we show that acentric chromosomes induce highly localized delays in the reassembly of the nuclear envelope. These delays result in a gap in the nuclear envelope that facilitates the inclusion of lagging acentrics into telophase daughter nuclei. Localized delays of nuclear envelope reassembly require Aurora B kinase activity. In cells with reduced Aurora B activity, there is a decrease in the frequency of local nuclear envelope reassembly delays, resulting in an increase in the frequency of acentric-bearing, lamin-coated micronuclei. These studies reveal a novel role of Aurora B in maintaining genomic integrity by promoting the formation of a passageway in the nuclear envelope through which late-segregating acentric chromosomes enter the telophase daughter nucleus. PMID:25877868

  12. Marker chromosomes lacking {alpha}-satellite DNA: A new intriguing class of abnormalities

    SciTech Connect

    Becker, L.A.; Zinn, A.B.; Stallard, J.R.

    1994-09-01

    Recent studies have implicated {alpha}-satellite DNA as an integral part of the centromere and important for the normal segregation of chromosomes. We analyzed four supernumerary marker chromosomes in which fluorescence in situ hybridization (FISH) could detect neither pancentromeric or chromosome specific {alpha}-satellite DNA. Mosaicism of the markers existed, but each was present in the majority of cells indicating that they segregated normally. FISH with chromosome-specific libraries identified the origins of these markers as chromosomes 13 (1 case) and 15 (3 cases). High resolution analysis, combined with hybridization of a series of cosmid probes, revealed that each marker was a symmetrical duplication of the terminal long arm of the parent chromosome. Telomeric sequences were detected by FISH indicating linear structures. Breakpoint heterogeneity, as defined by cosmid probes, was demonstrated in the three cases involving chromosome 15. No pericentromeric satellite III DNA could be detected on three markers. Studies with anti-centromere antibodies are in progress to assay for centromeric antigens on the markers, as expected at functional centromeric sites. Our results demonstrate that the precise structural identification and heterogeneity of these markers can be easily elucidated using FISH with unique sequence cosmid probes. We conclude from our studies and others in the literature: (1) there is a newly defined class of markers lacking {alpha}-satellite DNA and containing duplications of terminal sequences; (2)neither {alpha}-satellite nor satellite III DNA at levels detectable by FISH is necessary for fidelity in the normal segregation of chromosomes; and (3) these markers were most likely formed by recombination of the long arms during meiosis.

  13. Structural Chromosome Abnormalities Associated with Obesity: Report of Four New subjects and Review of Literature

    PubMed Central

    Dasouki, Majed J; Youngs, Erin L; Hovanes, Karine

    2011-01-01

    Obesity in humans is a complex polygenic trait with high inter-individual heritability estimated at 40–70%. Candidate gene, DNA linkage and genome-wide association studies (GWAS) have allowed for the identification of a large set of genes and genomic regions associated with obesity. Structural chromosome abnormalities usually result in congenital anomalies, growth retardation and developmental delay. Occasionally, they are associated with hyperphagia and obesity rather than growth delay. We report four new individuals with structural chromosome abnormalities involving 10q22.3-23.2, 16p11.2 and Xq27.1-q28 chromosomal regions with early childhood obesity and developmental delay. We also searched and summarized the literature for structural chromosome abnormalities reported in association with childhood obesity. PMID:22043167

  14. Cohesins: chromatin architects in chromosome segregation, control of gene expression and much more.

    PubMed

    Barbero, José L

    2009-07-01

    Cells have evolved to develop molecules and control mechanisms that guarantee correct chromosome segregation and ensure the proper distribution of genetic material to daughter cells. In this sense, the establishment, maintenance, and removal of sister chromatid cohesion is one of the most fascinating and dangerous processes in the life of a cell because errors in the control of these processes frequently lead to cell death or aneuploidy. The main protagonist in this mechanism is a four-protein complex denominated the cohesin complex. In the last 10 years, we have improved our understanding of the key players in the regulation of sister chromatid cohesion during cell division in mitosis and meiosis. The last 2 years have seen an increase in evidence showing that cohesins have important functions in non-dividing cells, revealing new, unexplored roles for these proteins in the control of gene expression, development, and other essential cell functions in mammals.

  15. Nuclear organisation in totipotent human nuclei and its relationship to chromosomal abnormality.

    PubMed

    Finch, Katie A; Fonseka, Gothami; Ioannou, Dimitris; Hickson, Nicholas; Barclay, Zoe; Chatzimeletiou, Katerina; Mantzouratou, Anna; Handyside, Alan; Delhanty, Joy; Griffin, Darren K

    2008-03-01

    Studies of nuclear organisation, most commonly determining the nuclear location of chromosome territories and individual loci, have furthered our understanding of nuclear function, differentiation and disease. In this study, by examining eight loci on different chromosomes, we tested hypotheses that: (1) totipotent human blastomeres adopt a nuclear organisation akin to that of committed cells; (2) nuclear organisation is different in chromosomally abnormal blastomeres; and (3) human blastomeres adopt a ;chromocentre' pattern. Analysis of in vitro fertilisation (IVF) conceptuses permits valuable insight into the cell biology of totipotent human nuclei. Here, extrapolations from images of preimplantation genetic screening (PGS) cases were used to make comparisons between totipotent blastomeres and several committed cells, showing some differences and similarities. Comparisons between chromosomally abnormal nuclei and those with no detected abnormality (NDA) suggest that the former display a significant non-random pattern for all autosomal loci, but there is a less distinct, possibly random, pattern in 'NDA' nuclei. No evidence was found that the presence of an extra chromosome is accompanied by an altered nuclear location for that chromosome. Centromeric loci on chromosomes 15 and 16 normally seen at the nuclear periphery were mostly centrally located in aneuploid cells, providing some evidence of a 'chromocentre'; however, the chromosome-18 centromere was more peripheral, similar to committed cells. Our results provide clues to the nature of totipotency in human cells and might have future applications for preimplantation diagnosis and nuclear transfer.

  16. Down-Turner Syndrome: A Case with Double Monoclonal Chromosomal Abnormality.

    PubMed

    Manassero-Morales, Gioconda; Alvarez-Manassero, Denisse; Merino-Luna, Alfredo

    2016-01-01

    Introduction. The coexistence of Down and Turner syndromes due to double chromosome aneuploidy is very rare; it is even more rare to find the presence of a double monoclonal chromosomal abnormality. Objective. To report a unique case of double monoclonal chromosomal abnormality with trisomy of chromosome 21 and an X ring chromosome in all cells studied; no previous report has been found. Case Report. Female, 28 months old, with pathological short stature from birth, with the following dysmorphic features: tilted upward palpebral fissures, short neck, brachycephaly, and low-set ears. During the neonatal period, the infant presented generalized hypotonia and lymphedema of hands and feet. Karyotype showed 47,X,r(X),+21 [30]. Conclusion. Clinical features of both Down and Turner syndromes were found, highlighting short stature that has remained below 3 z score from birth to the present, associated with delayed psychomotor development. G-banded karyotype analysis in peripheral blood is essential for a definitive diagnosis.

  17. Growth and differentiation of circulating hemopoietic stem cells with atomic bomb irradiation-induced chromosome abnormalities

    SciTech Connect

    Amenomori, T.; Honda, T.; Otake, M.; Tomonaga, M.; Ichimaru, M.

    1988-11-01

    The effects of atomic bomb irradiation on hemopoietic stem cells were studied cytogenetically using single colonies derived from hemopoietic progenitor cells. The subjects studied were 21 healthy atomic bomb survivors (10 males and 11 females) in the high dose exposure group (100+ rad) with a known high incidence (10% or more) of radiation-induced chromosome abnormalities in their peripheral blood lymphocytes (stimulated with phytohemagglutinin), and 11 nonexposed healthy controls (5 males and 6 females). Colony formation by circulating granulocyte-macrophage (GM-CFC) and erythroid (BFU-E) progenitor cells was made by the methylcellulose method using peripheral blood mononuclear cells. Chromosome specimens were prepared from single colonies by our micromethod. The total number of colonies analyzed in the exposed group was 131 for GM-CFC and 75 for BFU-E. Chromosome abnormalities were observed in 15 (11.5%) and 9 (12.0%) colonies, respectively. In the control group, the total number of colonies analyzed was 61 for GM-CFC and 41 for BFU-E. None of these colonies showed chromosome abnormalities. The difference in incidence of chromosome abnormalities was highly significant by an exact test; p = 0.003 for GM-CFC and 0.017 for BFU-E. The karyotypes of chromosome abnormalities obtained from the colonies in the exposed group were mostly translocations, but deletion and marker chromosomes were also observed. In two individuals, such karyotypic abnormalities as observed in the peripheral lymphocytes were also seen in the myeloid progenitor cells. This finding suggests that atomic bomb irradiation produced a chromosome aberration on multipotent hemopoietic stem cells common to myeloid and lymphoid lineages.

  18. Bipolar spindle attachments affect redistributions of ZW10, a Drosophila centromere/kinetochore component required for accurate chromosome segregation

    PubMed Central

    1996-01-01

    Previous efforts have shown that mutations in the Drosophila ZW10 gene cause massive chromosome missegregation during mitotic divisions in several tissues. Here we demonstrate that mutations in ZW10 also disrupt chromosome behavior in male meiosis I and meiosis II, indicating that ZW10 function is common to both equational and reductional divisions. Divisions are apparently normal before anaphase onset, but ZW10 mutants exhibit lagging chromosomes and irregular chromosome segregation at anaphase. Chromosome missegregation during meiosis I of these mutants is not caused by precocious separation of sister chromatids, but rather the nondisjunction of homologs. ZW10 is first visible during prometaphase, where it localizes to the kinetochores of the bivalent chromosomes (during meiosis I) or to the sister kinetochores of dyads (during meiosis II). During metaphase of both divisions, ZW10 appears to move from the kinetochores and to spread toward the poles along what appear to be kinetochore microtubules. Redistributions of ZW10 at metaphase require bipolar attachments of individual chromosomes or paired bivalents to the spindle. At the onset of anaphase I or anaphase II, ZW10 rapidly relocalizes to the kinetochore regions of the separating chromosomes. In other mutant backgrounds in which chromosomes lag during anaphase, the presence or absence of ZW10 at a particular kinetochore predicts whether or not the chromosome moves appropriately to the spindle poles. We propose that ZW10 acts as part of, or immediately downstream of, a tension-sensing mechanism that regulates chromosome separation or movement at anaphase onset. PMID:8794856

  19. Anal atresia, abnormal genitalia, and absent thumb: congenital malformations associated with mosaic ring chromosome 13.

    PubMed

    Ocak, Z; Ozlu, T; Vural, M

    2013-01-01

    Because of the deletion of a segment of the chromosome during the formation of a ring, several clinical findings may be associated with ring chromosomes. Ring chromosome 13 is one of such disorders in which the genotype-phenotype correlation is stronger by virtue of the accumulating literature. It can be associated with multiple congenital abnormalities and severe mental retardation. We report a case with mosaic ring chromosome 13 whose prenatal ultrasound revealed bilateral ventriculomegaly. Anal atresia, unidentifiable external genitalia, and an absent thumb were observed in the postmortem examination.

  20. Chromosomal abnormalities in neutron-induced acute myeloid leukemias in CBA/H mice

    SciTech Connect

    Bouffler, S.D.; Meijne, E.I.M.; Huiskamp, R.

    1996-09-01

    Acute myeloid leukemias (AMLs) induced in CBA/H mice by 1 MeV fission neutrons have been examined for chromosomal abnormalities by G-band analysis. In common with X-ray- and {alpha}-particle-induced AMLs in CBA/H mice, more than 90% (16/17) of the myeloid leukemias had chromosome 2 abnormalities, in this case, all interstitial deletions. Chromosome 2 breakpoints were not wholly consistent, but clustering in three specific G-band regions was observed. Very distal (H-region) breakpoints were more common in the neutron AMLs than in X-ray- or {alpha}-particle-induced leukemias. These data indicate that neutron-induced AMLs in CBA/H mice are not characterized by a specific chromosome deletion but that a variety of chromosome 2 deletion types are associated with the disease. Trisomy of chromosome 1 (12.5% AMLs) and aneusomy of chromosomes 6 (31% AMLs) and Y (37.5% AMLs) were noted. While chromatid breakage was observed occasionally in neutron-induced AML, no clear indications of persistent chromosomal instability or high levels of stable chromosomal change were apparent. 19 refs., 1 fig., 1 tab.

  1. Consistent chromosome abnormalities including double minutes (dms) in adenocarcinoma of the pancreas

    SciTech Connect

    Griffin, C.A.; Morsberger, L.; Ellingham, T.

    1994-09-01

    Little is known about the somatic genetic changes which characterize pancreatic adenocarcinoma (PA), and identification of acquired genomic alterations would further our understanding of the biology of this neoplasm. We have studied 62 primary specimens of PA using classical and FISH methods. Clonally abnormal karyotypes were observed in 44 neoplasms. Karyotypes were generally complex (greater than 3 abnormalities) including both numerical and structural chromosome changes. Many tumors contained at least one marker chromosome. The most frequent whole chromosomal gains were chromosomes 20 (7 tumors) and 7 (5 tumors). Losses were much more frequent: chromosome 18 was lost in 22 tumors, followed by chromosomes 13 (15 tumors), 12 (13 tumors), and 6 (12 tumors). Structural abnormalities were common. 200 chromosome breakpoints were identified. Excluding Robertsonian translocations, chromosomal arms most frequently involved were 6q (12 chromosomes), 1p and 3p (10 each), 11p and 17p (9 each), 1q (8), 8p and 19q (7 each). Of particular interest, we found dms in 6 cases. These represent the first PAs with cytogenetic evidence of gene amplification, and are under investigation using chromosome microdissection. To begin to define the smallest region of 6q which is deleted, 5 tumors with 6q deletions were hybridized with a biotin-labeled probe, made by microdissection of 6q24-qter. Loss of one copy of this region was verified in 4/5 tumors; additional probes are being made. Our results are similar to those of 34 other reported PAs, and the combined data suggest that gains of chromosomes 7 and 20 and deletions and rearrangements of 1p and 6q may be particularly important in the biology of adenocarcinoma of the pancreas.

  2. Two functionally distinct kinetochore pools of BubR1 ensure accurate chromosome segregation

    PubMed Central

    Zhang, Gang; Mendez, Blanca Lopez; Sedgwick, Garry G.; Nilsson, Jakob

    2016-01-01

    The BubR1/Bub3 complex is an important regulator of chromosome segregation as it facilitates proper kinetochore–microtubule interactions and is also an essential component of the spindle assembly checkpoint (SAC). Whether BubR1/Bub3 localization to kinetochores in human cells stimulates SAC signalling or only contributes to kinetochore–microtubule interactions is debated. Here we show that two distinct pools of BubR1/Bub3 exist at kinetochores and we uncouple these with defined BubR1/Bub3 mutants to address their function. The major kinetochore pool of BubR1/Bub3 is dependent on direct Bub1/Bub3 binding and is required for chromosome alignment but not for the SAC. A distinct pool of BubR1/Bub3 localizes by directly binding to phosphorylated MELT repeats on the outer kinetochore protein KNL1. When we prevent the direct binding of BubR1/Bub3 to KNL1 the checkpoint is weakened because BubR1/Bub3 is not incorporated into checkpoint complexes efficiently. In conclusion, kinetochore localization supports both known functions of BubR1/Bub3. PMID:27457023

  3. Systematic review of accuracy of prenatal diagnosis for abnormal chromosome diseases by microarray technology.

    PubMed

    Xu, H B; Yang, H; Liu, G; Chen, H

    2014-10-31

    The accuracy of prenatal diagnosis for abnormal chromosome diseases by chromosome microarray technology and karyotyping were compared. A literature search was carried out in the MEDLINE database with the keywords "chromosome" and "karyotype" and "genetic testing" and "prenatal diagnosis" and "oligonucleotide array sequence". The studies obtained were filtered by using the QUADAS tool, and studies conforming to the quality standard were fully analyzed. There was one paper conforming to the QUADAS standards including 4406 gravidas with adaptability syndromes of prenatal diagnosis including elderly parturient women, abnormal structure by type-B ultrasound, and other abnormalities. Microarray technology yielded successful diagnoses in 4340 cases (98.8%), and there was no need for tissue culture in 87.9% of the samples. All aneuploids and non-parallel translocations in 4282 cases of non-chimera identified by karyotyping could be detected using microarray analysis technology, whereas parallel translocations and fetal triploids could not be detected by microarray analysis technology. In the samples with normal karyotyping results, type-B ultrasound showed that 6% of chromosomal deficiencies or chromosome duplications could be detected by microarray technology, and the same abnormal chromosomes were detected in 1.7% of elderly parturient women and samples with positive serology screening results. In the prenatal diagnosis test, compared with karyotyping, microarray technology could identify the extra cell genetic information with clinical significance, aneuploids, and non-parallel translocations; however, its disadvantage is that it could not identify parallel translocations and triploids.

  4. Reproductive outcome of male carriers of chromosomal abnormalities: multidisciplinary approach for genetic counseling and its implications.

    PubMed

    Guo, K M; Wu, B; Wang, H B; Tian, R H

    2016-12-02

    Chromosomal abnormality is the most common genetic cause of infertility. Infertility, as a psychological problem, has received an increasing amount of attention. Psychological interventions have been shown to have beneficial effects on infertile patients with chromosomal abnormalities. The present study explored reproductive outcome of male carriers of chromosomal abnormalities, who accepted genetic counseling and psychological support. Cytogenetic analysis was performed using cultured peripheral blood lymphocytes and G-banding. The detection rate of chromosomal abnormalities was 10.3% in pre-pregnancy counseled males, with polymorphisms being most common, followed by 47,XXY and balanced translocation. Follow-up of 170 carriers with normozoospermia, after 3 years, showed that 94.7% of the cases resulted in live births. In the carriers of polymorphisms, balanced translocation, inv(9), Robertsonian translocation, inversion, and 47,XYY, live birth rates were 96.8, 85.7, 100, 83.3, 75, and 100%, respectively. Follow-up of 54 carriers with oligozoospermia or azoospermia, after 3 years, showed that 14.8% of the cases resulted in live births. In the carriers of 47,XXY with severe oligozoospermia or azoospermia, 80 or 5.9% of the cases resulted in live births, respectively. Therefore, timely psychological support would be beneficial and multidisciplinary approach should be preferentially considered for the management of individuals with chromosomal abnormalities.

  5. Detection of chromosomal abnormalities and the 22q11 microdeletion in fetuses with congenital heart defects.

    PubMed

    Lv, Wei; Wang, Shuyu

    2014-11-01

    Chromosomal abnormalities and the 22q11 microdeletion are implicated in congenital heart defects (CHDs). This study was designed to detect these abnormalities in fetuses and determine the effect of genetic factors on CHD etiology. Between January 2010 and December 2011, 113 fetuses with CHD treated at the Beijing Obstetrics and Gynecology Hospital were investigated, using chromosome karyotyping of either amniotic fluid cell or umbilical cord blood cell samples. Fetuses with a normal result were then investigated for the 22q11 microdeletion by fluorescence in situ hybridization. Of the 113 patients, 12 (10.6%) exhibited chromosomal abnormalities, while 6 (5.3%) of the remaining 101 cases presented with a 22q11 microdeletion. The incidence of chromosomal abnormalities was significantly higher in the group of fetuses presenting with extracardiac malformations in addition to CHD (P<0.001), although the detection of the 22q11 microdeletion was not significantly different between the two groups (P=0.583). In addition, all fetuses with the 22q11 microdeletion occurred de novo. In conclusion, genetic factors are important in the etiology of CHD. Where fetuses present with cardiac defects, additional chromosomal analysis is required to detect extracardiac abnormalities. Fetuses with heart defects should also be considered for 22q11 microdeletion detection to evaluate fetal prognosis, particularly prior to surgery.

  6. Phospho-Bcl-xL(Ser62) influences spindle assembly and chromosome segregation during mitosis.

    PubMed

    Wang, Jianfang; Beauchemin, Myriam; Bertrand, Richard

    2014-01-01

    Functional analysis of a series of phosphorylation mutants reveals that Bcl-xL(Ser62Ala) influences cell entry into anaphase and mitotic exit in taxol-exposed cells compared with cells expressing wild-type Bcl-xL or a series of other phosphorylation mutants, an effect that appears to be independent of its anti-apoptotic activity. During normal mitosis progression, Bcl-xL(Ser62) is strongly phosphorylated by PLK1 and MAPK14/SAPKp38α at the prometaphase, metaphase, and the anaphase boundaries, while it is de-phosphorylated at telophase and cytokinesis. Phospho-Bcl-xL(Ser62) localizes in centrosomes with γ-tubulin and in the mitotic cytosol with some spindle-assembly checkpoint signaling components, including PLK1, BubR1, and Mad2. In taxol- and nocodazole-exposed cells, phospho-Bcl-xL(Ser62) also binds to Cdc20- Mad2-, BubR1-, and Bub3-bound complexes, while Bcl-xL(Ser62Ala) does not. Silencing Bcl-xL expression and expressing the phosphorylation mutant Bcl-xL(Ser62Ala) lead to an increased number of cells harboring mitotic spindle defects including multipolar spindle, chromosome lagging and bridging, aneuploidy with micro-, bi-, or multi-nucleated cells, and cells that fail to resolve undergo mitosis within 6 h. Together, the data indicate that during mitosis, Bcl-xL(Ser62) phosphorylation impacts on spindle assembly and chromosome segregation, influencing chromosome stability. Observations of mitotic cells harboring aneuploidy with micro-, bi-, or multi-nucleated cells, and cells that fail to resolve undergo mitosis within 6 h were also made with cells expressing the phosphorylation mutant Bcl-xL(Ser49Ala) and dual mutant Bcl-xL(Ser49/62Ala).

  7. Msh2 deficiency leads to chromosomal abnormalities, centrosome amplification, and telomere capping defect

    SciTech Connect

    Wang, Yisong; Liu, Yie

    2006-01-01

    Msh2 is a key mammalian DNA mismatch repair (MMR) gene and mutations or deficiencies in mammalian Msh2 gene result in microsatellite instability (MSI+) and the development of cancer. Here, we report that primary mouse embryonic fibroblasts (MEFs) deficient in the murine MMR gene Msh2 (Msh2-/-) showed a significant increase in chromosome aneuploidy, centrosome amplification, and defective mitotic spindle organization and unequal chromosome segregation. Although Msh2-/- mouse tissues or primary MEFs had no apparent change in telomerase activity, telomere length, or recombination at telomeres, Msh2-/- MEFs showed an increase in chromosome end-to-end fusions or chromosome ends without detectable telomeric DNA. These data suggest that MSH2 helps to maintain genomic stability through the regulation of the centrosome and normal telomere capping in vivo and that defects in MMR can contribute to oncogenesis through multiple pathways.

  8. Three-dimensional ultrasonographic visualization of fetal chromosome abnormalities: a preliminary experience report of 4 cases.

    PubMed

    Komwilaisak, Ratana; Ratanasiri, Thawalwong; Kleebkaow, Pilaiwan

    2004-10-01

    The accurate diagnosis of fetal malformations in utero can provide both heath care providers and parents a number of management options. Three-dimensional ultrasonography is a new technique of diagnosis which has several potential advantages to allow for evaluation of specific anomalies by permitting high-quality views of body surface. We report 4 cases of fetal chromosomal abnormalities including 2 cases of trisomy 21, 1 case of trisomy 13 and 1 case of 48, XXY/+18. All cases were proved to have abnormal chromosomes by amniocentesis or percutaneous umbilical cord blood sampling. After 3D reconstruction, we can identify specific facial abnormalities which can not be visualized by conventional two-dimensional ultrasound such as low set ear Mongolian's slant eyes, facial dysmorphism of trisomy 13 and trisomy 18. We also clearly visualized abnormalities of digits such as overlapping fingers, club hands and sandal gap. Three-dimensional reconstruction of the fetal body surface improves the antenatal diagnosis of chromosomal abnormalities characterized by a particular dysmorphism. Our report suggests that three-dimensional ultrasonography has the potential to provide novel informations on the fetal anatomy and be useful in visualization and identification of chromosomal abnormalities in utero.

  9. Risk of chromosomal abnormalities, with emphasis on live-born offspring of young mothers.

    PubMed Central

    Little, B B; Ramin, S M; Cambridge, B S; Schneider, N R; Cohen, D S; Snell, L M; Harrod, M J; Johnston, W L

    1995-01-01

    In a large public urban hospital obstetrics service with > 123,000 deliveries in a 10-year period (1980-89), the frequencies (0.12%) of any type of chromosomal abnormality and of trisomy syndromes were analyzed for maternal age-related risk, by logistic regression. Focusing on very young gravidas, we found that in the study period there were 9,332 births (7.5% of all deliveries) to mothers < or = 16 years old. Estimated risks of chromosomal abnormalities among offspring associated with very young maternal age (9-16 years) were similar to those age-associated risks of mothers 20-29 years old. Risks of chromosomal abnormalities increase with advancing maternal age and are independent of ethnicity. PMID:7485170

  10. Chromosome 2 (2p16) abnormalities in Carney complex tumours

    PubMed Central

    Matyakhina, L; Pack, S; Kirschner, L; Pak, E; Mannan, P; Jaikumar, J; Taymans, S; Sandrini, F; Carney, J; Stratakis, C

    2003-01-01

    Carney complex (CNC) is an autosomal dominant multiple endocrine neoplasia and lentiginosis syndrome characterised by spotty skin pigmentation, cardiac, skin, and breast myxomas, and a variety of endocrine and other tumours. The disease is genetically heterogeneous; two loci have been mapped to chromosomes 17q22–24 (the CNC1 locus) and 2p16 (CNC2). Mutations in the PRKAR1A tumour suppressor gene were recently found in CNC1 mapping kindreds, while the CNC2 and perhaps other genes remain unidentified. Analysis of tumour chromosome rearrangements is a useful tool for uncovering genes with a role in tumorigenesis and/or tumour progression. CGH analysis showed a low level 2p amplification recurrently in four of eight CNC tumours; one tumour showed specific amplification of the 2p16-p23 region only. To define more precisely the 2p amplicon in these and other tumours, we completed the genomic mapping of the CNC2 region, and analysed 46 tumour samples from CNC patients with and without PRKAR1A mutations by fluorescence in situ hybridisation (FISH) using bacterial artificial chromosomes (BACs). Consistent cytogenetic changes of the region were detected in 40 (87%) of the samples analysed. Twenty-four samples (60%) showed amplification of the region represented as homogeneously stained regions (HSRs). The size of the amplicon varied from case to case, and frequently from cell to cell in the same tumour. Three tumours (8%) showed both amplification and deletion of the region in their cells. Thirteen tumours (32%) showed deletions only. These molecular cytogenetic changes included the region that is covered by BACs 400-P-14 and 514-O-11 and, in the genetic map, corresponds to an area flanked by polymorphic markers D2S2251 and D2S2292; other BACs on the centromeric and telomeric end of this region were included in varying degrees. We conclude that cytogenetic changes of the 2p16 chromosomal region that harbours the CNC2 locus are frequently observed in tumours from CNC

  11. Increased sex chromosome expression and epigenetic abnormalities in spermatids from male mice with Y chromosome deletions.

    PubMed

    Reynard, Louise N; Turner, James M A

    2009-11-15

    During male meiosis, the X and Y chromosomes are transcriptionally silenced, a process termed meiotic sex chromosome inactivation (MSCI). Recent studies have shown that the sex chromosomes remain substantially transcriptionally repressed after meiosis in round spermatids, but the mechanisms involved in this later repression are poorly understood. Mice with deletions of the Y chromosome long arm (MSYq-) have increased spermatid expression of multicopy X and Y genes, and so represent a model for studying post-meiotic sex chromosome repression. Here, we show that the increase in sex chromosome transcription in spermatids from MSYq- mice affects not only multicopy but also single-copy XY genes, as well as an X-linked reporter gene. This increase in transcription is accompanied by specific changes in the sex chromosome histone code, including almost complete loss of H4K8Ac and reduction of H3K9me3 and CBX1. Together, these data show that an MSYq gene regulates sex chromosome gene expression as well as chromatin remodelling in spermatids.

  12. Hypoxia-Induced Reactive Oxygen Species Cause Chromosomal Abnormalities in Endothelial Cells in the Tumor Microenvironment

    PubMed Central

    Hida, Yasuhiro; Maishi, Nako; Towfik, Alam Mohammad; Inoue, Nobuo; Shindoh, Masanobu; Hida, Kyoko

    2013-01-01

    There is much evidence that hypoxia in the tumor microenvironment enhances tumor progression. In an earlier study, we reported abnormal phenotypes of tumor-associated endothelial cells such as those resistant to chemotherapy and chromosomal instability. Here we investigated the role of hypoxia in the acquisition of chromosomal abnormalities in endothelial cells. Tumor-associated endothelial cells isolated from human tumor xenografts showed chromosomal abnormalities, >30% of which were aneuploidy. Aneuploidy of the tumor-associated endothelial cells was also shown by simultaneous in-situ hybridization for chromosome 17 and by immunohistochemistry with anti-CD31 antibody for endothelial staining. The aneuploid cells were surrounded by a pimonidazole-positive area, indicating hypoxia. Human microvascular endothelial cells expressed hypoxia-inducible factor 1 and vascular endothelial growth factor A in response to either hypoxia or hypoxia-reoxygenation, and in these conditions, they acquired aneuploidy in 7 days. Induction of aneuploidy was inhibited by either inhibition of vascular endothelial growth factor signaling with vascular endothelial growth factor receptor 2 inhibitor or by inhibition of reactive oxygen species by N-acetyl-L-cysteine. These results indicate that hypoxia induces chromosomal abnormalities in endothelial cells through the induction of reactive oxygen species and excess signaling of vascular endothelial growth factor in the tumor microenvironment. PMID:24260373

  13. Ring chromosome 5 associated with severe growth retardation as the sole major physical abnormality

    SciTech Connect

    Migliori, M.V.; Pettinari, A.; Cherubini, V.; Bartolotta, E.; Pecora, R.

    1994-01-01

    The authors report on a case of ring chromosome 5 in a 36-month-old girl with severe growth retardation, clinodactyly, mild psychological abnormalities, and normal facial appearance. Endocrine tests showed partial growth hormone deficiency. Cytogenetic investigation failed to demonstrate any apparent microscopic deletion of either the short or long arm of chromosome 5 as a consequence of ring formation. In 12% of cells examined, the ring was either absent or present in multiple copies. Only 3 previous cases of ring chromosome 5 have been reported in association with short stature of prenatal onset and minor anomalies, without mental retardation. 12 refs., 3 figs.

  14. Method of detecting genetic deletions identified with chromosomal abnormalities

    DOEpatents

    Gray, Joe W; Pinkel, Daniel; Tkachuk, Douglas

    2013-11-26

    Methods and compositions for staining based upon nucleic acid sequence that employ nucleic acid probes are provided. Said methods produce staining patterns that can be tailored for specific cytogenetic analyzes. Said probes are appropriate for in situ hybridization and stain both interphase and metaphase chromosomal material with reliable signals. The nucleic acids probes are typically of a complexity greater tha 50 kb, the complexity depending upon the cytogenetic application. Methods and reagents are provided for the detection of genetic rearrangements. Probes and test kits are provided for use in detecting genetic rearrangements, particlularly for use in tumor cytogenetics, in the detection of disease related loci, specifically cancer, such as chronic myelogenous leukemia (CML) and for biological dosimetry. Methods and reagents are described for cytogenetic research, for the differentiation of cytogenetically similar ut genetically different diseases, and for many prognostic and diagnostic applications.

  15. [Klinefelter syndrome affects mostly boys. An underdiagnosed chromosome abnormality].

    PubMed

    Hagenäs, L; Arver, S

    1998-06-03

    Although Klinefelter's syndrome is the most common sex chromosome anomaly, affecting one in 5-800 boys, our knowledge of the syndrome is still poor. This is reflected in the paucity of published literature as compared, for example, with the vastly greater number of publications on Turner's syndrome with its lower incidence of 1/2,500 girls. Klinefelter's syndrome is manifestly underdiagnosed. Existing knowledge mainly derives from cases characterised by prominent symptomatology. Early diagnosis is important if additional support and resources are to be made available to the patient and his family. Testosterone replacement therapy should be initiated as soon as clinical and laboratory evidence becomes available. In selected cases, testosterone treatment can be started already during adolescence. At present, there is no established treatment for the infertility which almost always accompanies the condition.

  16. Method of detecting genetic translocations identified with chromosomal abnormalities

    DOEpatents

    Gray, Joe W.; Pinkel, Daniel; Tkachuk, Douglas

    2001-01-01

    Methods and compositions for staining based upon nucleic acid sequence that employ nucleic acid probes are provided. Said methods produce staining patterns that can be tailored for specific cytogenetic analyses. Said probes are appropriate for in situ hybridization and stain both interphase and metaphase chromosomal material with reliable signals. The nucleic acid probes are typically of a complexity greater than 50 kb, the complexity depending upon the cytogenetic application. Methods and reagents are provided for the detection of genetic rearrangements. Probes and test kits are provided for use in detecting genetic rearrangements, particularly for use in tumor cytogenetics, in the detection of disease related loci, specifically cancer, such as chronic myelogenous leukemia (CML) and for biological dosimetry. Methods and reagents are described for cytogenetic research, for the differentiation of cytogenetically similar but genetically different diseases, and for many prognostic and diagnostic applications.

  17. Chromosomal abnormalities in couples with repeated fetal loss: An Indian retrospective study

    PubMed Central

    Sheth, Frenny J; Liehr, Thomas; Kumari, Pritti; Akinde, Ralph; Sheth, Harsh J; Sheth, Jayesh J

    2013-01-01

    BACKGROUND: Recurrent pregnancy loss is a common occurrence and a matter of concern for couples planning the pregnancy. Chromosomal abnormalities, mainly balanced rearrangements, are common in couples with repeated miscarriages. PURPOSE: The purpose of this study is to evaluate the contribution of chromosomal anomalies causing repeated spontaneous miscarriages and provide detailed characterization of a few structurally altered chromosomes. MATERIALS AND METHODS: A retrospective cytogenetic study was carried out on 4859 individuals having a history of recurrent miscarriages. The cases were analyzed using G-banding and fluorescence in situ hybridization wherever necessary. RESULTS: Chromosomal rearrangements were found in 170 individuals (3.5%). Translocations were seen in 72 (42.35%) cases. Of these, reciprocal translocations constituted 42 (24.70%) cases while Robertsonian translocations were detected in 30 (17.64%) cases. 7 (4.11%) cases were mosaic, 8 (4.70%) had small supernumerary marker chromosomes and 1 (0.6%) had an interstitial microdeletion. Nearly, 78 (1.61%) cases with heteromorphic variants were seen of which inversion of Y chromosome (57.70%) and chromosome 9 pericentromeric variants (32.05%) were predominantly involved. CONCLUSIONS: Chromosomal analysis is an important etiological investigation in couples with repeated miscarriages. Characterization of variants/marker chromosome enable calculation of a more precise recurrent risk in a subsequent pregnancy thereby facilitating genetic counseling and deciding further reproductive options. PMID:24497706

  18. Dbf4-dependent CDC7 kinase links DNA replication to the segregation of homologous chromosomes in meiosis I.

    PubMed

    Matos, Joao; Lipp, Jesse J; Bogdanova, Aliona; Guillot, Sylvine; Okaz, Elwy; Junqueira, Magno; Shevchenko, Andrej; Zachariae, Wolfgang

    2008-11-14

    Meiosis differs from mitosis in that DNA replication is followed by the segregation of homologous chromosomes but not sister chromatids. This depends on the formation of interhomolog connections through crossover recombination and on the attachment of sister kinetochores to microtubules emanating from the same spindle pole. We show that in yeast, the Dbf4-dependent Cdc7 kinase (DDK) provides a link between premeiotic S phase, recombination, and monopolar attachment. Independently from its established role in initiating DNA replication, DDK promotes double-strand break formation, the first step of recombination, and the recruitment of the monopolin complex to kinetochores, which is essential for monopolar attachment. DDK regulates monopolin localization together with the polo-kinase Cdc5 bound to Spo13, probably through phosphorylation of the monopolin subunit Lrs4. Thus, activation of DDK both initiates DNA replication and commits meiotic cells to reductional chromosome segregation in the first division of meiosis.

  19. Chromosome 1 abnormalities in elderly patients with newly diagnosed multiple myeloma treated with novel therapies

    PubMed Central

    Caltagirone, Simona; Ruggeri, Marina; Aschero, Simona; Gilestro, Milena; Oddolo, Daniela; Gay, Francesca; Bringhen, Sara; Musolino, Caterina; Baldini, Luca; Musto, Pellegrino; Petrucci, Maria T.; Gaidano, Gianluca; Passera, Roberto; Bruno, Benedetto; Palumbo, Antonio; Boccadoro, Mario; Omedè, Paola

    2014-01-01

    Multiple myeloma is a plasma cell disorder characterized by malignant plasma cell infiltration in the bone marrow, serum and/or urine monoclonal protein and organ damage. The aim of this study was to investigate the impact of chromosome 1 abnormalities in a group of elderly patients (>65 years) with newly diagnosed multiple myeloma enrolled in the GIMEMA-MM-03-05 trial and treated with bortezomib, melphalan and prednisone or bortezomib, melphalan, prednisone and thalidomide followed by bortezomib and thalidomide maintenance. We also evaluated the link between chromosome 1 abnormalities and other clinical, genetic and immunophenotypic features by a multivariate logistic regression model. Interphase fluorescence in situ hybridization on immunomagnetically purified plasma cells and bone marrow multiparameter flow cytometry were employed. A multivariate Cox model showed that chromosome 1 abnormalities, age >75 years and a CD19+/CD117− immunophenotype of bone marrow plasma cells were independent risk factors for overall survival in elderly patients with newly diagnosed multiple myeloma. Moreover, a detrimental effect of thalidomide, even when administered in association with bortezomib, was observed in patients with abnormal chromosome 1 as well as in those with 17p deletion, while the benefit of adding thalidomide to the bortezomib-melphalan-prednisone regimen was noted in patients carrying an aggressive CD19+/CD117− bone marrow plasma cell immunophenotype. This trial was registered at www.clinicaltri-als.gov as #NCT01063179. PMID:25015938

  20. Overview of epidemiology, genetics, birth defects, and chromosome abnormalities associated with CDH.

    PubMed

    Pober, Barbara R

    2007-05-15

    Congenital diaphragmatic hernia (CDH) is a common and well-studied birth defect. The etiology of most cases remains unknown but increasing evidence points to genetic causation. The data supporting genetic etiologies which are detailed below include the association of CDH with recurring chromosome abnormalities, the existence of CDH-multiplex families, and the co-occurrence of CDH with additional congenital malformations.

  1. Maternal translocation (9;18) with two abnormal offspring each with different chromosome derivatives.

    PubMed Central

    Pearson, M; Riske, C; Allanson, J E

    1989-01-01

    We report a phenotypically normal woman with an apparently balanced reciprocal translocation between chromosomes 9 and 18 [46,XX,t(9;18)(p22;p11.2)], giving rise to unbalanced chromosome complements in two of her children, each of whom received a different derivative chromosome. The proband's karyotype is 46,XY,-18,+der(18), t(9;18)(p22;p11.2)mat, which results in a duplication of the distal portion of the short arm of chromosome 9 with a concomitant deletion of much of the short arm of chromosome 18. The karyotype of the proband's brother is 46, XY,-9,+der(9),t(9;18)(p22;p11.2)mat, which results in a deletion of the distal short arm of chromosome 9 and a duplication of most of the short arm of chromosome 18. The phenotype of each child is significantly different from that of his sib and is not consistent with any previously reported chromosome abnormality. Images PMID:2585464

  2. Constitutional abnormalities of chromosome 21 predispose to iAMP21-acute lymphoblastic leukaemia.

    PubMed

    Harrison, Christine J; Schwab, Claire

    2016-03-01

    In addition to Down syndrome, individuals with other constitutional abnormalities of chromosome 21 have an increased risk of developing childhood acute lymphoblastic leukaemia (ALL). Specifically, carriers of the Robertsonian translocation between chromosomes 15 and 21, rob(15;21) (q10; q10)c, have ∼2,700 increased risk of developing ALL with iAMP21 (intrachromosomal amplification of chromosome 21). In these patients, chromosome 15 as well as chromosome 21 is involved in the formation of iAMP21, referred to here as der(21)(15;21). Individuals with constitutional ring chromosomes involving chromosome 21, r(21)c, are also predisposed to iAMP21-ALL, involving the same series of mutational processes as seen in sporadic- and der(21)(15;21)-iAMP21 ALL. Evidence is accumulating that the dicentric nature of the Robertsonian and ring chromosome is the initiating factor in the formation of the complex iAMP21 structure. Unravelling these intriguing predispositions to iAMP21-ALL may provide insight into how other complex rearrangements arise in cancer.

  3. Chromosome abnormalities, mental retardation and the search for genes in bipolar disorder and schizophrenia.

    PubMed

    Blackwood, D H R; Thiagarajah, T; Malloy, P; Pickard, B S; Muir, W J

    2008-10-01

    Genetic factors contribute to schizophrenia and bipolar disorder, and linkage and association studies have been successful in identifying several candidate genes. However these genes explain only a very small part of the total population risk and the psychoses appear to be very heterogeneous with several models of genetic inheritance relevant to different groups of patients, including some cases caused by multiple common genetic variants, while others are single gene disorders. Studying chromosomal abnormalities is a useful strategy for identifying genes in illness, and patients with both mental retardation and psychosis form a special group where large chromosomal abnormalities detected by routine cytogenetic analysis are more prevalent than in patients with schizophrenia or bipolar disorder alone, or in the general population. Studying these patients provides valuable opportunities to identify genes contributing to psychoses. This review of the literature on large chromosomal rearrangements in patients with mental retardation and psychotic illness illustrates how schizophrenia and bipolar phenotypes are associated with a large number of different chromosomal disruptions. Recent genome wide association studies have identified an excess of small chromosomal deletions and duplications in schizophrenia, adding further support to the importance of chromosomal structural variation in psychotic illness. The genes GRIK4 and NPAS3, each associated with psychosis in patients with mental retardation are discussed to illustrate the value of rare cytogenetic events as a means to signpost neurobiological pathways of general importance for illness in the wider population.

  4. Segregation analysis in a man heterozygous for a pericentric inversion of chromosome 7 (p13; q36) by sperm chromosome studies

    SciTech Connect

    Navarror, J.; Benet, J.; Martorell, M.R.; Templado, C.; Egozcue, J. )

    1993-07-01

    The authors have analyzed 140 sperm chromosome complements from a subfertile man heterozygous for an inv(7)(p13;q36). Seventy-five percent of the chromosome complements were not recombinant: 37.9% contained the normal chromosome 7, and 37.1% contained the inverted chromosome 7. Twenty-five percent of the 140 were recombinant: 7.1% carried a recombinant chromosome 7 with a duplication p and deletion q, 17.1% carried a recombinant chromosome 7 with a duplication q and deletion p, and 0.7% carried both recombinant chromosomes. The frequency of structural chromosomal aberrations unrelated to the inversion was 11.4%, and the frequency of aneuploidy was 2.9%. Both frequencies were not significantly different from those in control donors. Two sperm complements with a second independent, contiguous inversion involving one of the original breakpoints (q36) were observed (1.4%). The risk of producing chromosomally abnormal offspring or spontaneous abortions would be 34.3%. The proportion of X-bearing and Y-bearing sperm was 46.8% and 53.2%, respectively, not significantly different from the expected 1:1 ratio. 28 refs., 4 figs., 1 tab.

  5. Health-related quality of life experienced by children with chromosomal abnormalities and congenital heart defects.

    PubMed

    Garcia Guerra, Gonzalo; Joffe, Ari R; Robertson, Charlene M T; Atallah, Joseph; Alton, Gwen; Sauve, Reg S; Dinu, Irina A; Ross, David B; Rebeyka, Ivan M

    2014-03-01

    Long-term outcomes are fundamental in advising parents about the potential future of their children with congenital heart disease (CHD). No published reports have described the health-related quality of life (HRQL) experienced by children with chromosomal abnormalities who had surgery in early infancy for CHD. A study was undertaken to assess HRQL among children with chromosomal abnormalities and CHD. The authors hypothesized that these children have a worse HRQL than healthy children or a cohort of children matched for CHD diagnosis. Infants with chromosomal abnormalities undergoing cardiac surgery for CHD at 6 weeks of age or younger at the Stollery Children's Hospital between July 2000 and June 2005 were included in the study. The HRQL of these infants was assessed using the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales completed by their parents at a 4-year follow-up evaluation. The study compared the scores for 16 children with normative data. The children with chromosomal abnormalities and CHD had significantly lower mean total PedsQL (71.3 vs. 87.3; p < 0.0001), Psychosocial Summary (70.3 vs. 86.1; p < 0.0001), and Physical Summary (74.3 vs. 89.2; p = 0.0006) scores. Compared with the matched children, those with chromosomal abnormalities had a significantly lower median total PedsQL (75.0 vs. 84.6; p = 0.03), Physical Summary (79.5 vs. 96.9; p = 0.007), and School Functioning (68.5 vs. 83.0; p = 0.03) scores. A better understanding of the mechanisms and determinants of HRQL in these children has the potential to yield important implications for clinical practice including clarity for treatment decision making as well as determination of targeted supports and services to meet the needs of these children and their families differentially.

  6. Molecular investigation of a dicentric 13;17 chromosome found in a 21-week gestation fetus with multiple congenital abnormalities.

    PubMed

    Cockwell, A E; Maloney, V K; Thomas, N S; Smith, E L; Gonda, P; Bass, P; Crolla, J A

    2006-01-01

    We report a 21-week gestation fetus terminated because of multiple congenital abnormalities seen on ultrasound scan, including ventriculomegaly, possible clefting of the hard palate, cervical hemivertebrae, micrognathia, abnormal heart, horseshoe kidney and a 2-vessel umbilical cord. On cytogenetic examination, the fetus was found to have a male karyotype with 45 chromosomes with a dicentric chromosome, which appeared to consist of the long arms of chromosomes 13 and 17. Molecular genetic investigations and fluorescence in situ hybridization (FISH) unexpectedly showed that the derivative chromosome contained two interstitial blocks of chromosome 17 short arm sequences, totalling approximately 7 Mb, between the two centromeres. This effectively made the fetus monosomic for approximately 15 Mb of 17p without the concurrent trisomy for another chromosome normally seen following malsegregation of reciprocal translocations. It also illustrates the complexity involved in the formation of some structurally abnormal chromosomes, which can only be resolved by detailed molecular investigations.

  7. The CENP-F-like proteins HCP-1 and HCP-2 target CLASP to kinetochores to mediate chromosome segregation.

    PubMed

    Cheeseman, Iain M; MacLeod, Ian; Yates, John R; Oegema, Karen; Desai, Arshad

    2005-04-26

    During chromosome segregation, kinetochores form dynamic connections with spindle microtubules. In vertebrates, these attachments require the activities of a number of outer kinetochore proteins, including CENP-F [1, 2] and the widely conserved microtubule-associated protein CLASP [3]. Here, we investigate the functional relationship between HCP-1/2, two redundant CENP-F-like proteins, and CLASP(CLS-2) in Caenorhabditis elegans. HCP-1/2 and CLASP(CLS-2) localize transiently to mitotic C. elegans kinetochores with nearly identical kinetic profiles, and biochemical purifications demonstrate that they also associate physically. In embryos depleted of HCP-1/2, CLASP(CLS-2) no longer localizes to chromosomes, whereas CLASP(CLS-2) depletion does not prevent HCP-1/2 targeting. Consistent with the localization dependency and biochemical association, depletion of HCP-1/2 or CLASP(CLS-2) resulted in virtually identical defects in mitotic chromosome segregation characterized by a failure of sister-chromatid biorientation. This phenotype could be partially suppressed by disrupting the astral forces that pull spindle poles apart in the 1 cell embryo, indicating that CLASP(CLS-2) is required for biorientation when chromosome-spindle attachments are subjected to poleward force. Our results establish that the key role of HCP-1/2 is to target CLASP(CLS-2) to kinetochores, and they support the recently proposed model that CLASP functions to promote the polymerization of kinetochore bound microtubules [4].

  8. ParA and ParB coordinate chromosome segregation with cell elongation and division during Streptomyces sporulation

    PubMed Central

    Donczew, Magdalena; Mackiewicz, Paweł; Wróbel, Agnieszka; Flärdh, Klas; Zakrzewska-Czerwińska, Jolanta

    2016-01-01

    In unicellular bacteria, the ParA and ParB proteins segregate chromosomes and coordinate this process with cell division and chromosome replication. During sporulation of mycelial Streptomyces, ParA and ParB uniformly distribute multiple chromosomes along the filamentous sporogenic hyphal compartment, which then differentiates into a chain of unigenomic spores. However, chromosome segregation must be coordinated with cell elongation and multiple divisions. Here, we addressed the question of whether ParA and ParB are involved in the synchronization of cell-cycle processes during sporulation in Streptomyces. To answer this question, we used time-lapse microscopy, which allows the monitoring of growth and division of single sporogenic hyphae. We showed that sporogenic hyphae stop extending at the time of ParA accumulation and Z-ring formation. We demonstrated that both ParA and ParB affect the rate of hyphal extension. Additionally, we showed that ParA promotes the formation of massive nucleoprotein complexes by ParB. We also showed that FtsZ ring assembly is affected by the ParB protein and/or unsegregated DNA. Our results indicate the existence of a checkpoint between the extension and septation of sporogenic hyphae that involves the ParA and ParB proteins. PMID:27248800

  9. ParA and ParB coordinate chromosome segregation with cell elongation and division during Streptomyces sporulation.

    PubMed

    Donczew, Magdalena; Mackiewicz, Paweł; Wróbel, Agnieszka; Flärdh, Klas; Zakrzewska-Czerwińska, Jolanta; Jakimowicz, Dagmara

    2016-04-01

    In unicellular bacteria, the ParA and ParB proteins segregate chromosomes and coordinate this process with cell division and chromosome replication. During sporulation of mycelial Streptomyces, ParA and ParB uniformly distribute multiple chromosomes along the filamentous sporogenic hyphal compartment, which then differentiates into a chain of unigenomic spores. However, chromosome segregation must be coordinated with cell elongation and multiple divisions. Here, we addressed the question of whether ParA and ParB are involved in the synchronization of cell-cycle processes during sporulation in Streptomyces To answer this question, we used time-lapse microscopy, which allows the monitoring of growth and division of single sporogenic hyphae. We showed that sporogenic hyphae stop extending at the time of ParA accumulation and Z-ring formation. We demonstrated that both ParA and ParB affect the rate of hyphal extension. Additionally, we showed that ParA promotes the formation of massive nucleoprotein complexes by ParB. We also showed that FtsZ ring assembly is affected by the ParB protein and/or unsegregated DNA. Our results indicate the existence of a checkpoint between the extension and septation of sporogenic hyphae that involves the ParA and ParB proteins.

  10. Analysis of non-clonal chromosome abnormalities observed in hematologic malignancies among Southwest Oncology Group patients

    SciTech Connect

    McConnell, T.S.; Dobin, S.M.

    1994-09-01

    From 1987-1994, the Southwest Oncology Group Cytogenetics Committee reviewed 1571 studies in 590 adult patient cases with ALL, AML, CML or CLL. These were analyzed for the presence of clinically important non-clonal abnormalities (NCA). Abnormalities were defined as non-clonal if one metaphase had a structural abnormality or an extra chromosome. Chromosome loss was not analyzed due to the possibility of random loss. In 72 cases (12%) comprising 136 studies, at least one NCA was observed. In 21 of these cases (29%), NCAs consisted of obvious clonal evolution or instability, and thus were not included in the analysis. At least one structural NCA was observed in which the abnormality differed from the mainline in 36 (50%) patients. Seventeen of the 36 cases had a normal mode. Nineteen of the 36 patients had an abnormal or normal/abnormal mode. At least one numerical NCA was found in 15 cases (21%). Fifteen cases (21%) contained at least one marker chromosome. Several cases involved NCA in more than one of the above divisions. NCAs could be classified into several categories: (1){open_quotes}the clone to come{close_quotes}, (2) evolving clones which then disappeared, (3) NCAs with putative clinical importance that never became clonal, (4) NCAs during remission identical to the preceding clonal abnormality, (5) NCAs which indicated clonal evolution or instability. Examples include one metaphase with t(9;22) or del(20q) or inv(16) or +8 which either preceded or followed clonal findings of the same aberration. Such findings should be communicated to the clinician.

  11. Abnormal dicentric chromosome with co-amplification of sequences from chromosomes 11 and 19: a novel rearrangement in a patient with myelodysplastic syndrome transforming to acute myeloid leukemia.

    PubMed

    Smith, A; Heaps, L S; Sharma, P; Jarvis, A; Forsyth, C

    2001-10-01

    A 66-year-old man with a myelodysplastic syndrome transforming to acute myeloid leukemia showed a complex abnormal karyotype on bone marrow aspirate. An unbalanced dicentric translocation with a very long der(11) long arm-dic(11;19)(q25;p13.4)-was present. Fluorescence in situ hybridization studies utilised paints for chromosomes 11 and 19 as well as the locus specific probe MLL, localised to 11q23. The abnormal chromosome 11q contained 6 copies of intact MLL and 6 copies of chromosome 19 (unidentified) sequences. To our knowledge, gene co-amplification of chromosomes 11 and 19 sequences has not been reported before.

  12. Clinical and molecular cytogenetic studies in ring chromosome 5: report of a child with congenital abnormalities.

    PubMed

    Basinko, Audrey; Giovannucci Uzielli, Maria Luisa; Scarselli, Gloria; Priolo, Manuela; Timpani, Giuseppina; De Braekeleer, Marc

    2012-02-01

    We report here a child with a ring chromosome 5 (r(5)) associated with facial dysmorphology and multiple congenital abnormalities. Fluorescent in situ hybridization (FISH) using bacterial artificial chromosome (BAC) clones was performed to determine the breakpoints involved in the r(5). The 5p deletion extended from 5p13.2-3 to 5pter and measured 34.61 Mb (range: 33.7-35.52 Mb) while the 5q deletion extended from 5q35.3 to 5qter and measured 2.44 Mb (range: 2.31-2.57 Mb). The patient presented signs such as microcephaly, hypertelorism, micrognathia and epicanthal folds, partially recalling those of a deletion of the short arm of chromosome 5 and the "cri-du-chat" syndrome. The most striking phenotypic features were the congenital heart abnormalities which have been frequently reported in deletions of the distal part of the long arm of chromosome 5 and in rings leading to a 5q35-5qter deletion. However, the NKX2-5 gene, which has been related to congenital heart defects, was not deleted in our patient, nor presumably to some other patients with 5q35.3-5qter deletion. We propose that VEGFR3, deleted in our patient, could be a candidate gene for the congenital heart abnormalities observed.

  13. Combined Use of Cytogenetic and Molecular Methods in Prenatal Diagnostics of Chromosomal Abnormalities

    PubMed Central

    Stomornjak-Vukadin, Meliha; Kurtovic-Basic, Ilvana; Mehinovic, Lejla; Konjhodzic, Rijad

    2015-01-01

    Aim: The aim of prenatal diagnostics is to provide information of the genetic abnormalities of the fetus early enough for the termination of pregnancy to be possible. Chromosomal abnormalities can be detected in an unborn child through the use of cytogenetic, molecular- cytogenetic and molecular methods. In between them, central spot is still occupied by cytogenetic methods. In cases where use of such methods is not informative enough, one or more molecular cytogenetic methods can be used for further clarification. Combined use of the mentioned methods improves the quality of the final findings in the diagnostics of chromosomal abnormalities, with classical cytogenetic methods still occupying the central spot. Material and methods: Conducted research represent retrospective-prospective study of a four year period, from 2008 through 2011. In the period stated, 1319 karyotyping from amniotic fluid were conducted, along with 146 FISH analysis. Results: Karyotyping had detected 20 numerical and 18 structural aberrations in that period. Most common observed numerical aberration were Down syndrome (75%), Klinefelter syndrome (10%), Edwards syndrome, double Y syndrome and triploidy (5% each). Within observed structural aberrations more common were balanced chromosomal aberrations then non balanced ones. Most common balanced structural aberrations were as follows: reciprocal translocations (60%), Robertson translocations (13.3%), chromosomal inversions, duplications and balanced de novo chromosomal rearrangements (6.6% each). Conclusion: With non- balanced aberrations observed in the samples of amniotic fluid, non- balanced translocations, deletions and derived chromosomes were equally represented. Number of detected aneuploidies with FISH, prior to obtaining results with karyotyping, were 6. PMID:26005269

  14. Additional chromosome abnormalities in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and chemotherapy

    PubMed Central

    Cervera, José; Montesinos, Pau; Hernández-Rivas, Jesús M.; Calasanz, María J.; Aventín, Anna; Ferro, María T.; Luño, Elisa; Sánchez, Javier; Vellenga, Edo; Rayón, Chelo; Milone, Gustavo; de la Serna, Javier; Rivas, Concha; González, José D.; Tormo, Mar; Amutio, Elena; González, Marcos; Brunet, Salut; Lowenberg, Bob; Sanz, Miguel A.

    2010-01-01

    Background Acute promyelocytic leukemia is a subtype of acute myeloid leukemia characterized by the t(15;17). The incidence and prognostic significance of additional chromosomal abnormalities in acute promyelocytic leukemia is still a controversial matter. Design and Methods Based on cytogenetic data available for 495 patients with acute promyelocytic leukemia enrolled in two consecutive PETHEMA trials (LPA96 and LPA99), we analyzed the incidence, characteristics, and outcome of patients with acute promyelocytic leukemia with and without additional chromosomal abnormalities who had been treated with all-trans retinoic acid plus anthracycline monochemotherapy for induction and consolidation. Results Additional chromosomal abnormalities were observed in 140 patients (28%). Trisomy 8 was the most frequent abnormality (36%), followed by abn(7q) (5%). Patients with additional chromosomal abnormalities more frequently had coagulopathy (P=0.03), lower platelet counts (P=0.02), and higher relapse-risk scores (P=0.02) than their counterparts without additional abnormalities. No significant association with FLT3/ITD or other clinicopathological characteristics was demonstrated. Patients with and without additional chromosomal abnormalities had similar complete remission rates (90% and 91%, respectively). Univariate analysis showed that additional chromosomal abnormalities were associated with a lower relapse-free survival in the LPA99 trial (P=0.04), but not in the LPA96 trial. However, neither additional chromosomal abnormalities overall nor any specific abnormality was identified as an independent risk factor for relapse in multivariate analysis. Conclusions The lack of independent prognostic value of additional chromosomal abnormalities in acute promyelocytic leukemia does not support the use of alternative therapeutic strategies when such abnormalities are found. PMID:19903674

  15. Persistent Mosaicism for 12p Duplication/Triplication Chromosome Structural Abnormality in Peripheral Blood

    PubMed Central

    Shackelford, Amy L.; Conlin, Laura K.; Spinner, Nancy B.; Wenger, Sharon L.

    2013-01-01

    We present a rare case of mosaicism for a structural abnormality of chromosome 12 in a patient with phenotypic features of Pallister-Killian syndrome. A six-month-old child with dysmorphic features, exotropia, hypotonia, and developmental delay was mosaic for both a normal karyotype and a cell line with 12p duplication/triplication in 25 percent of metaphase cells. Utilization of fluorescence in situ hybridization (FISH) identified three copies of probes from the end of the short arm of chromosome 12 (TEL(12p13) locus and the subtelomere (12p terminal)) on the structurally abnormal chromosome 12. Genome-wide SNP array analysis revealed that the regions of duplication and triplication were of maternal origin. The abnormal cell line in our patient was present at 25 percent at six months and 19 months of age in both metaphase and interphase cells from peripheral blood, where typically the isochromosome 12p is absent in the newborn. This may suggest that the gene(s) resulting in a growth disadvantage of abnormal cells in peripheral blood of patients with tetrasomy 12p may not have the same influence when present in only three copies. PMID:24151566

  16. Sex without sex chromosomes: genetic architecture of multiple loci independently segregating to determine sex ratios in the copepod Tigriopus californicus.

    PubMed

    Alexander, H J; Richardson, J M L; Edmands, S; Anholt, B R

    2015-12-01

    Sex-determining systems are remarkably diverse and may evolve rapidly. Polygenic sex-determination systems are predicted to be transient and evolutionarily unstable, yet examples have been reported across a range of taxa. Here, we provide the first direct evidence of polygenic sex determination in Tigriopus californicus, a harpacticoid copepod with no heteromorphic sex chromosomes. Using genetically distinct inbred lines selected for male- and female-biased clutches, we generated a genetic map with 39 SNPs across 12 chromosomes. Quantitative trait locus mapping of sex ratio phenotype (the proportion of male offspring produced by an F2 female) in four F2 families revealed six independently segregating quantitative trait loci on five separate chromosomes, explaining 19% of the variation in sex ratios. The sex ratio phenotype varied among loci across chromosomes in both direction and magnitude, with the strongest phenotypic effects on chromosome 10 moderated to some degree by loci on four other chromosomes. For a given locus, sex ratio phenotype varied in magnitude for individuals derived from different dam lines. These data, together with the environmental factors known to contribute to sex determination, characterize the underlying complexity and potential lability of sex determination, and confirm the polygenic architecture of sex determination in T. californicus.

  17. [Prenatal diagnosis. II. Importance of ultrasonographic markers in prenatal diagnosis of chromosome abnormalities].

    PubMed

    Prieto-Carrasquero, M; Molero, A; Carrasquero, N; Del Villar, A; González-Ferrer, S; Rojas, A; Brito, J; Mena, R; González, L; Pérez, F; Alvarez, F; Quintero, M; Fulcado, W

    1998-12-01

    The Medical Genetic Unit of the University of Zulia (MGUUZ) has developed a Prenatal Diagnosis Program (PDP) since January-1993, in which Genetic Risk Factors are determined in couples who request prenatal genetic counseling. In this program, different prenatal diagnostic procedures are performed to detect congenital defects during intrauterine life. One of these procedures is the Fetal Sonogram (FS). FS is a non invasive technique which permits the prenatal diagnosis of many genetic dysmorphic syndromes. Through the search of abnormal specific characteristics in the fetus, chromosomopathies may be suspected. These findings are named "Echosonographic Markers of Chromosomal Abnormalities" (EMCA). During three years (January-1993 to December-1996), patients attended in the PDP included 321 pregnant women in which 312 FS were performed. Abnormal outcomes were 22 (17 with isolated congenital malformations and 5 with EMCA). Only one fetus with chromosome abnormality (46,XX21q-) could not be detected by FS. The goals of this paper are: 1) to report 5 patients with sonographic markers suggestive of chromosomal abnormalities and 2) to show the FS usefulness in prenatal diagnosis of chromosompathies. We conclude that, in the search of the EMCA the FS should be offered systematically to all pregnant women without recognizable genetic risk. They are the main group with optimal reproductive age and in consequence, with the possibility of having a relatively major number of conception outcomes with congenital defects, with or without chromosomic etiology. The majority of those defects can be detected by FS and could allow us to select the patients in which the use of an invasive prenatal diagnostic procedure could be justified.

  18. Duplication 15q14 --> pter: a rare chromosomal abnormality underlying bipolar affective disorder.

    PubMed

    Reif, Andreas; Kress, Wolfgang; Wurm, Karl; Benninghoff, Jens; Pfuhlmann, Bruno; Lesch, Klaus-Peter

    2004-05-01

    We have followed up a patient with 8q24.2 --> qter and 15q14 --> pter duplication due to a maternal reciprocal translocation, a condition related to Prader-Willi Syndrome. Apart from dysmorphic features, the patient suffered from recurring episodes of bipolar psychosis. Interestingly, PET scanning revealed revealed prominent bilateral hypometabolism in the frontal, temporal, and parietal lobes as well as in the cerebellum. Possible implications of this rare chromosomal abnormality with regards to psychiatric disorders are discussed, with emphasis on recent evidence suggesting chromosome 15q13-15 as a susceptibility locus for psychosis.

  19. Congenital Abnormalities

    MedlinePlus

    ... Listen Español Text Size Email Print Share Congenital Abnormalities Page Content Article Body About 3% to 4% ... of congenital abnormalities earlier. 5 Categories of Congenital Abnormalities Chromosome Abnormalities Chromosomes are structures that carry genetic ...

  20. X chromosome-linked and mitochondrial gene control of Leber hereditary optic neuropathy: Evidence from segregation analysis for dependence on X chromosome inactivation

    SciTech Connect

    Xiangdong Bu; Rotter, J.I. Univ. of California, Los Angeles )

    1991-09-15

    Leber hereditary optic neuropathy (LHON) has been shown to involve mutation(s) of mitochondrial DNA, yet there remain several confusing aspects of its inheritance not explained by mitochondrial inheritance alone, including male predominance, reduced penetrance, and a later age of onset in females. By extending segregation analysis methods to disorders that involve both a mitochondrial and a nuclear gene locus, the authors show that the available pedigree data for LHON are most consistent with a two-locus disorder, with one responsible gene being mitochondrial and the other nuclear and X chromosome-linked. Furthermore, they have been able to extend the two-locus analytic method and demonstrate that a proportion of affected females are likely heterozygous at the X chromosome-linked locus and are affected due to unfortunate X chromosome inactivation, thus providing an explanation for the later age of onset in females. The estimated penetrance for a heterozygous female is 0.11{plus minus}0.02. The calculated frequency of the X chromosome-linked gene for LHON is 0.l08. Among affected females, 60% are expected to be heterozygous, and the remainder are expected to be homozygous at the responsible X chromosome-linked locus.

  1. X chromosome-linked and mitochondrial gene control of Leber hereditary optic neuropathy: evidence from segregation analysis for dependence on X chromosome inactivation.

    PubMed

    Bu, X D; Rotter, J I

    1991-09-15

    Leber hereditary optic neuropathy (LHON) has been shown to involve mutation(s) of mitochondrial DNA, yet there remain several confusing aspects of its inheritance not explained by mitochondrial inheritance alone, including male predominance, reduced penetrance, and a later age of onset in females. By extending segregation analysis methods to disorders that involve both a mitochondrial and a nuclear gene locus, we show that the available pedigree data for LHON are most consistent with a two-locus disorder, with one responsible gene being mitochondrial and the other nuclear and X chromosome-linked. Furthermore, we have been able to extend the two-locus analytic method and demonstrate that a proportion of affected females are likely heterozygous at the X chromosome-linked locus and are affected due to unfortunate X chromosome inactivation, thus providing an explanation for the later age of onset in females. The estimated penetrance for a heterozygous female is 0.11 +/- 0.02. The calculated frequency of the X chromosome-linked gene for LHON is 0.08. Among affected females, 60% are expected to be heterozygous, and the remainder are expected to be homozygous at the responsible X chromosome-linked locus.

  2. A synaptonemal complex-derived mechanism for meiotic segregation precedes the evolutionary loss of homology between sex chromosomes in arvicolid mammals.

    PubMed

    de la Fuente, Roberto; Sánchez, Antonio; Marchal, Juan Alberto; Viera, Alberto; Parra, María Teresa; Rufas, Julio S; Page, Jesús

    2012-10-01

    Synapsis and reciprocal recombination between sex chromosomes are restricted to the pseudoautosomal region. In some animal species, sex chromosomes do not present this region, although they utilize alternative mechanisms that ensure meiotic pairing and segregation. The subfamily Arvicolinae (Rodentia, Cricetidae) includes numerous species with achiasmate sex chromosomes. In order to know whether the mechanism involved in achiasmate segregation is an ancient feature in arvicolid species, we have compared the sex chromosomes of both the Mediterranean vole (Microtus duodecimcostatus) and the water vole (Arvicola terrestris). By means of immunofluorescence, we have found that sex chromosomes in M. duodecimcostatus are asynaptic and develop a synaptonemal complex-derived structure that mediates pairing and facilitates segregation. In A. terrestris, sex chromosomes are synaptic and chiasmate but also exhibit a synaptonemal complex-derived filament during anaphase I. Since phylogenetic relationships indicate that the synaptic condition is ancestral in arvicolids, this finding indicates that the mechanism for achiasmate sex chromosome segregation precedes the switching to the asynaptic condition. We discuss the origin of this synaptonemal complex-derived mechanism that, in turn, could counterbalance the disruption of homology in the sex chromosomes of those species.

  3. Implication of sperm chromosomal abnormalities in recurrent abortion and multiple implantation failure.

    PubMed

    Caseiro, Ana Lara; Regalo, Ana; Pereira, Elisa; Esteves, Telma; Fernandes, Fernando; Carvalho, Joaquim

    2015-10-01

    Currently, some infertility treatment centres provide sperm karyotype analysis, although the impact of sperm chromosomal abnormalities on fertility is not yet fully understood. Several studies using fluorescence in-situ hybridization (FISH) to analyse sperm chromosomal constitution discovered that the incidence of aneuploidy is increased in individuals with a history of repeated abortion or implantation failure and is even higher in cases of oligoasthenoteratozoospermia (OAT), abnormal somatic karyotype or in spermatozoa retrieved directly from the testis or epididymis, showing that the application of FISH in these cases may be of some benefit for improving the reproductive outcome. This article presents the results of clinical trials of FISH analysis on spermatozoa, the medical indications for performing this examination, its results in infertile patients and the advantages when performing genetic counselling prior to treatment. Also discussed is the possibility of applying the latest techniques of genetic analysis in these cases and the potential benefits for improving the prognosis of male infertility.

  4. Solar activity cycle and the incidence of foetal chromosome abnormalities detected at prenatal diagnosis

    NASA Astrophysics Data System (ADS)

    Halpern, Gabrielle J.; Stoupel, Eliahu G.; Barkai, Gad; Chaki, Rina; Legum, Cyril; Fejgin, Moshe D.; Shohat, Mordechai

    1995-06-01

    We studied 2001 foetuses during the period of minimal solar activity of solar cycle 21 and 2265 foetuses during the period of maximal solar activity of solar cycle 22, in all women aged 37 years and over who underwent free prenatal diagnosis in four hospitals in the greater Tel Aviv area. There were no significant differences in the total incidence of chromosomal abnormalities or of trisomy between the two periods (2.15% and 1.8% versus 2.34% and 2.12%, respectively). However, the trend of excessive incidence of chromosomal abnormalities in the period of maximal solar activity suggests that a prospective study in a large population would be required to rule out any possible effect of extreme solar activity.

  5. Overview of Epidemiology, Genetics, Birth Defects, and Chromosome Abnormalities Associated With CDH

    PubMed Central

    Pober, Barbara R.

    2010-01-01

    Congenital diaphragmatic hernia (CDH) is a common and well-studied birth defect. The etiology of most cases remains unknown but increasing evidence points to genetic causation. The data supporting genetic etiologies which are detailed below include the association of CDH with recurring chromosome abnormalities, the existence of CDH-multiplex families, and the co-occurrence of CDH with additional congenital malformations. PMID:17436298

  6. Chromosome Abnormalities

    MedlinePlus

    ... Database Newsroom Calendar of Events Current News Releases Image Gallery GenomeTV Media Contacts Media Resources NHGRI-Related News Journal Articles from NHGRI Social Media Careers Educational Programs Health Professional Education Intramural ...

  7. The Argonaute CSR-1 and its 22G-RNA cofactors are required for holocentric chromosome segregation.

    PubMed

    Claycomb, Julie M; Batista, Pedro J; Pang, Ka Ming; Gu, Weifeng; Vasale, Jessica J; van Wolfswinkel, Josien C; Chaves, Daniel A; Shirayama, Masaki; Mitani, Shohei; Ketting, René F; Conte, Darryl; Mello, Craig C

    2009-10-02

    RNAi-related pathways regulate diverse processes, from developmental timing to transposon silencing. Here, we show that in C. elegans the Argonaute CSR-1, the RNA-dependent RNA polymerase EGO-1, the Dicer-related helicase DRH-3, and the Tudor-domain protein EKL-1 localize to chromosomes and are required for proper chromosome segregation. In the absence of these factors chromosomes fail to align at the metaphase plate and kinetochores do not orient to opposing spindle poles. Surprisingly, the CSR-1-interacting small RNAs (22G-RNAs) are antisense to thousands of germline-expressed protein-coding genes. Nematodes assemble holocentric chromosomes in which continuous kinetochores must span the expressed domains of the genome. We show that CSR-1 interacts with chromatin at target loci but does not downregulate target mRNA or protein levels. Instead, our findings support a model in which CSR-1 complexes target protein-coding domains to promote their proper organization within the holocentric chromosomes of C. elegans.

  8. Accurate Chromosome Segregation at First Meiotic Division Requires AGO4, a Protein Involved in RNA-Dependent DNA Methylation in Arabidopsis thaliana.

    PubMed

    Oliver, Cecilia; Santos, Juan Luis; Pradillo, Mónica

    2016-10-01

    The RNA-directed DNA methylation (RdDM) pathway is important for the transcriptional repression of transposable elements and for heterochromatin formation. Small RNAs are key players in this process by regulating both DNA and histone methylation. Taking into account that methylation underlies gene silencing and that there are genes with meiosis-specific expression profiles, we have wondered whether genes involved in RdDM could play a role during this specialized cell division. To address this issue, we have characterized meiosis progression in pollen mother cells from Arabidopsis thaliana mutant plants defective for several proteins related to RdDM. The most relevant results were obtained for ago4-1 In this mutant, meiocytes display a slight reduction in chiasma frequency, alterations in chromatin conformation around centromeric regions, lagging chromosomes at anaphase I, and defects in spindle organization. These abnormalities lead to the formation of polyads instead of tetrads at the end of meiosis, and might be responsible for the fertility defects observed in this mutant. Findings reported here highlight an involvement of AGO4 during meiosis by ensuring accurate chromosome segregation at anaphase I.

  9. Structural chromosomal abnormalities in patients with mental retardation and/or multiple congenital anomalies: a new series of 24 patients.

    PubMed

    Tos, T; Karaman, A; Aksoy, A; Tukun, A

    2012-01-01

    Chromosomal abnormalities are a major cause of mental retardation and/or multiple congenital anomalies (MCA/MR). Screening for these chromosomal imbalances has mainly been done by standard karyotyping. The objective of this study was to report standard chromosome analysis and FISH screening of a series of 24 patients with MCA/MR. Structural chromosomal abnormalities were detected in 24 alterations and included 5 deletions, 2 duplications, 6 unbalanced translocations, 3 inversions, 2 insertions, 3 derivative chromosomes, 2 marker chromosomes and 1 isochromosome. We confirm that a high percentage of MCA/MR cases hitherto considered idiopathic is caused by chromosomal imbalances. We conclude that patients with MCA/MR should be routinely karyotyped.

  10. Radiation exposure and chromosome abnormalities. Human cytogenetic studies at the National Institute of Radiological Sciences, Japan, 1963-1988

    SciTech Connect

    Ishihara, T.; Kohno, S.; Minamihisamatsu, M. )

    1990-03-01

    The results of human cytogenetic studies performed at the National Institute of Radiological Sciences (NIRS), Chiba, Japan for about 25 years are described. The studies were pursued primarily under two major projects: one involving people exposed to radiation under various conditions and the other involving patients with malignant diseases, especially leukemias. Whereas chromosome abnormalities in radiation-exposed people are excellent indicators of radiation exposure, their behavior in bone marrow provide useful information for a better understanding of chromosome abnormalities in leukemias and related disorders. The role of chromosome abnormalities in the genesis and development of leukemia and related disorders is considered, suggesting a view for future studies in this field.

  11. Rejuvenation of meiotic cohesion in oocytes during prophase I is required for chiasma maintenance and accurate chromosome segregation.

    PubMed

    Weng, Katherine A; Jeffreys, Charlotte A; Bickel, Sharon E

    2014-09-01

    Chromosome segregation errors in human oocytes are the leading cause of birth defects, and the risk of aneuploid pregnancy increases dramatically as women age. Accurate segregation demands that sister chromatid cohesion remain intact for decades in human oocytes, and gradual loss of the original cohesive linkages established in fetal oocytes is proposed to be a major cause of age-dependent segregation errors. Here we demonstrate that maintenance of meiotic cohesion in Drosophila oocytes during prophase I requires an active rejuvenation program, and provide mechanistic insight into the molecular events that underlie rejuvenation. Gal4/UAS inducible knockdown of the cohesion establishment factor Eco after meiotic S phase, but before oocyte maturation, causes premature loss of meiotic cohesion, resulting in destabilization of chiasmata and subsequent missegregation of recombinant homologs. Reduction of individual cohesin subunits or the cohesin loader Nipped B during prophase I leads to similar defects. These data indicate that loading of newly synthesized replacement cohesin rings by Nipped B and establishment of new cohesive linkages by the acetyltransferase Eco must occur during prophase I to maintain cohesion in oocytes. Moreover, we show that rejuvenation of meiotic cohesion does not depend on the programmed induction of meiotic double strand breaks that occurs during early prophase I, and is therefore mechanistically distinct from the DNA damage cohesion re-establishment pathway identified in G2 vegetative yeast cells. Our work provides the first evidence that new cohesive linkages are established in Drosophila oocytes after meiotic S phase, and that these are required for accurate chromosome segregation. If such a pathway also operates in human oocytes, meiotic cohesion defects may become pronounced in a woman's thirties, not because the original cohesive linkages finally give out, but because the rejuvenation program can no longer supply new cohesive linkages

  12. Familial Constitutional Rearrangement of Chromosomes 4 & 8: Phenotypically Normal Mother and Abnormal Progeny

    PubMed Central

    Kunwar, Fulesh

    2016-01-01

    Balanced chromosome translocations carriers mostly do not have recognizable phenotypic expression but may have more risk of recurrent spontaneous abortions &/or children with serious birth defects due to unbalanced chromosome complements. Unbalanced chromosomal rearrangements have variable clinical expression and are rare. We present here a case report of three siblings affected with intellectual disability and minor dysmorphic features of face and limbs, born to a non-consanguineous couple in which mother had 5 abortions. The constitutional chromosome analysis revealed balanced translocation t (4;8) in mother and all the three siblings were karyotypically normal. Chromosomal microarray in one of the probands revealed partial monosomy 8pter-p23 and a partial trisomy 4pter-p16. Phenotypic features were recorded in 3 probands using Human Phenotype Ontology terms to query web-based tool Phenomizer. The harmonized description using globally accepted ontology is very important especially in case of rare genetic conditions and the heterogeneous phenotypes which make it even more challenging. The prevalence of sub-microscopic unbalanced translocations may be under-reported due to lesser use of molecular genetic analysis. The familial expression of abnormal phenotypes including intellectual disability make the individuals candidate for molecular genetic analysis and phenotyping to help defer the status of idiopathic mental retardation and identify sub-entity of genetic condition. PMID:27190830

  13. Molecular detection of chromosomal abnormalities in germ and somatic cells of aged male mice

    SciTech Connect

    Lowe, X.; Baulch, J.; Quintana, L.; Ramsey, M.; Breneman, J.; Tucker, J.; Wyrobek, A.; Collins, B.; Allen, J.; Holland, N.

    1994-12-31

    Three cytogenetic methods were applied to eight B6C3F1 male mice aged 22.5 - 30.5mo to determine if advanced age was associated with an elevated risk of producing chromosomally defective germinal and somatic cells; sperm aneuploidy analysis by multi-color fluorescence in situ hybridization for three chromosomes, spermatid micronucleus analysis with anti-kinetochore antibodies, and translocation analysis of somatic metaphases by {open_quotes}painting{close_quotes} for two chromosomes. Eight mice aged 2.4mo served as controls. Sperm aneuploidy was measured by multi-color fluorescence in situ co-hybridization with DNA probes specific for chromosomes X, Y and 8, scoring 10,000 cells per animal. The aged group showed significant 1.5 - 2.0 fold increases in the hyperhaploidy phenotypes X-X-8, Y-Y-8, 8-8-Y, and 8-8-X with the greater effects appearing in animals aged >29mo. The aged group also showed significantly increased frequencies of micronucleated spermatids (2.0 vs 0.4 per 1000; all were kinetochore negative). Analysis of metaphase chromosomes from blood by {open_quotes}painting{close_quotes} of chromosomes 2 and 8 yielded 4 translocation per 858 cell-equivalents in the aged group which was a non-significant elevation over 0/202 in controls. Although interpretation must be cautious due to the small number of animals analyzed, these findings suggest that advanced paternal age may be a risk factor for chromosomal abnormalities of reproductive and somatic importance.

  14. Abnormalities in Chromosomes 1q and 13 Independently Correlate With Factors of Poor Prognosis in Multiple Myeloma

    PubMed Central

    Kim, Miyoung; Ju, Young-Su; Lee, Eun Jin; Kang, Hee Jung; Kim, Han-Sung; Cho, Hyoun Chan; Kim, Hyo Jung; Kim, Jung-Ah; Lee, Dong Soon

    2016-01-01

    Background We comprehensively profiled cytogenetic abnormalities in multiple myeloma (MM) and analyzed the relationship between cytogenetic abnormalities of undetermined prognostic significance and established prognostic factors. Methods The karyotype of 333 newly diagnosed MM cases was analyzed in association with established prognostic factors. Survival analysis was also performed. Results MM with abnormal karyotypes (41.1%) exhibited high international scoring system (ISS) stage, frequent IgA type, elevated IgG or IgA levels, elevated calcium levels, elevated creatine (Cr) levels, elevated β2-microglobulin levels, and decreased Hb levels. Structural abnormalities in chromosomes 1q, 4, and 13 were independently associated with elevated levels of IgG or IgA, calcium, and Cr, respectively. Chromosome 13 abnormalities were associated with poor prognosis and decreased overall survival. Conclusions This is the first study to demonstrate that abnormalities in chromosomes 1q, 4, and 13 are associated with established factors for poor prognosis, irrespective of the presence of other concurrent chromosomal abnormalities. Chromosome 13 abnormalities have a prognostic impact on overall survival in association with elevated Cr levels. Frequent centromeric breakpoints appear to be related to MM pathogenesis. PMID:27578511

  15. Molecular Cytogenetic Approach to Characterize Novel and Cryptic Chromosome Abnormalities in Childhood Myeloid Malignances of Fanconi Anemia.

    PubMed

    Borges, Maria L R; Capela de Matos, Roberto R; Amaral, Bethânia D A Silva; Soares-Ventura, Eliane M; Leite, Edinalva P; Silva, Mariluze O D; Cornélio, Maria T M Nogueira; Silva, Maria L M; Liehr, Thomas; Marques-Salles, Terezinha D J

    2017-03-01

    Myeloid malignancies can be either primary or secondary, whether or not a specific cause can be determined. Fanconi anemia (FA), a rare constitutional bone marrow failure, usually presents an increased possibility of clonal evolution, due to the increase in chromosomal instability, TP53 activation, and cell death. The evolution of FA may include aplastic anemia by the progressive failure of the bone marrow and myelod neoplasias, such as acute myeloid leukemia and myelodysplastic syndrome. Chromosome abnormalities, particularly of chromosomes, 1, 3, and 7, during the aplastic phase of the disease are predictive of evolution to acute myeloid leukemia/myelodysplastic syndrome. Cytogenetic studies are indispensable to characterize chromosome abnormalities, and thus an important part of the clinical management, and for planning of therapeutic interventions. Here, clinical data and outcomes of 4 FA, 3 of them with myeloid malignances and 1 asymptomatic, and detailed characterization of their chromosome abnormalities using cytogenetics techniques are described.

  16. Split hand/foot malformation genetics supports the chromosome 7 copy segregation mechanism for human limb development

    PubMed Central

    Klar, Amar J. S.

    2016-01-01

    Genetic aberrations of several unlinked loci cause human congenital split hand/foot malformation (SHFM) development. Mutations of the DLX5 (distal-less) transcription factor-encoding gene in chromosome 7 cause SHFM through haploinsufficiency, but the vast majority of cases result from heterozygous chromosomal aberrations of the region without mutating the DLX5 gene. To resolve this paradox, we invoke a chromosomal epigenetic mechanism for limb development. It is composed of a monochromatid gene expression phenomenon that we discovered in two fission yeasts with the selective chromosome copy segregation phenomenon that we discovered in mouse cells. Accordingly, one daughter cell inherits both expressed DLX5 copies while the other daughter inherits both epigenetically silenced ones from a single deterministic cell of the developing limb. Thus, differentiated daughter cells after further proliferation will correspondingly produce proximal/distal-limb tissues. Published results of a Chr. 7 translocation with a centromere-proximal breakpoint situated over 41 million bases away from the DLX locus, centromeric and DLX5-region inversions have satisfied key genetic and developmental biology predictions of the mechanism. Further genetic tests of the mechanism are proposed. We propose that the DNA double helical structure itself causes the development of sister cells' gene regulation asymmetry. We also argue against the conventionally invoked morphogen model of development. This article is part of the themed issue ‘Provocative questions in left–right asymmetry’. PMID:27821526

  17. Split hand/foot malformation genetics supports the chromosome 7 copy segregation mechanism for human limb development.

    PubMed

    Klar, Amar J S

    2016-12-19

    Genetic aberrations of several unlinked loci cause human congenital split hand/foot malformation (SHFM) development. Mutations of the DLX5 (distal-less) transcription factor-encoding gene in chromosome 7 cause SHFM through haploinsufficiency, but the vast majority of cases result from heterozygous chromosomal aberrations of the region without mutating the DLX5 gene. To resolve this paradox, we invoke a chromosomal epigenetic mechanism for limb development. It is composed of a monochromatid gene expression phenomenon that we discovered in two fission yeasts with the selective chromosome copy segregation phenomenon that we discovered in mouse cells. Accordingly, one daughter cell inherits both expressed DLX5 copies while the other daughter inherits both epigenetically silenced ones from a single deterministic cell of the developing limb. Thus, differentiated daughter cells after further proliferation will correspondingly produce proximal/distal-limb tissues. Published results of a Chr. 7 translocation with a centromere-proximal breakpoint situated over 41 million bases away from the DLX locus, centromeric and DLX5-region inversions have satisfied key genetic and developmental biology predictions of the mechanism. Further genetic tests of the mechanism are proposed. We propose that the DNA double helical structure itself causes the development of sister cells' gene regulation asymmetry. We also argue against the conventionally invoked morphogen model of development.This article is part of the themed issue 'Provocative questions in left-right asymmetry'.

  18. Sex chromosomal abnormalities associated with equine infertility: validation of a simple molecular screening tool in the Purebred Spanish Horse.

    PubMed

    Anaya, G; Molina, A; Valera, M; Moreno-Millán, M; Azor, P; Peral-García, P; Demyda-Peyrás, S

    2017-02-22

    Chromosomal abnormalities in the sex chromosome pair (ECAX and ECAY) are widely associated with reproductive problems in horses. However, a large proportion of these abnormalities remains undiagnosed due to the lack of an affordable diagnostic tool that allows for avoiding karyotyping tests. Hereby, we developed an STR (single-tandem-repeat)-based molecular method to determine the presence of the main sex chromosomal abnormalities in horses in a fast, cheap and reliable way. The frequency of five ECAX-linked (LEX026, LEX003, TKY38, TKY270 and UCDEQ502) and two ECAY-linked (EcaYH12 and SRY) markers was characterized in 261 Purebred Spanish Horses to determine the efficiency of the methodology developed to be used as a chromosomal diagnostic tool. All the microsatellites analyzed were highly polymorphic, with a sizeable number of alleles (polymorphic information content > 0.5). Based on this variability, the methodology showed 100% sensitivity and 99.82% specificity to detect the most important sex chromosomal abnormalities reported in horses (chimerism, Turner's syndrome and sex reversal syndromes). The method was also validated with 100% efficiency in 10 individuals previously diagnosed as chromosomally aberrant. This STR screening panel is an efficient and reliable molecular-cytogenetic tool for the early detection of sex chromosomal abnormalities in equines that could be included in breeding programs to save money, effort and time of veterinary practitioners and breeders.

  19. Endocrine abnormalities in ring chromosome 11: a case report and review of the literature

    PubMed Central

    Lange, Renata; Von Linsingen, Caoê; Mata, Fernanda; Moraes, Aline Barbosa; Arruda, Mariana

    2015-01-01

    Summary Ring chromosomes (RCs) are uncommon cytogenetic findings, and RC11 has only been described in 19 cases in the literature. Endocrine abnormalities associated with RC11 were reported for two of these cases. The clinical features of RC11 can result from an alteration in the structure of the genetic material, ring instability, mosaicism, and various extents of genetic material loss. We herein describe a case of RC11 with clinical features of 11q-syndrome and endocrine abnormalities that have not yet been reported. A 20-year-old female patient had facial dysmorphism, short stature, psychomotor developmental delays, a ventricular septal defect, and thrombocytopenia. Karyotyping demonstrated RC11 (46,XX,r(11)(p15q25)). This patient presented with clinical features that may be related to Jacobsen syndrome, which is caused by partial deletion of the long arm of chromosome 11. Regarding endocrine abnormalities, our patient presented with precocious puberty followed by severe hirsutism, androgenic alopecia, clitoromegaly, and amenorrhea, which were associated with overweight, type 2 diabetes mellitus (T2DM), and hyperinsulinemia; therefore, this case meets the diagnostic criteria for polycystic ovary syndrome. Endocrine abnormalities are rare in patients with RC11, and the association of RC11 with precocious puberty, severe clinical hyperandrogenism, insulin resistance, and T2DM has not been reported previously. We speculate that gene(s) located on chromosome 11 might be involved in the pathogenesis of these conditions. Despite the rarity of RCs, studies to correlate the genes located on the chromosomes with the phenotypes observed could lead to major advances in the understanding and treatment of more prevalent diseases. Learning points We hypothesize that the endocrine features of precocious puberty, severe clinical hyperandrogenism, insulin resistance, and T2DM might be associated with 11q-syndrome.A karyotype study should be performed in patients with short

  20. Scoliosis and vertebral anomalies: additional abnormal phenotypes associated with chromosome 16p11.2 rearrangement.

    PubMed

    Al-Kateb, Hussam; Khanna, Geetika; Filges, Isabel; Hauser, Natalie; Grange, Dorothy K; Shen, Joseph; Smyser, Christopher D; Kulkarni, Shashikant; Shinawi, Marwan

    2014-05-01

    The typical chromosome 16p11.2 rearrangements are estimated to occur at a frequency of approximately 0.6% of all samples tested clinically and have been identified as a major cause of autism spectrum disorders, developmental delay, behavioral abnormalities, and seizures. Careful examination of patients with these rearrangements revealed association with abnormal head size, obesity, dysmorphism, and congenital abnormalities. In this report, we extend this list of phenotypic abnormalities to include scoliosis and vertebral anomalies. We present detailed characterization of phenotypic and radiological data of 10 new patients, nine with the 16p11.2 deletion and one with the duplication within the coordinates chr16:29,366,195 and 30,306,956 (hg19) with a minimal size of 555 kb. We discuss the phenotypical and radiological findings in our patients and review 5 previously reported patients with 16p11.2 rearrangement and similar skeletal abnormalities. Our data suggest that patients with the recurrent 16p11.2 rearrangement have increased incidence of scoliosis and vertebral anomalies. However, additional studies are required to confirm this observation and to establish the incidence of these anomalies. We discuss the potential implications of our findings on the diagnosis, surveillance and genetic counseling of patients with 16p11.2 rearrangement.

  1. Complex chromosomal abnormalities in a patient with HTLV-1 positive T-cell leukemia

    SciTech Connect

    Hyde, P.; Macera, M.J.; Gogineni, S.K.

    1994-09-01

    HTLV-1 positive adult T-cell leukemia (ATL) is associated with numerous chromosomal abnormalities. The chromosomal rearrangements can be extremely complex and additional material is often present, making precise identification by routine cytogenetic techniques difficult. We report a case of ATL that was established of bone marrow cells by both QFQ and GTG banding techniques revealed a highly complex 49,XX,der(2)t(2;?)(q37;?),+5,+2mar karyotype in the dividing cells. The identical cytogenetic findings were also seen in unstimulated peripheral blood collected one week later. Using the FISH-technique, we applied spectrum green-labeled No. 1- and No. 7-specific WCP, spectrum orange-labeled No. 2- and No. 5-specific WCP (GIBCO/BRL, Gaithersburg, MD) and biotin-labeled No. 18-specific WCP (Oncor, Gaithersburg, MD) to metaphase chromosomes. The large marker chromosome was identified as an extra 1q arm, the material attached to the distal 2q was additional 7q. The presence of three No. 5 chromosomes was verified and the small marker was determined to be an extra partial 5p in Robertsonian translocation with an additional partial 18q arm. The karyotype was revised to 49,XX,+1q,der(2)t(2;7)(q37;q22),+5,+t(5;18)(p14{r_arrow}p11::q11{r_arrow}q12). Identification of the numerous chromosomal anomalies associated with the disease by molecular techniques shall lead to a better understanding of this deadly cancer.

  2. Prader-Willi-like phenotypes: a systematic review of their chromosomal abnormalities.

    PubMed

    Rocha, C F; Paiva, C L A

    2014-03-31

    Prader-Willi syndrome (PWS) is caused by the lack of expression of genes located on paternal chromosome 15q11-q13. This lack of gene expression may be due to a deletion in this chromosomal segment, to maternal uniparental disomy of chromosome 15, or to a defect in the imprinting center on 15q11-q13. PWS is characterized by hypotonia during the neonatal stage and in childhood, accompanied by a delay in neuropsychomotor development. Overeating, obesity, and mental deficiency arise later on. The syndrome has a clinical overlap with other diseases, which makes it difficult to accurately diagnose. The purpose of this article is to review the Prader-Willi-like phenotype in the scientific literature from 2000 to 2013, i.e., to review the cases of PWS caused by chromosomal abnormalities different from those found on chromosome 15. A search was carried out using the "National Center for Biotechnology Information" (www.pubmed.com) and "Scientific Electronic Library Online (www.scielo.br) databases and combinations of key words such as "Prader-Willi-like phenotype" and "Prader-Willi syndrome phenotype". Editorials, letters, reviews, and guidelines were excluded. Articles chosen contained descriptions of patients diagnosed with the PWS phenotype but who were negative for alterations on 15q11-q13. Our search found 643 articles about PWS, but only 14 of these matched with the Prader-Willi-like phenotype and with the selected years of publication (2000-2013). If two or more articles reported the same chromosomal alterations for Prader-Willi-like phenotype, the most recent was chosen. Twelve articles of 14 were case reports and 2 reported series of cases.

  3. Abnormal segregation of alleles in CEPH pedigree DNAs arising from allele loss in lymphoblastoid DNA

    SciTech Connect

    Royle, N.J.; Armour, J.A.L.; Crosier, M.; Jeffreys, A.J. )

    1993-01-01

    Somatic events that result in the reduction to hemior homozygosity at all loci affected by the event have been identified in lymphoblastoid DNA from mothers of two CEPH families. Using suitably informative probes, the allele deficiencies were detected by the abnormal transmission of alleles from grandparents to grandchildren, with the apparent absence of the alleles from the parent. Undetected somatic deficiencies in family DNAs could result in misscoring of recombination events and consequently introduce errors into linkage analysis. 15 refs., 2 figs.

  4. Prenatal diagnosis of chromosome 15 abnormalities in the Prader-Willi/Angelman syndrome region by traditional and molecular cytogenetics

    SciTech Connect

    Toth-Fejel, S.; Magenis, R.E.; Leff, S.

    1995-02-13

    With improvements in culturing and banding techniques, amniotic fluid studies now achieve a level of resolution at which the Prader-Willi syndrome (PWS) and Angelman syndrome (AS) region may be questioned. Chromosome 15 heteromorphisms, detected with Q- and R-banding and used in conjunction with PWS/AS region-specific probes, can confirm a chromosome deletion and establish origin to predict the clinical outcome. We report four de novo cases of an abnormal-appearing chromosome 15 in amniotic fluid samples referred for advanced maternal age or a history of a previous chromosomally abnormal child. The chromosomes were characterized using G-, Q-, and R-banding, as well as isotopic and fluorescent in situ hybridization of DNA probes specific for the proximal chromosome 15 long arm. In two cases, one chromosome 15 homolog showed a consistent deletion of the ONCOR PWS/AS region A and B. In the other two cases, one of which involved an inversion with one breakpoint in the PWS/AS region, all of the proximal chromosome 15 long arm DNA probes used in the in situ hybridization were present on both homologs. Clinical follow-up was not available on these samples, as in all cases the parents chose to terminate the pregnancies. These cases demonstrate the ability to prenatally diagnose chromosome 15 abnormalities associated with PWS/AS. In addition, they highlight the need for a better understanding of this region for accurate prenatal diagnosis. 41 refs., 5 figs.

  5. Diversity and abundance of the abnormal chromosome 10 meiotic drive complex in Zea mays

    PubMed Central

    Kanizay, L B; Pyhäjärvi, T; Lowry, E G; Hufford, M B; Peterson, D G; Ross-Ibarra, J; Dawe, R K

    2013-01-01

    Maize Abnormal chromosome 10 (Ab10) contains a classic meiotic drive system that exploits the asymmetry of meiosis to preferentially transmit itself and other chromosomes containing specialized heterochromatic regions called knobs. The structure and diversity of the Ab10 meiotic drive haplotype is poorly understood. We developed a bacterial artificial chromosome (BAC) library from an Ab10 line and used the data to develop sequence-based markers, focusing on the proximal portion of the haplotype that shows partial homology to normal chromosome 10. These molecular and additional cytological data demonstrate that two previously identified Ab10 variants (Ab10-I and Ab10-II) share a common origin. Dominant PCR markers were used with fluorescence in situ hybridization to assay 160 diverse teosinte and maize landrace populations from across the Americas, resulting in the identification of a previously unknown but prevalent form of Ab10 (Ab10-III). We find that Ab10 occurs in at least 75% of teosinte populations at a mean frequency of 15%. Ab10 was also found in 13% of the maize landraces, but does not appear to be fixed in any wild or cultivated population. Quantitative analyses suggest that the abundance and distribution of Ab10 is governed by a complex combination of intrinsic fitness effects as well as extrinsic environmental variability. PMID:23443059

  6. Chromosome rearrangements, recombination suppression, and limited segregation distortion in hybrids between Yellowstone cutthroat trout (Oncorhynchus clarkii bouvieri) and rainbow trout (O. mykiss)

    USGS Publications Warehouse

    Ostberg, Carl O.; Hauser, Lorenz; Pritchard, Victoria L.; Garza, John C.; Naish, Kerry A.

    2013-01-01

    Chromosome rearrangements suppressed recombination in the hybrids. This result supports several previous findings demonstrating that recombination suppression restricts gene flow between chromosomes that differ by arrangement. Conservation of synteny and map order between the hybrid and rainbow trout maps and minimal segregation distortion in the hybrids suggest rainbow and Yellowstone cutthroat trout genomes freely introgress across chromosomes with similar arrangement. Taken together, these results suggest that rearrangements impede introgression. Recombination suppression across rearrangements could enable large portions of non-recombined chromosomes to persist within admixed populations.

  7. Investigation of chromosome abnormalities and early embryonic mortality in goose lines.

    PubMed

    Liptói, Krisztina; Hidas, A; Rouvier, R

    2005-01-01

    Early embryonic mortality and chromosome abnormalities were studied in three goose lines: Grey Landes (line 7), White Polish (line 4) and their synthetic line (line 9). Eggs laid at the beginning, in the middle and at the end of the laying season were set. At candling at 5th day after egg set, all eggs (2847) were examined and those showing no normal embryonic development were opened 2847. Dead embryos were classified phenotypically and karyotyped. The mean ratio of embryonic mortality (EM) among fertile eggs was 9.4%, 5.2%, 7.3% in the lines 4, 7 and 9, respectively. The mean ratio of embryos with chromosomal abnormalities (CA) among the dead embryos was 8.0%, 14.8% and 13.1% in the lines 4, 7 and 9, respectively. Gander effect and layer within gander effect on embryo mortality were significant, indicating genetic factors. Father and mother of the layer effects were also significant, showing family effects. Animals producing dead embryos and embryos with chromosome abnormalities in high proportion were selected. In the selected groups the mean EM was 17.7-22.9%, and the mean CA was 11.7-34.7% among the three lines. The repetition of CA was not observed in the reproductive season of following year, while animals repeated the high EM (repeatability coefficient of 0.54). This shows that some part of EM may be resulted from other genetic factors. Ganders and layers progeny of these selected animals showed also high EM. It was concluded that culling pairs giving high EM value in their embryos could increase the average level of embryo viability and that the study of genetic determinism of that trait should be continued in geese.

  8. Bub3–BubR1-dependent sequestration of Cdc20Fizzy at DNA breaks facilitates the correct segregation of broken chromosomes

    PubMed Central

    Derive, Nicolas; Landmann, Cedric; Montembault, Emilie; Claverie, Marie-Charlotte; Pierre-Elies, Priscillia; Goutte-Gattat, Damien; Founounou, Nabila; McCusker, Derek

    2015-01-01

    The presence of DNA double-strand breaks during mitosis is particularly challenging for the cell, as it produces broken chromosomes lacking a centromere. This situation can cause genomic instability resulting from improper segregation of the broken fragments into daughter cells. We recently uncovered a process by which broken chromosomes are faithfully transmitted via the BubR1-dependent tethering of the two broken chromosome ends. However, the mechanisms underlying BubR1 recruitment and function on broken chromosomes were largely unknown. We show that BubR1 requires interaction with Bub3 to localize on the broken chromosome fragments and to mediate their proper segregation. We also find that Cdc20, a cofactor of the E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C), accumulates on DNA breaks in a BubR1 KEN box–dependent manner. A biosensor for APC/C activity demonstrates a BubR1-dependent local inhibition of APC/C around the segregating broken chromosome. We therefore propose that the Bub3–BubR1 complex on broken DNA inhibits the APC/C locally via the sequestration of Cdc20, thus promoting proper transmission of broken chromosomes. PMID:26553926

  9. Bub3-BubR1-dependent sequestration of Cdc20Fizzy at DNA breaks facilitates the correct segregation of broken chromosomes.

    PubMed

    Derive, Nicolas; Landmann, Cedric; Montembault, Emilie; Claverie, Marie-Charlotte; Pierre-Elies, Priscillia; Goutte-Gattat, Damien; Founounou, Nabila; McCusker, Derek; Royou, Anne

    2015-11-09

    The presence of DNA double-strand breaks during mitosis is particularly challenging for the cell, as it produces broken chromosomes lacking a centromere. This situation can cause genomic instability resulting from improper segregation of the broken fragments into daughter cells. We recently uncovered a process by which broken chromosomes are faithfully transmitted via the BubR1-dependent tethering of the two broken chromosome ends. However, the mechanisms underlying BubR1 recruitment and function on broken chromosomes were largely unknown. We show that BubR1 requires interaction with Bub3 to localize on the broken chromosome fragments and to mediate their proper segregation. We also find that Cdc20, a cofactor of the E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C), accumulates on DNA breaks in a BubR1 KEN box-dependent manner. A biosensor for APC/C activity demonstrates a BubR1-dependent local inhibition of APC/C around the segregating broken chromosome. We therefore propose that the Bub3-BubR1 complex on broken DNA inhibits the APC/C locally via the sequestration of Cdc20, thus promoting proper transmission of broken chromosomes.

  10. High frequency of submicroscopic chromosomal imbalances in patients with syndromic craniosynostosis detected by a combined approach of microsatellite segregation analysis, multiplex ligation-dependent probe amplification and array-based comparative genome hybridisation.

    PubMed

    Jehee, F S; Krepischi-Santos, A C V; Rocha, K M; Cavalcanti, D P; Kim, C A; Bertola, D R; Alonso, L G; D'Angelo, C S; Mazzeu, J F; Froyen, G; Lugtenberg, D; Vianna-Morgante, A M; Rosenberg, C; Passos-Bueno, M R

    2008-07-01

    We present the first comprehensive study, to our knowledge, on genomic chromosomal analysis in syndromic craniosynostosis. In total, 45 patients with craniosynostotic disorders were screened with a variety of methods including conventional karyotype, microsatellite segregation analysis, subtelomeric multiplex ligation-dependent probe amplification) and whole-genome array-based comparative genome hybridisation. Causative abnormalities were present in 42.2% (19/45) of the samples, and 27.8% (10/36) of the patients with normal conventional karyotype carried submicroscopic imbalances. Our results include a wide variety of imbalances and point to novel chromosomal regions associated with craniosynostosis. The high incidence of pure duplications or trisomies suggests that these are important mechanisms in craniosynostosis, particularly in cases involving the metopic suture.

  11. A Co-segregating Microduplication of Chromosome 15q11.2 Pinpoints Two Risk Genes for Autism Spectrum Disorder

    PubMed Central

    van der Zwaag, Bert; Staal, Wouter G; Hochstenbach, Ron; Poot, Martin; Spierenburg, Henk A; de Jonge, Maretha V; Verbeek, Nienke E; van ’t Slot, R.; van Es, Michael A; Staal, Frank J; Freitag, Christine M; Buizer-Voskamp, Jacobine E; Nelen, Marcel R; van den Berg, Leonard H; van Amstel, Hans K Ploos; van Engeland, Herman; Burbach, J Peter H

    2010-01-01

    High resolution genomic copy-number analysis has shown that inherited and de novo copy-number variations contribute significantly to autism pathology, and that identification of small chromosomal aberrations related to autism will expedite the discovery of risk genes involved. Here, we report a microduplication of chromosome 15q11.2, spanning only four genes, co-segregating with autism in a Dutch pedigree, identified by SNP microarray analysis, and independently confirmed by FISH and MLPA analysis. Quantitative RT-PCR analysis revealed over 70 % increase in peripheral blood mRNA levels for the four genes present in the duplicated region in patients, and RNA in situ hybridization on mouse embryonic and adult brain sections revealed that two of the four genes, CYFIP1 and NIPA1, were highly expressed in the developing mouse brain. These findings point towards a contribution of microduplications at chromosome 15q11.2 to autism, and highlight CYFIP1 and NIPA1 as autism risk genes functioning in axonogenesis and synaptogenesis. Thereby, these findings further implicate defects in dosage-sensitive molecular control of neuronal connectivity in autism. However, the prevalence of this microduplication in patient samples was statistically not significantly different from control samples (0.94% in patients vs 0.42% controls, p=0.247), which suggests that our findings should be interpreted with caution and indicates the need for studies that include large numbers of control subjects to ascertain the impact of these changes on a population scale. PMID:20029941

  12. Phosphorylation of SKAP by GSK3β ensures chromosome segregation by a temporal inhibition of Kif2b activity.

    PubMed

    Qin, Bo; Cao, Dan; Wu, Huihui; Mo, Fei; Shao, Hengyi; Chu, Jane; Powell, Michael; Aikhionbare, Felix; Wang, Dongmei; Fu, Chuanhai; He, Ping; Pan, Weijun; Wang, Wenwen; Liu, Xing; Yao, Xuebiao

    2016-12-16

    Chromosome segregation in mitosis is orchestrated by the dynamic interactions between the kinetochore and spindle microtubules. Our recent study shows SKAP is an EB1-dependent, microtubule plus-end tracking protein essential for kinetochore oscillations during mitosis. Here we show that phosphorylation of SKAP by GSK3β regulates Kif2b depolymerase activity by competing Kif2b for microtubule plus-end binding. SKAP is a bona fide substrate of GSK3β in vitro and the phosphorylation is essential for an accurate kinetochore-microtubule attachment in cells. The GSK3β-elicited phosphorylation sites were mapped by mass spectrometry and the phosphomimetic mutant of SKAP can rescue the phenotype of chromosome missegregation in SKAP-suppressed cells. Importantly, GSK3β-elicited phosphorylation promotes SKAP binding to Kif2b to regulate its depolymerase activity at the microtubule plus-ends. Based on those findings, we reason that GSK3β-SKAP-Kif2b signaling axis constitutes a dynamic link between spindle microtubule plus-ends and mitotic chromosomes to achieve faithful cell division.

  13. Mutation of histone H3 serine 86 disrupts GATA factor Ams2 expression and precise chromosome segregation in fission yeast.

    PubMed

    Lim, Kim Kiat; Ong, Terenze Yao Rui; Tan, Yue Rong; Yang, Eugene Guorong; Ren, Bingbing; Seah, Kwi Shan; Yang, Zhe; Tan, Tsu Soo; Dymock, Brian W; Chen, Ee Sin

    2015-09-15

    Eukaryotic genomes are packed into discrete units, referred to as nucleosomes, by organizing around scaffolding histone proteins. The interplay between these histones and the DNA can dynamically regulate the function of the chromosomal domain. Here, we interrogated the function of a pair of juxtaposing serine residues (S86 and S87) that reside within the histone fold of histone H3. We show that fission yeast cells expressing a mutant histone H3 disrupted at S86 and S87 (hht2-S86AS87A) exhibited unequal chromosome segregation, disrupted transcriptional silencing of centromeric chromatin, and reduced expression of Ams2, a GATA-factor that regulates localization of the centromere-specific histone H3 variant CENP-A. We found that overexpression of ams2(+) could suppress the chromosome missegregation phenotype that arose in the hht2-S86AS87A mutant. We further demonstrate that centromeric localization of SpCENP-A(cnp1-1) was significantly compromised in hht2-S86AS87A, suggesting synergism between histone H3 and the centromere-targeting domain of SpCENP-A. Taken together, our work presents evidence for an uncharacterized serine residue in fission yeast histone H3 that affects centromeric integrity via regulating the expression of the SpCENP-A-localizing Ams2 protein. [173/200 words].

  14. Phosphorylation of SKAP by GSK3β ensures chromosome segregation by a temporal inhibition of Kif2b activity

    PubMed Central

    Qin, Bo; Cao, Dan; Wu, Huihui; Mo, Fei; Shao, Hengyi; Chu, Jane; Powell, Michael; Aikhionbare, Felix; Wang, Dongmei; Fu, Chuanhai; He, Ping; Pan, Weijun; Wang, Wenwen; Liu, Xing; Yao, Xuebiao

    2016-01-01

    Chromosome segregation in mitosis is orchestrated by the dynamic interactions between the kinetochore and spindle microtubules. Our recent study shows SKAP is an EB1-dependent, microtubule plus-end tracking protein essential for kinetochore oscillations during mitosis. Here we show that phosphorylation of SKAP by GSK3β regulates Kif2b depolymerase activity by competing Kif2b for microtubule plus-end binding. SKAP is a bona fide substrate of GSK3β in vitro and the phosphorylation is essential for an accurate kinetochore-microtubule attachment in cells. The GSK3β-elicited phosphorylation sites were mapped by mass spectrometry and the phosphomimetic mutant of SKAP can rescue the phenotype of chromosome missegregation in SKAP-suppressed cells. Importantly, GSK3β-elicited phosphorylation promotes SKAP binding to Kif2b to regulate its depolymerase activity at the microtubule plus-ends. Based on those findings, we reason that GSK3β-SKAP-Kif2b signaling axis constitutes a dynamic link between spindle microtubule plus-ends and mitotic chromosomes to achieve faithful cell division. PMID:27982129

  15. Ring Chromosome 4 in a Child with Multiple Congenital Abnormalities: A Case Report and Review of the Literature.

    PubMed

    Paththinige, C S; Sirisena, N D; Kariyawasam, U G I U; Saman Kumara, L P C; Dissanayake, V H W

    2016-01-01

    A female child born preterm with intrauterine growth retardation and presenting with facial dysmorphism with clefts, microcephaly, limb deformities, and congenital abnormalities involving cardiovascular and urinary systems is described. Chromosomal analysis showed a de novo 46,XX,r(4)(p15.3q35) karyotype. The clinical features of the patient were compared with the phenotypic characteristics of 17 previously reported cases with ring chromosome 4 and those with Wolf-Hirschhorn syndrome (4p-). Clinical features observed in this case are consistent with the consensus phenotype in ring chromosome 4. Patent ductus arteriosus and bilateral talipes equinovarus observed in this baby widen the phenotypic spectrum associated with ring chromosome 4.

  16. New tools for the study of chromosome segregation and aneuploidy at the molecular level

    SciTech Connect

    Charlieu, J.P.; Marcais, B.; Laurent, A.M.; Roizes, G.

    1993-12-31

    The molecular mechanisms which allow the correct distribution of chromosomes during cell division are not yet well known. The centromere, because of its possible involvement in the attachment of sister chromatids and its participation in the formation of the kinetochore, may play an important role in these mechanisms. Trisomy 21 (down syndrome, DS) provides a good model for studying aneuploidy resulting from the dysfunction of the chromosome distribution process. A possible means of analyzing the mechanisms leading to non-disjunction (NDJ) could be to determine the origin of the supernumerary chromosome 21 and to attempt to find some structural or physical characteristics of the potentially responsible centromere. This could be performed by using molecular tools which allow each of the two parental chromosomes 21 to be distinguished. Possible markers suitable for this purpose are DNA fragments that exhibit length polymorphisms. We present here some examples of such molecular tools, and discuss ways to use them in order to study the parental origin and the meiotic stage of nondisjunction, and we propose an hypothesis suggesting a possible cause of nondisjunction in human chromosomes.

  17. Inhibition of the Binding between RGS2 and β-Tubulin Interferes with Spindle Formation and Chromosome Segregation during Mouse Oocyte Maturation In Vitro

    PubMed Central

    Sun, Zhao-Gui; Zhang, Zhi; Zhu, Yan

    2016-01-01

    RGS2 is a negative regulator of G protein signaling that contains a GTPase-activating domain and a β-tubulin binding region. This study aimed to determine the localization and function of RGS2 during mouse oocyte maturation in vitro. Immunofluorescent staining revealed that RGS2 was widely expressed in the cytoplasm with a greater abundance on both meiotic spindles and first/second polar bodies from the fully-grown germinal vesicle (GV) stage to the MII stages. Co-expression of RGS2 and β-tubulin could also be detected in the spindle and polar body of mouse oocytes at the MI, AI, and MII stages. Inhibition of the binding site between RGS2 and β-tubulin was accomplished by injecting anti-RGS2 antibody into GV-stage oocytes, which could result in oocytes arrest at the MI or AI stage during in vitro maturation, but it did not affect germinal vesicle breakdown. Moreover, injecting anti-RGS2 antibody into oocytes resulted in a significant reduction in the rate of first polar body extrusion and abnormal spindle formation. Additionally, levels of phosphorylated MEK1/2 were significantly reduced in anti-RGS2 antibody injected oocytes compared with control oocytes. These findings suggest that RGS2 might play a critical role in mouse oocyte meiotic maturation by affecting β-tubulin polymerization and chromosome segregation. PMID:27463806

  18. The DNase domain-containing protein TATDN1 plays an important role in chromosomal segregation and cell cycle progression during zebrafish eye development

    PubMed Central

    Yang, Hui; Liu, Changwei; Jamsen, Joonas; Wu, Zhenxing; Wang, Yingjie; Chen, Jun; Zheng, Li; Shen, Binghui

    2012-01-01

    The DNase domain-containing protein TATDN1 is a conserved nuclease in both prokaryotes and eukaryotes. It was previously implicated to play a role in apoptotic DNA fragmentation in yeast and C. elegans. However, its biological function in higher organisms, such as vertebrates, is unknown. Here, we report that zebrafish TATDN1 (zTATDN1) possesses a novel endonuclease activity, which first makes a nick at the DNA duplex and subsequently converts the nick into a DNA double-strand break in vitro. This biochemical property allows zTATDN1 to catalyze decatenation of catenated kinetoplast DNA to produce separated linear DNA in vitro. We further determine that zTATDN1 is predominantly expressed in eye cells during embryonic development. Knockdown of TATDN1 in zebrafish embryos results in an abnormal cell cycle progression, formation of polyploidy and aberrant chromatin structures. Consequently, the TATDN1-deficient morphants have disordered eye cell layers and significantly smaller eyes compared with the WT control. Altogether, our current studies suggest that zTATDN1 plays an important role in chromosome segregation and eye development in zebrafish. PMID:23187801

  19. Array-Based Comparative Genomic Hybridization for the Genomewide Detection of Submicroscopic Chromosomal Abnormalities

    PubMed Central

    Vissers, Lisenka E. L. M. ; de Vries, Bert B. A. ; Osoegawa, Kazutoyo ; Janssen, Irene M. ; Feuth, Ton ; Choy, Chik On ; Straatman, Huub ; van der Vliet, Walter ; Huys, Erik H. L. P. G. ; van Rijk, Anke ; Smeets, Dominique ; van Ravenswaaij-Arts, Conny M. A. ; Knoers, Nine V. ; van der Burgt, Ineke ; de Jong, Pieter J. ; Brunner, Han G. ; van Kessel, Ad Geurts ; Schoenmakers, Eric F. P. M. ; Veltman, Joris A. 

    2003-01-01

    Microdeletions and microduplications, not visible by routine chromosome analysis, are a major cause of human malformation and mental retardation. Novel high-resolution, whole-genome technologies can improve the diagnostic detection rate of these small chromosomal abnormalities. Array-based comparative genomic hybridization allows such a high-resolution screening by hybridizing differentially labeled test and reference DNAs to arrays consisting of thousands of genomic clones. In this study, we tested the diagnostic capacity of this technology using ∼3,500 flourescent in situ hybridization–verified clones selected to cover the genome with an average of 1 clone per megabase (Mb). The sensitivity and specificity of the technology were tested in normal-versus-normal control experiments and through the screening of patients with known microdeletion syndromes. Subsequently, a series of 20 cytogenetically normal patients with mental retardation and dysmorphisms suggestive of a chromosomal abnormality were analyzed. In this series, three microdeletions and two microduplications were identified and validated. Two of these genomic changes were identified also in one of the parents, indicating that these are large-scale genomic polymorphisms. Deletions and duplications as small as 1 Mb could be reliably detected by our approach. The percentage of false-positive results was reduced to a minimum by use of a dye-swap-replicate analysis, all but eliminating the need for laborious validation experiments and facilitating implementation in a routine diagnostic setting. This high-resolution assay will facilitate the identification of novel genes involved in human mental retardation and/or malformation syndromes and will provide insight into the flexibility and plasticity of the human genome. PMID:14628292

  20. Chromosome 12p abnormalities and IMP3 expression in prepubertal pure testicular teratomas.

    PubMed

    Cornejo, Kristine M; Cheng, Liang; Church, Alanna; Wang, Mingsheng; Jiang, Zhong

    2016-03-01

    Although the histologic appearance of pure testicular teratomas (PTTs) is similar in children and adults, the prognosis is dramatically different. Prepubertal PTTs are rare, with a benign clinical course, whereas the adult cases typically have malignant outcomes. Chromosome 12p abnormalities are seen in most adult testicular germ cell tumors but have not been found in prepubertal PTTs. IMP3 is an oncofetal protein that is highly expressed in many malignancies. Recently, we demonstrated IMP3 is expressed in adult mature testicular teratomas but not in mature ovarian teratomas. The aim of this study was to evaluate prepubertal PTTs for chromosome 12p abnormalities and expression of IMP3. A total of 11 cases (excision, n=1; orchiectomy, n=10) were obtained from the surgical pathology archives of 2 large medical centers (1957-2013). All 11 cases were investigated for isochromosome 12p and 12p copy number gain using interphase fluorescence in situ hybridization analysis and were examined by immunohistochemistry for IMP3 expression. Patients ranged in age from 0.9 to 7.0 (mean, 2.4) years. A positive immunohistochemical stain for IMP3 (cytoplasmic staining) was identified in 5 (46%) of 11 cases. Isochromosome 12p was detected in 2 cases (18%) that also expressed IMP3. Somatic copy number alterations of 12p were not observed (0%). We are the first to describe 12p abnormalities and IMP3 expression in prepubertal PTTs. Our data demonstrate a small subset of PTTs harbor typical molecular alterations observed in adult testicular germ cell tumors. Although prepubertal PTTs are considered to be benign neoplasms, it may be a heterogeneous group.

  1. The role of meiotic cohesin REC8 in chromosome segregation in {gamma} irradiation-induced endopolyploid tumour cells

    SciTech Connect

    Erenpreisa, Jekaterina; Cragg, Mark S.; Salmina, Kristine; Hausmann, Michael; Scherthan, Harry

    2009-09-10

    Escape from mitotic catastrophe and generation of endopolyploid tumour cells (ETCs) represents a potential survival strategy of tumour cells in response to genotoxic treatments. ETCs that resume the mitotic cell cycle have reduced ploidy and are often resistant to these treatments. In search for a mechanism for genome reduction, we previously observed that ETCs express meiotic proteins among which REC8 (a meiotic cohesin component) is of particular interest, since it favours reductional cell division in meiosis. In the present investigation, we induced endopolyploidy in p53-dysfunctional human tumour cell lines (Namalwa, WI-L2-NS, HeLa) by gamma irradiation, and analysed the sub-cellular localisation of REC8 in the resulting ETCs. We observed by RT-PCR and Western blot that REC8 is constitutively expressed in these tumour cells, along with SGOL1 and SGOL2, and that REC8 becomes modified after irradiation. REC8 localised to paired sister centromeres in ETCs, the former co-segregating to opposite poles. Furthermore, REC8 localised to the centrosome of interphase ETCs and to the astral poles in anaphase cells where it colocalised with the microtubule-associated protein NuMA. Altogether, our observations indicate that radiation-induced ETCs express features of meiotic cell divisions and that these may facilitate chromosome segregation and genome reduction.

  2. Nuclear pore complex evolution: a trypanosome Mlp analogue functions in chromosomal segregation but lacks transcriptional barrier activity.

    PubMed

    Holden, Jennifer M; Koreny, Ludek; Obado, Samson; Ratushny, Alexander V; Chen, Wei-Ming; Chiang, Jung-Hsien; Kelly, Steven; Chait, Brian T; Aitchison, John D; Rout, Michael P; Field, Mark C

    2014-05-01

    The nuclear pore complex (NPC) has dual roles in nucleocytoplasmic transport and chromatin organization. In many eukaryotes the coiled-coil Mlp/Tpr proteins of the NPC nuclear basket have specific functions in interactions with chromatin and defining specialized regions of active transcription, whereas Mlp2 associates with the mitotic spindle/NPC in a cell cycle-dependent manner. We previously identified two putative Mlp-related proteins in African trypanosomes, TbNup110 and TbNup92, the latter of which associates with the spindle. We now provide evidence for independent ancestry for TbNup92/TbNup110 and Mlp/Tpr proteins. However, TbNup92 is required for correct chromosome segregation, with knockout cells exhibiting microaneuploidy and lowered fidelity of telomere segregation. Further, TbNup92 is intimately associated with the mitotic spindle and spindle anchor site but apparently has minimal roles in control of gene transcription, indicating that TbNup92 lacks major barrier activity. TbNup92 therefore acts as a functional analogue of Mlp/Tpr proteins, and, together with the lamina analogue NUP-1, represents a cohort of novel proteins operating at the nuclear periphery of trypanosomes, uncovering complex evolutionary trajectories for the NPC and nuclear lamina.

  3. Haspin inhibitors reveal centromeric functions of Aurora B in chromosome segregation

    PubMed Central

    Wang, Fangwei; Ulyanova, Natalia P.; Daum, John R.; Patnaik, Debasis; Kateneva, Anna V.; Gorbsky, Gary J.

    2012-01-01

    Haspin phosphorylates histone H3 at threonine-3 (H3T3ph), providing a docking site for the Aurora B complex at centromeres. Aurora B functions to correct improper kinetochore–microtubule attachments and alert the spindle checkpoint to the presence of misaligned chromosomes. We show that Haspin inhibitors decreased H3T3ph, resulting in loss of centromeric Aurora B and reduced phosphorylation of centromere and kinetochore Aurora B substrates. Consequently, metaphase chromosome alignment and spindle checkpoint signaling were compromised. These effects were phenocopied by microinjection of anti-H3T3ph antibodies. Retargeting Aurora B to centromeres partially restored checkpoint signaling and Aurora B–dependent phosphorylation at centromeres and kinetochores, bypassing the need for Haspin activity. Haspin inhibitors did not obviously affect phosphorylation of histone H3 at serine-10 (H3S10ph) by Aurora B on chromosome arms but, in Aurora B reactivation assays, recovery of H3S10ph was delayed. Haspin inhibitors did not block Aurora B localization to the spindle midzone in anaphase or Aurora B function in cytokinesis. Thus, Haspin inhibitors reveal centromeric roles of Aurora B in chromosome movement and spindle checkpoint signaling. PMID:23071152

  4. Chromosomal Abnormalities among Offspring of Childhood-Cancer Survivors in Denmark: A Population-Based Study

    PubMed Central

    Winther, Jeanette Falck; Boice Jr., John D.; Mulvihill, John J.; Stovall, Marilyn; Frederiksen, Kirsten; Tawn, E. Janet; Olsen, Jørgen H.

    2004-01-01

    Ionizing radiation and many cancer drugs have the potential to produce germ-cell mutations that might lead to genetic disease in the next generation. In a population-based study, we identified, from records in the Danish Cancer Registry, 4,676 children treated for cancer. Their 6,441 siblings provided a comparison cohort. The results of a search of the Central Population Register identified 2,630 live-born offspring of the survivors and 5,504 live-born offspring of their siblings. The occurrence of abnormal karyotypes diagnosed in these offspring and also in any pregnancies terminated following prenatal diagnosis of a chromosome abnormality was determined from the Danish Cytogenetic Registry. After exclusion of hereditary cases and inclusion of the prenatal cases, after correction for expected viability, the adjusted proportion of live-born children in survivor families with abnormal karyotypes (5.5/2,631.5 [0.21%]) was the same as that among the comparison sibling families (11.8/5,505.8 [0.21%]). There were no significant differences in the occurrence of Down syndrome (relative risk [RR]=1.07; 95% CI 0.16–5.47) or Turner syndrome (RR=1.32; 95% CI 0.17–7.96) among the children of cancer survivors, compared with the children of their siblings. These reassuring results are of importance to the survivors, to their families, and to genetic counselors. PMID:15106125

  5. Self-correction of chromosomal abnormalities in human preimplantation embryos and embryonic stem cells.

    PubMed

    Bazrgar, Masood; Gourabi, Hamid; Valojerdi, Mojtaba Rezazadeh; Yazdi, Poopak Eftekhari; Baharvand, Hossein

    2013-09-01

    Aneuploidy is commonly seen in human preimplantation embryos, most particularly at the cleavage stage because of genome activation by third cell division. Aneuploid embryos have been used for the derivation of normal embryonic stem cell (ESC) lines and developmental modeling. This review addresses aneuploidies in human preimplantation embryos and human ESCs and the potential of self-correction of these aberrations. Diploid-aneuploid mosaicism is the most frequent abnormality observed; hence, embryos selected by preimplantation genetic diagnosis at the cleavage or blastocyst stage could be partly abnormal. Differentiation is known as the barrier for eliminating mosaic embryos by death and/or decreased division of abnormal cells. However, some mosaicisms, such as copy number variations could be compatible with live birth. Several reasons have been proposed for self-correction of aneuploidies during later stages of development, including primary misdiagnosis, allocation of the aneuploidy in the trophectoderm, cell growth advantage of diploid cells in mosaic embryos, lagging of aneuploid cell division, extrusion or duplication of an aneuploid chromosome, and the abundance of DNA repair gene products. Although more studies are needed to understand the mechanisms of self-correction as a rare phenomenon, most likely, it is related to overcoming mosaicism.

  6. Post-transplant lymphoproliferative disorder subtypes correlate with different recurring chromosomal abnormalities.

    PubMed

    Djokic, Miroslav; Le Beau, Michelle M; Swinnen, Lode J; Smith, Sonali M; Rubin, Charles M; Anastasi, John; Carlson, Katrin M

    2006-03-01

    Although cytogenetic analysis advanced the understanding of the pathogenesis of primary non-Hodgkin lymphoma and led to improved clinical management, there have been no large cytogenetic studies of post-transplant lymphoproliferative disorder (PTLD). We examined the karyotypes of 36 PTLD cases and correlated them with clinical, laboratory, and pathologic findings. The cases included 2 early lesions, 13 polymorphic PTLDs, and 21 monomorphic PTLDs (18 B-cell and 3 T-cell proliferations). Cytogenetic abnormalities were identified in 72% of monomorphic B-cell PTLDs and in all T-cell PTLDs, but in only 15% of polymorphic PTLDs and in no early lesions. The most frequent clonal abnormalities in monomorphic PTLD were trisomies 9 and/or 11 (5 cases), followed by rearrangements of 8q24.1 (4 cases), 3q27 (2 cases), and 14q32 (2 cases). MYC rearrangement (8q24.1) and T-cell-associated chromosomal abnormalities correlated with poor outcome and short survival. PTLD with trisomy 9 and/or 11 developed early after transplant, presenting as Epstein-Barr virus-positive large B-cell lymphoma with prolonged survival.

  7. [Variations of heterochromatic chromosomal regions and chromosome abnormalities in children with autism: identification of genetic markers in autistic spectrum disorders].

    PubMed

    Vorsanova, S G; Iurov, I Iu; Demidova, I A; Voinova-Ulas, V Iu; Kravets, V S; Solov'ev, I V; Gorbachevskaia, N L; Iurov, Iu B

    2006-01-01

    In the present study, the cytogenetic and molecular cytogenetic analysis of 90 children with autism and their mothers (18 subjects) was carried out. Chromosome fragility and abnormalities were found in four cases: mos 47,XXX[98]/ 46,XX[2]; 46,XY,r(22)(p11q13); 46,XY,inv(2)(p11.2q13),16qh-; 46Y,fra(X)(q27.3)16qh-. Using C-banding and quantitative fluorescent in situ hybridization (FISH), the significantly increased incidence of heterochromatic region variation was shown in autism as compared to the controls (48 and 16%, respectively). Pericentric 9phqh inversion was not characteristic of the patients with autism whereas heterochromatic variations 1phqh, 9qh+ and 16qh- were more frequent in autism (p<0,05). Basing on the data obtained, a possible role of position effect in autism pathogenesis as well as a potential of heterochromatic region variation analysis for the search of biological markers of autistic spectrum disorders are discussed.

  8. PP2ACdc55’s role in reductional chromosome segregation during achiasmate meiosis in budding yeast is independent of its FEAR function

    PubMed Central

    Kerr, Gary W.; Wong, Jin Huei; Arumugam, Prakash

    2016-01-01

    PP2ACdc55 is a highly conserved serine-threonine protein phosphatase that is involved in diverse cellular processes. In budding yeast, meiotic cells lacking PP2ACdc55 activity undergo a premature exit from meiosis I which results in a failure to form bipolar spindles and divide nuclei. This defect is largely due to its role in negatively regulating the Cdc Fourteen Early Anaphase Release (FEAR) pathway. PP2ACdc55 prevents nucleolar release of the Cdk (Cyclin-dependent kinase)-antagonising phosphatase Cdc14 by counteracting phosphorylation of the nucleolar protein Net1 by Cdk. CDC55 was identified in a genetic screen for monopolins performed by isolating suppressors of spo11Δ spo12Δ lethality suggesting that Cdc55 might have a role in meiotic chromosome segregation. We investigated this possibility by isolating cdc55 alleles that suppress spo11Δ spo12Δ lethality and show that this suppression is independent of PP2ACdc55’s FEAR function. Although the suppressor mutations in cdc55 affect reductional chromosome segregation in the absence of recombination, they have no effect on chromosome segregation during wild type meiosis. We suggest that Cdc55 is required for reductional chromosome segregation during achiasmate meiosis and this is independent of its FEAR function. PMID:27455870

  9. PICH promotes mitotic chromosome segregation: Identification of a novel role in rDNA disjunction.

    PubMed

    Nielsen, Christian F; Hickson, Ian D

    2016-10-17

    PICH is an SNF2-family DNA translocase that appears to play a role specifically in mitosis. Characterization of PICH in human cells led to the initial discovery of "ultra-fine DNA bridges" (UFBs) that connect the 2 segregating DNA masses in the anaphase of mitosis. These bridge structures, which arise from specific regions of the genome, are a normal feature of anaphase but had escaped detection previously because they do not stain with commonly used DNA dyes. Nevertheless, UFBs are important for genome maintenance because defects in UFB resolution can lead to cytokinesis failure. We reported recently that PICH stimulates the unlinking (decatenation) of entangled DNA by Topoisomerase IIα (Topo IIα), and is important for the resolution of UFBs. We also demonstrated that PICH and Topo IIα co-localize at the rDNA (rDNA). In this Extra View article, we discuss the mitotic roles of PICH and explore further the role of PICH in the timely segregation of the rDNA locus.

  10. A role for maternal serum screening in detecting chromosomal abnormalities in fetuses with isolated choroid plexus cysts: a prospective multicentre study.

    PubMed

    Brown, T; Kliewer, M A; Hertzberg, B S; Ruiz, C; Stamper, T H; Rosnes, J; Lucas, A; Wright, L N; Chescheir, N C; Farmer, L; Jordan, S; Kay, H H

    1999-05-01

    A prospective multicentre study was performed to identify patients with fetal choroid plexus cysts and examine the association between choroid plexus cysts and chromosome abnormalities in the context of variables such as maternal age, serum triple-screen results, race, other prenatally-identified fetal anomalies and cyst characteristics. A total of 18 437 scans were performed in 5 centres and 257 fetuses were identified with choroid plexus cysts. Outcome was available on 250 patients, and of these, chromosomal abnormalities were detected in a total of 13 (5.2 per cent) fetuses. 26 patients in the group had additional ultrasound abnormalities, and 8 of these had fetal chromosome abnormalities. Among the 224 patients with isolated choroid plexus cysts, 5 (2.2 per cent) were found to have chromosomal abnormalities. All cases with identified chromosomal abnormalities were associated with an additional risk factor, such as other ultrasound findings, advanced maternal age or abnormal maternal serum triple-screen results.

  11. Allelic interaction of F1 pollen sterility loci and abnormal chromosome behaviour caused pollen sterility in intersubspecific autotetraploid rice hybrids.

    PubMed

    He, J H; Shahid, M Q; Li, Y J; Guo, H B; Cheng, X A; Liu, X D; Lu, Y G

    2011-08-01

    The intersubspecific hybrids of autotetraploid rice has many features that increase rice yield, but lower seed set is a major hindrance in its utilization. Pollen sterility is one of the most important factors which cause intersubspecific hybrid sterility. The hybrids with greater variation in seed set were used to study how the F(1) pollen sterile loci (S-a, S-b, and S-c) interact with each other and how abnormal chromosome behaviour and allelic interaction of F(1) sterility loci affect pollen fertility and seed set of intersubspecific autotetraploid rice hybrids. The results showed that interaction between pollen sterility loci have significant effects on the pollen fertility of autotetraploid hybrids, and pollen fertility further decreased with an increase in the allelic interaction of F(1) pollen sterility loci. Abnormal ultra-structure and microtubule distribution patterns during pollen mother cell (PMC) meiosis were found in the hybrids with low pollen fertility in interphase and leptotene, suggesting that the effect-time of pollen sterility loci interaction was very early. There were highly significant differences in the number of quadrivalents and bivalents, and in chromosome configuration among all the hybrids, and quadrivalents decreased with an increase in the seed set of autotetraploid hybrids. Many different kinds of chromosomal abnormalities, such as chromosome straggling, chromosome lagging, asynchrony of chromosome disjunction, and tri-fission were found during the various developmental stages of PMC meiosis. All these abnormalities were significantly higher in sterile hybrids than in fertile hybrids, suggesting that pollen sterility gene interactions tend to increase the chromosomal abnormalities which cause the partial abortion of male gametes and leads to the decline in the seed set of the autotetraploid rice hybrids.

  12. Intact Cohesion, Anaphase, and Chromosome Segregation in Human Cells Harboring Tumor-Derived Mutations in STAG2

    PubMed Central

    Kim, Jung-Sik; He, Xiaoyuan; Orr, Bernardo; Wutz, Gordana; Hill, Victoria; Peters, Jan-Michael; Compton, Duane A.; Waldman, Todd

    2016-01-01

    Somatic mutations of the cohesin complex subunit STAG2 are present in diverse tumor types. We and others have shown that STAG2 inactivation can lead to loss of sister chromatid cohesion and alterations in chromosome copy number in experimental systems. However, studies of naturally occurring human tumors have demonstrated little, if any, correlation between STAG2 mutational status and aneuploidy, and have further shown that STAG2-deficient tumors are often euploid. In an effort to provide insight into these discrepancies, here we analyze the effect of tumor-derived STAG2 mutations on the protein composition of cohesin and the expected mitotic phenotypes of STAG2 mutation. We find that many mutant STAG2 proteins retain their ability to interact with cohesin; however, the presence of mutant STAG2 resulted in a reduction in the ability of regulatory subunits WAPL, PDS5A, and PDS5B to interact with the core cohesin ring. Using AAV-mediated gene targeting, we then introduced nine tumor-derived mutations into the endogenous allele of STAG2 in cultured human cells. While all nonsense mutations led to defects in sister chromatid cohesion and a subset induced anaphase defects, missense mutations behaved like wild-type in these assays. Furthermore, only one of nine tumor-derived mutations tested induced overt alterations in chromosome counts. These data indicate that not all tumor-derived STAG2 mutations confer defects in cohesion, chromosome segregation, and ploidy, suggesting that there are likely to be other functional effects of STAG2 inactivation in human cancer cells that are relevant to cancer pathogenesis. PMID:26871722

  13. Karyotypic complexity rather than chromosome 8 abnormalities aggravates the outcome of chronic lymphocytic leukemia patients with TP53 aberrations.

    PubMed

    Blanco, Gonzalo; Puiggros, Anna; Baliakas, Panagiotis; Athanasiadou, Anastasia; García-Malo, MªDolores; Collado, Rosa; Xochelli, Aliki; Rodríguez-Rivera, María; Ortega, Margarita; Calasanz, Mª José; Luño, Elisa; Vargas, MªTeresa; Grau, Javier; Martínez-Laperche, Carolina; Valiente, Alberto; Cervera, José; Anagnostopoulos, Achilles; Gimeno, Eva; Abella, Eugènia; Stalika, Evangelia; Hernández-Rivas, Jesús Mª; Ortuño, Francisco José; Robles, Diego; Ferrer, Ana; Ivars, David; González, Marcos; Bosch, Francesc; Abrisqueta, Pau; Stamatopoulos, Kostas; Espinet, Blanca

    2016-12-06

    Patients with chronic lymphocytic leukemia (CLL) harboring TP53 aberrations (TP53abs; chromosome 17p deletion and/or TP53 mutation) exhibit an unfavorable clinical outcome. Chromosome 8 abnormalities, namely losses of 8p (8p-) and gains of 8q (8q+) have been suggested to aggravate the outcome of patients with TP53abs. However, the reported series were small, thus hindering definitive conclusions. To gain insight into this issue, we assessed a series of 101 CLL patients harboring TP53 disruption. The frequency of 8p- and 8q+ was 14.7% and 17.8% respectively. Both were associated with a significantly (P < 0.05) higher incidence of a complex karyotype (CK, ≥3 abnormalities) detected by chromosome banding analysis (CBA) compared to cases with normal 8p (N-8p) and 8q (N-8q), respectively. In univariate analysis for 10-year overall survival (OS), 8p- (P = 0.002), 8q+ (P = 0.012) and CK (P = 0.009) were associated with shorter OS. However, in multivariate analysis only CK (HR = 2.47, P = 0.027) maintained independent significance, being associated with a dismal outcome regardless of chromosome 8 abnormalities. In conclusion, our results highlight the association of chromosome 8 abnormalities with CK amongst CLL patients with TP53abs, while also revealing that CK can further aggravate the prognosis of this aggressive subgroup.

  14. Karyotypic complexity rather than chromosome 8 abnormalities aggravates the outcome of chronic lymphocytic leukemia patients with TP53 aberrations

    PubMed Central

    Blanco, Gonzalo; Puiggros, Anna; Baliakas, Panagiotis; Athanasiadou, Anastasia; García-Malo, MªDolores; Collado, Rosa; Xochelli, Aliki; Rodríguez-Rivera, María; Ortega, Margarita; Calasanz, Mª José; Luño, Elisa; Vargas, MªTeresa; Grau, Javier; Martínez-Laperche, Carolina; Valiente, Alberto; Cervera, José; Anagnostopoulos, Achilles; Gimeno, Eva; Abella, Eugènia; Stalika, Evangelia; Hernández-Rivas, Jesús Mª; Ortuño, Francisco José; Robles, Diego; Ferrer, Ana; Ivars, David; González, Marcos; Bosch, Francesc; Abrisqueta, Pau; Stamatopoulos, Kostas; Espinet, Blanca

    2016-01-01

    Patients with chronic lymphocytic leukemia (CLL) harboring TP53 aberrations (TP53abs; chromosome 17p deletion and/or TP53 mutation) exhibit an unfavorable clinical outcome. Chromosome 8 abnormalities, namely losses of 8p (8p−) and gains of 8q (8q+) have been suggested to aggravate the outcome of patients with TP53abs. However, the reported series were small, thus hindering definitive conclusions. To gain insight into this issue, we assessed a series of 101 CLL patients harboring TP53 disruption. The frequency of 8p− and 8q+ was 14.7% and 17.8% respectively. Both were associated with a significantly (P < 0.05) higher incidence of a complex karyotype (CK, ≥3 abnormalities) detected by chromosome banding analysis (CBA) compared to cases with normal 8p (N-8p) and 8q (N-8q), respectively. In univariate analysis for 10-year overall survival (OS), 8p− (P = 0.002), 8q+ (P = 0.012) and CK (P = 0.009) were associated with shorter OS. However, in multivariate analysis only CK (HR = 2.47, P = 0.027) maintained independent significance, being associated with a dismal outcome regardless of chromosome 8 abnormalities. In conclusion, our results highlight the association of chromosome 8 abnormalities with CK amongst CLL patients with TP53abs, while also revealing that CK can further aggravate the prognosis of this aggressive subgroup. PMID:27821812

  15. Occurrence of fetal choroid plexus cysts in siblings: concerns regarding recurrence and chromosomal abnormality.

    PubMed

    Koyama, Shinsuke; Kimura, Tadashi; Tokugawa, Yoshihiro; Koyama, Masayasu; Murata, Yuji; Shimizu, Takashi

    2005-12-01

    Choroid plexus cysts (CPC) are a well-known ultrasound aneuploidy marker easily detectable at second-trimester ultrasound examination. However, their genetic etiology is totally unknown. We report two cases of Japanese mothers who carried two and three siblings respectively; all the fetuses that had CPC were noticed at second trimester. Genetic amniocentesis revealed that each fetus had different karyotypes, that is, trisomy 18 and 46,XX in the case of one mother, and trisomy 18, 46,XY and trisomy 21 in the case of the other. These observations indicate that the genetic basis of the cysts is not linked to abnormal chromosomes. We propose that careful ultrasound observation and genetic counseling of the siblings should be offered to patients who have previously had a baby with CPC, despite that baby having a normal karyotype.

  16. A dominantly acting murine allele of Mcm4 causes chromosomal abnormalities and promotes tumorigenesis.

    PubMed

    Bagley, Bruce N; Keane, Thomas M; Maklakova, Vilena I; Marshall, Jonathon G; Lester, Rachael A; Cancel, Michelle M; Paulsen, Alex R; Bendzick, Laura E; Been, Raha A; Kogan, Scott C; Cormier, Robert T; Kendziorski, Christina; Adams, David J; Collier, Lara S

    2012-01-01

    Here we report the isolation of a murine model for heritable T cell lymphoblastic leukemia/lymphoma (T-ALL) called Spontaneous dominant leukemia (Sdl). Sdl heterozygous mice develop disease with a short latency and high penetrance, while mice homozygous for the mutation die early during embryonic development. Sdl mice exhibit an increase in the frequency of micronucleated reticulocytes, and T-ALLs from Sdl mice harbor small amplifications and deletions, including activating deletions at the Notch1 locus. Using exome sequencing it was determined that Sdl mice harbor a spontaneously acquired mutation in Mcm4 (Mcm4(D573H)). MCM4 is part of the heterohexameric complex of MCM2-7 that is important for licensing of DNA origins prior to S phase and also serves as the core of the replicative helicase that unwinds DNA at replication forks. Previous studies in murine models have discovered that genetic reductions of MCM complex levels promote tumor formation by causing genomic instability. However, Sdl mice possess normal levels of Mcms, and there is no evidence for loss-of-heterozygosity at the Mcm4 locus in Sdl leukemias. Studies in Saccharomyces cerevisiae indicate that the Sdl mutation produces a biologically inactive helicase. Together, these data support a model in which chromosomal abnormalities in Sdl mice result from the ability of MCM4(D573H) to incorporate into MCM complexes and render them inactive. Our studies indicate that dominantly acting alleles of MCMs can be compatible with viability but have dramatic oncogenic consequences by causing chromosomal abnormalities.

  17. A Dominantly Acting Murine Allele of Mcm4 Causes Chromosomal Abnormalities and Promotes Tumorigenesis

    PubMed Central

    Bagley, Bruce N.; Keane, Thomas M.; Maklakova, Vilena I.; Marshall, Jonathon G.; Lester, Rachael A.; Cancel, Michelle M.; Paulsen, Alex R.; Bendzick, Laura E.; Been, Raha A.; Kogan, Scott C.; Cormier, Robert T.; Kendziorski, Christina; Adams, David J.; Collier, Lara S.

    2012-01-01

    Here we report the isolation of a murine model for heritable T cell lymphoblastic leukemia/lymphoma (T-ALL) called Spontaneous dominant leukemia (Sdl). Sdl heterozygous mice develop disease with a short latency and high penetrance, while mice homozygous for the mutation die early during embryonic development. Sdl mice exhibit an increase in the frequency of micronucleated reticulocytes, and T-ALLs from Sdl mice harbor small amplifications and deletions, including activating deletions at the Notch1 locus. Using exome sequencing it was determined that Sdl mice harbor a spontaneously acquired mutation in Mcm4 (Mcm4D573H). MCM4 is part of the heterohexameric complex of MCM2–7 that is important for licensing of DNA origins prior to S phase and also serves as the core of the replicative helicase that unwinds DNA at replication forks. Previous studies in murine models have discovered that genetic reductions of MCM complex levels promote tumor formation by causing genomic instability. However, Sdl mice possess normal levels of Mcms, and there is no evidence for loss-of-heterozygosity at the Mcm4 locus in Sdl leukemias. Studies in Saccharomyces cerevisiae indicate that the Sdl mutation produces a biologically inactive helicase. Together, these data support a model in which chromosomal abnormalities in Sdl mice result from the ability of MCM4D573H to incorporate into MCM complexes and render them inactive. Our studies indicate that dominantly acting alleles of MCMs can be compatible with viability but have dramatic oncogenic consequences by causing chromosomal abnormalities. PMID:23133403

  18. Insertional Mutation on Mouse Chromosome 18 with Vestibular and Craniofacial Abnormalities

    PubMed Central

    Ting, C. N.; Kohrman, D.; Burgess, D. L.; Boyle, A.; Altschuler, R. A.; Gholizadeh, G.; Samuelson, L. C.; Jang, W.; Meisler, M. H.

    1994-01-01

    A dominant mutation was generated in transgenic mice as a consequence of insertional mutation. Heterozygous mice from transgenic line 9257 (Tg(9257)) are hyperactive with bidirectional circling behavior and have a distinctive facial appearance due to hypoplasia of the nasal bone. Morphological analysis of the inner ear revealed asymmetric abnormalities of the horizontal canal and flattening or invagination of the crista ampullaris, which can account for the circling behavior. The sensory epithelium appeared to be normal. The transgene insertion site was localized by in situ hybridization to the B1 band of mouse chromosome 18. Genetic mapping in an interspecific backcross demonstrated the gene order centromere--Tg(9257)--8.8 +/- 3.4--Grl-1, Egr-1, Fgf-1, Apc--14.7 +/- 4.3--Pdgfr. The phenotype and the mapping data suggest that the transgene may be inserted at the Twirler locus. Homozygosity for the transgene results in prenatal lethality, but compound heterozygotes carrying the Tw allele and the transgene are viable. The function of the closely linked ataxia locus is not disrupted by the transgene insertion. This insertional mutant will provide molecular access to genes located in the Twirler region of mouse chromosome 18. PMID:7511123

  19. Mortality and cancer incidence in persons with numerical sex chromosome abnormalities: a cohort study.

    PubMed

    Swerdlow, A J; Hermon, C; Jacobs, P A; Alberman, E; Beral, V; Daker, M; Fordyce, A; Youings, S

    2001-03-01

    Mortality and cancer incidence were assessed in a cohort of 1373 patients with numerical sex chromosome abnormalities diagnosed at three cytogenetics centres in Britain during 1959-90, and were compared with expectations from national rates. Four hundred patients with Turner's syndrome were followed, of whom 62 died, with a relative risk (RR) of death of 4.16 (95% confidence interval (CI) 3.22-5.39). Turner's syndrome patients had greatly raised risks of death from diseases of the nervous, cardiovascular, respiratory, digestive and genitourinary systems. One hundred and sixty three deaths occurred among 646 patients with Klinefelter's syndrome with a 47,XXY constitution, giving an RR of 1.63 (1.40-1.91). Mortality in these patients was significantly raised from diabetes and diseases of the cardiovascular, respiratory and digestive systems. There was also significantly increased mortality for patients with X polysomy (RR = 2.11 (1.43-3.02)) and Y polysomy (RR = 1.90 (1.20-2.85)), the former with significantly increased mortality from cardiovascular disease and the latter from respiratory disease. The only significantly raised risks of cancer incidence or mortality in the cohort were for lung cancer and breast cancer in patients with Klinefelter's syndrome with a 47,XXY constitution, and non-Hodgkin's lymphoma in men with more than three sex chromosomes.

  20. A novel syndrome of abnormal striatum and congenital cataract: evidence for linkage to chromosomes 11.

    PubMed

    Al-Owain, M; Al-Zahrani, J; Al-Bakheet, A; Abudheim, N; Al-Younes, B; Aldhalaan, H; Al-Zaidan, H; Colak, D; Almohaileb, F; Abouzied, M E; Al-Fadhli, F; Meyer, B; Kaya, N

    2013-09-01

    We report a consanguineous family of three girls and one boy affected with a novel syndrome involving the lens and the basal ganglia. The phenotype is strikingly similar between affected siblings with cognitive impairment, attention deficit hyperactivity disorder (ADHD), microcephaly, growth retardation, congenital cataract, and dystonia. The magnetic resonance imaging showed unusual pattern of swelling of the caudate heads and thinning of the putamina with severe degree of hypometabolism on the [18F] deoxyglucose positron emission tomography. Furthermore, the clinical assessment provides the evidence that the neurological phenotype is very slowly progressive. We utilized the 10K single-nucleotide polymorphism (SNP) microarray genotyping for linkage analysis. Genome-wide scan indicated a 45.9-Mb region with a 4.2353 logarithm of the odds score on chromosome 11. Affymetrix genome-wide human SNP array 6.0 assay did not show any gross chromosomal abnormality. Targeted sequencing of two candidate genes within the linkage interval (PAX6 and B3GALTL) as well as mtDNA genome sequencing did not reveal any putative mutations.

  1. Characterization of a complex chromosomal rearrangement using chromosome, FISH, and microarray assays in a girl with multiple congenital abnormalities and developmental delay

    PubMed Central

    2014-01-01

    Complex chromosomal rearrangements (CCRs) are balanced or unbalanced structural rearrangements involving three or more cytogenetic breakpoints on two or more chromosomal pairs. The phenotypic anomalies in such cases are attributed to gene disruption, superimposed cryptic imbalances in the genome, and/or position effects. We report a 14-year-old girl who presented with multiple congenital anomalies and developmental delay. Chromosome and FISH analysis indicated a highly complex chromosomal rearrangement involving three chromosomes (3, 7 and 12), seven breakpoints as a result of one inversion, two insertions, and two translocations forming three derivative chromosomes. Additionally, chromosomal microarray study (CMA) revealed two submicroscopic deletions at 3p12.3 (467 kb) and 12q13.12 (442 kb). We postulate that microdeletion within the ROBO1 gene at 3p12.3 may have played a role in the patient’s developmental delay, since it has potential activity-dependent role in neurons. Additionally, factors other than genomic deletions such as loss of function or position effects may also contribute to the abnormal phenotype in our patient. PMID:25478007

  2. Characterization of a complex chromosomal rearrangement using chromosome, FISH, and microarray assays in a girl with multiple congenital abnormalities and developmental delay.

    PubMed

    Hemmat, Morteza; Yang, Xiaojing; Chan, Patricia; McGough, Robert A; Ross, Leslie; Mahon, Loretta W; Anguiano, Arturo L; Boris, Wang T; Elnaggar, Mohamed M; Wang, Jia-Chi J; Strom, Charles M; Boyar, Fatih Z

    2014-01-01

    Complex chromosomal rearrangements (CCRs) are balanced or unbalanced structural rearrangements involving three or more cytogenetic breakpoints on two or more chromosomal pairs. The phenotypic anomalies in such cases are attributed to gene disruption, superimposed cryptic imbalances in the genome, and/or position effects. We report a 14-year-old girl who presented with multiple congenital anomalies and developmental delay. Chromosome and FISH analysis indicated a highly complex chromosomal rearrangement involving three chromosomes (3, 7 and 12), seven breakpoints as a result of one inversion, two insertions, and two translocations forming three derivative chromosomes. Additionally, chromosomal microarray study (CMA) revealed two submicroscopic deletions at 3p12.3 (467 kb) and 12q13.12 (442 kb). We postulate that microdeletion within the ROBO1 gene at 3p12.3 may have played a role in the patient's developmental delay, since it has potential activity-dependent role in neurons. Additionally, factors other than genomic deletions such as loss of function or position effects may also contribute to the abnormal phenotype in our patient.

  3. [Biologic mechanisms of mitotic abnormalities and chromosome number changes in malignant tumors].

    PubMed

    Hegyi, Katalin

    2015-12-01

    The main goal of this work was to study the effect of Aurora kinase expression on cell ploidy and tumorigenesis. Fifty invasive breast cancer, 50 diffuse large B-cell lymphoma and 10 reactive lymph node samples were recruited in the study. Because of the significant correlation with the overall cell proliferation rate, the overexpression of Aurora B could not be stated on the basis of kinase expressing tumor cell fractions alone. The relative expression of Aurora B kinase is better reflected by the AMI index which represents the Aurora B expression in relation to the whole proliferative fraction of the tumor. A higher relative Aurora B expression was associated with higher mitotic activity in B-cell lymphoma. FISH analysis of the AURKB locus did not show any gains or amplifications in the samples analyzed. On the other hand, we have observed the loss of the gene in breast carcinoma and lymphoma samples as well. A strong correlation was shown between AURKB and TP53 copy numbers: AURKB loss was associated with TP53 deletion in all samples. According to our results on breast carcinoma, losses at 17p13.1 and chromosome 17 aneusomy determined by FISH showed a statistically significant correlation. Our study presents the frequent occurrence of chromosome 17 aneusomy in breast carcinoma and B-cell lymphoma samples. Chromosome 17 aneusomy evaluated by FISH correlated with aneuploidy determined by flow cytometry. Direct correlation between kinase expression and ploidy could not be shown. The highest AMI values were seen in B-ALCL samples, and it was associated with high chromosome 17 copy numbers and mitotic activity. The damaged Aurora B kinase function results in regulatory deficiencies in the CPC complex leading to mitotic errors, while p53 deficiency helps malignant cells to survive due to insufficient activation of the intrinsic apoptotic pathways. The upregulation of Aurora kinase B function may cause error in an important mitotic checkpoint, thus resulting in

  4. CDC-48/p97 is required for proper meiotic chromosome segregation via controlling AIR-2/Aurora B kinase localization in Caenorhabditis elegans.

    PubMed

    Sasagawa, Yohei; Higashitani, Atsushi; Urano, Takeshi; Ogura, Teru; Yamanaka, Kunitoshi

    2012-08-01

    CDC-48/p97 is a AAA (ATPases associated with diverse cellular activities) chaperone involved in protein conformational changes such as the disassembly of protein complexes. We previously reported that Caenorhabditis elegans CDC-48.1 and CDC-48.2 (CDC-48s) are essential for the progression of meiosis I metaphase. Here, we report that CDC-48s are required for proper chromosome segregation during meiosis in C. elegans. In wild-type worms, at the diakinesis phase, phosphorylation of histone H3, one of the known substrates of aurora B kinase (AIR-2), on meiosis I chromatids correlated with AIR-2 localization at the cohesion sites of homologous chromatids. Conversely, depletion of CDC-48s resulted in a significant expansion of signals for AIR-2 and phosphorylated histone H3 over the entire length of meiotic chromosomes, leading to defective chromosome segregation, while the total amount of AIR-2 in lysates was not changed by the depletion of CDC-48s. The defective segregation of meiotic chromosomes caused by the depletion of CDC-48s was suppressed by the simultaneous depletion of AIR-2 and is similar to that observed following the depletion of protein phosphatase 1 (PP1) phosphatases. However, the amount and localization of PP1 were not changed by the depletion of CDC-48s. These results suggest that CDC-48s control the restricted localization of AIR-2 to the cohesion sites of homologous chromatids in meiosis I.

  5. Disorders of sexual development and abnormal early development in domestic food-producing mammals: the role of chromosome abnormalities, environment and stress factors.

    PubMed

    Favetta, L A; Villagómez, D A F; Iannuzzi, L; Di Meo, G; Webb, A; Crain, S; King, W A

    2012-01-01

    The management of disorders of sexual development (DSD) in humans and domestic animals has been the subject of intense interest for decades. The association between abnormal chromosome constitutions and DSDs in domestic animals has been recorded since the beginnings of conventional cytogenetic analysis. Deviated karyotypes consisting of abnormal sex chromosome sets and/or the coexistence of cells with different sex chromosome constitutions in an individual seem to be the main causes of anomalies of sex determination and sex differentiation. In recent years, a growing interest has developed around the environmental insults, such as endocrine-disrupting compounds (EDC) and heat stressors, which affect fertility, early embryonic development and, in some instances, directly the sex ratio and/or the development of 1 specific sex versus the other. A variety of chemical compounds present in the environment at low doses has been shown to have major effects on the reproductive functions in human and domestic animals following prolonged exposure. In this review, we present an overview of congenital/chromosomal factors that are responsible for the DSDs and link them and the lack of proper embryonic development to environmental factors that are becoming a major global concern.

  6. Abnormalities in the expression of nebulin in chromosome-2 linked nemaline myopathy.

    PubMed

    Sewry, C A; Brown, S C; Pelin, K; Jungbluth, H; Wallgren-Pettersson, C; Labeit, S; Manzur, A; Muntoni, F

    2001-03-01

    Nemaline myopathy is clinically and genetically heterogeneous. The most common autosomal recessive form affecting infants (NEM2) links to chromosome 2q, and is caused by mutations in the gene for nebulin. We have examined the immunocytochemical expression of nebulin in skeletal muscle in 11 cases of nemaline myopathy, from ten families, with linkage compatible to chromosome 2q.22, the locus for nebulin. Mutations in the gene for nebulin have been found in eight of these cases. Immunolabelling with polyclonal antibodies to C-terminal regions of nebulin was compared with antibodies to fibre-type-specific myofibrillar proteins, including myosin heavy chain isoforms and alpha-actinin isoforms. No cases showed a complete absence of C-terminal nebulin, and no enhancement of labelling of the rods was seen with conventional fluorescence microscopy. In control muscle an antibody to the M176-181 repeat region of nebulin showed higher expression in fibres with slow myosin, while ones to the serine-rich domain and to the SH3 domain showed uniform expression. In some cases of nemaline myopathy differences in these patterns were observed. Two siblings with a homozygous mutation in exon 185, that produces a stop codon, showed an absence of labelling only with the SH3 antibody, and other cases showed uneven labelling with this antibody or some fibres devoid of label. Fibre type correlations also showed differences from controls, as some fibres had a fast isoform of one protein but a slow isoform of another. These results indicate that analysis of nebulin expression may detect abnormalities in some cases linked to the corresponding locus and may help to direct molecular analysis. In addition, they may also be relevant to studies of fibre type plasticity and diversity in nemaline myopathy.

  7. Pervasive and essential roles of the Top3-Rmi1 decatenase orchestrate recombination and facilitate chromosome segregation in meiosis

    PubMed Central

    Tang, Shangming; Wu, Michelle Ka Yan; Zhang, Ruoxi; Hunter, Neil

    2015-01-01

    Summary The Bloom’s helicase ortholog, Sgs1, plays central roles to coordinate the formation and resolution of joint molecule intermediates (JMs) during meiotic recombination in budding yeast. Sgs1 can associate with type-I topoisomerase Top3 and its accessory factor Rmi1 to form a conserved complex best known for its unique ability to decatenate double-Holliday junctions. Contrary to expectations, we show that the strand-passage activity of Top3-Rmi1 is required for all known functions of Sgs1 in meiotic recombination, including channeling JMs into physiological crossover and noncrossover pathways, and suppression of non-allelic recombination. We infer that Sgs1 always functions in the context of the Sgs1-Top3-Rmi1 complex to regulate meiotic recombination. In addition, we reveal a distinct late role for Top3-Rmi1 in resolving recombination-dependent chromosome entanglements to allow segregation at anaphase. Surprisingly, Sgs1 does not share this essential role of Top3-Rmi1. These data reveal an essential and unexpectedly pervasive role for the Top3-Rmi1 decatenase during meiosis. PMID:25699709

  8. Amphibian interorder nuclear transfer embryos reveal conserved embryonic gene transcription, but deficient DNA replication or chromosome segregation.

    PubMed

    Narbonne, Patrick; Gurdon, John B

    2012-01-01

    Early interspecies nuclear transfer (iNT) experiments suggested that a foreign nucleus may become permanently damaged after a few rounds of cell division in the cytoplasm of another species. That is, in some distant species combinations, nucleocytoplasmic hybrid (cybrid) blastula nuclei can no longer support development, even if they are back-transferred into their own kind of egg cytoplasm. We monitored foreign DNA amplification and RNA production by quantitative PCR (qPCR) and RT-qPCR in interorder amphibian hybrids and cybrids formed by the transfer of newt (Pleurodeles waltl) embryonic nuclei into intact and enucleated frog (Xenopus laevis) eggs. We found a dramatic reduction in the expansion of foreign DNA and cell numbers in developing cybrid embryos that correlated with reduced gene transcription. Interestingly, expansion in cell numbers was rescued by the recipient species (Xenopus) maternal genome in iNT hybrids, but it did not improve P. waltl DNA expansion or gene transcription. Also, foreign gene transcripts, normalized to DNA copy numbers, were mostly normal in both iNT hybrids and cybrids. Thus, incomplete foreign DNA replication and/or chromosome segregation during cell division may be the major form of nuclear damage occurring as a result of nuclear replication in a foreign cytoplasmic environment. It also shows that the mechanisms of embryonic gene transcription are highly conserved across amphibians and may not be a major cause of cybrid lethality.

  9. Cdk5rap2 regulates centrosome function and chromosome segregation in neuronal progenitors

    PubMed Central

    Lizarraga, Sofia B.; Margossian, Steven P.; Harris, Marian H.; Campagna, Dean R.; Han, An-Ping; Blevins, Sherika; Mudbhary, Raksha; Barker, Jane E.; Walsh, Christopher A.; Fleming, Mark D.

    2010-01-01

    Microcephaly affects ∼1% of the population and is associated with mental retardation, motor defects and, in some cases, seizures. We analyzed the mechanisms underlying brain size determination in a mouse model of human microcephaly. The Hertwig's anemia (an) mutant shows peripheral blood cytopenias, spontaneous aneuploidy and a predisposition to hematopoietic tumors. We found that the an mutation is a genomic inversion of exon 4 of Cdk5rap2, resulting in an in-frame deletion of exon 4 from the mRNA. The finding that CDK5RAP2 human mutations cause microcephaly prompted further analysis of Cdk5rap2an/an mice and we demonstrated that these mice exhibit microcephaly comparable to that of the human disease, resulting from striking neurogenic defects that include proliferative and survival defects in neuronal progenitors. Cdk5rap2an/an neuronal precursors exit the cell cycle prematurely and many undergo apoptosis. These defects are associated with impaired mitotic progression coupled with abnormal mitotic spindle pole number and mitotic orientation. Our findings suggest that the reduction in brain size observed in humans with mutations in CDK5RAP2 is associated with impaired centrosomal function and with changes in mitotic spindle orientation during progenitor proliferation. PMID:20460369

  10. Acute promyelocytic leukaemia with a PML-RARA insertional translocation and a chromosome 21 abnormality in XYY syndrome: case report.

    PubMed

    He, Yi; Li, Xudong; Wang, Dongning; Zhang, Erhong; Hu, Yuan; Wang, Wenwen; Huang, Renwei; Xiao, Ruozhi

    2014-12-01

    The concomitant presence of the XYY syndrome with haematological malignancies is rare. This report presents a case of acute promyelocytic leukaemia (APL) with the promyelocytic leukaemia-retinoic acid receptor alpha (PML-RARA) gene insertional translocation and a chromosome 21 abnormality in a 29-year-old XYY male patient. Karyotype analysis revealed an abnormal karyotype of 47,XYY [14]/46,XYY,-21[16]. Fluorescence in situ hybridization and reverse transcription-polymerase chain reaction analysis showed the existence of a PML-RARA fusion gene. The patient was treated by all-trans retinoic acid (ATRA) and chemotherapy. Laboratory results revealed that the coagulopathy improved and the patient achieved complete remission, based on bone-marrow morphology. The patient then received sequential monthly therapy using arsenic trioxide, followed by ATRA, followed by chemotherapy; he has survived disease-free for 36 months. Our findings suggest that the additional chromosomal abnormalities involving the sex chromosomes and chromosome 21 did not affect the prognosis of APL, and that the sequential treatment strategy had a good clinical effect without being associated with severe side-effects.

  11. Studies on Brahma rasayana in male swiss albino mice: Chromosomal aberrations and sperm abnormalities

    PubMed Central

    Guruprasad, K. P.; Mascarenhas, Roshan; Gopinath, P. M.; Satyamoorthy, K.

    2010-01-01

    Ayurveda, the Indian holistic healthcare system encompasses traditional medicines with a principle of creating harmony and maintaining balance within the natural rhythms of the body. Rasayana is one of the branches of Ayurveda frequently used as rejuvenant therapy to overcome many discomforts and prevent diseases. It has been reported that rasayanas have immunomodulatory, antioxidant and antitumor functions. However, the genotoxic potential of many rasayanas remains to be evaluated. The present study was undertaken to assess the role of Brahma rasayana(BR) on genotoxicity in vivo in a mouse test system. The older mice (9 months) were orally fed with rasayana for 8 weeks. The treated groups showed no signs of dose-dependent toxicity at the dosage levels tested. The body weight loss/gain and feed consumption were unaffected at tested doses. Furthermore, sperm abnormalities and chromosomal aberrations were insignificant in the treatment group when compared to controls. However, there was a marginal increase in sperm count in the BR treated animals. These findings clearly indicate that there are no observed adverse genotoxic effects elicited by BR in experimental animals such as mice. PMID:21829300

  12. Studies on Brahma rasayana in male swiss albino mice: Chromosomal aberrations and sperm abnormalities.

    PubMed

    Guruprasad, K P; Mascarenhas, Roshan; Gopinath, P M; Satyamoorthy, K

    2010-01-01

    Ayurveda, the Indian holistic healthcare system encompasses traditional medicines with a principle of creating harmony and maintaining balance within the natural rhythms of the body. Rasayana is one of the branches of Ayurveda frequently used as rejuvenant therapy to overcome many discomforts and prevent diseases. It has been reported that rasayanas have immunomodulatory, antioxidant and antitumor functions. However, the genotoxic potential of many rasayanas remains to be evaluated. The present study was undertaken to assess the role of Brahma rasayana(BR) on genotoxicity in vivo in a mouse test system. The older mice (9 months) were orally fed with rasayana for 8 weeks. The treated groups showed no signs of dose-dependent toxicity at the dosage levels tested. The body weight loss/gain and feed consumption were unaffected at tested doses. Furthermore, sperm abnormalities and chromosomal aberrations were insignificant in the treatment group when compared to controls. However, there was a marginal increase in sperm count in the BR treated animals. These findings clearly indicate that there are no observed adverse genotoxic effects elicited by BR in experimental animals such as mice.

  13. Analysis of Turner syndrome patients within the Jordanian population, with a focus on four patients with Y chromosome abnormalities.

    PubMed

    Daggag, H; Srour, W; El-Khateeb, M; Ajlouni, K

    2013-01-01

    This study presents findings in Turner syndrome (TS) patients from the Jordanian population, with focus on 4 patients with Y chromosomal abnormalities. From 1989 to 2011, 504 patients with TS stigmata were referred to our institute for karyotyping, resulting in 142 positive TS cases. Of these, 62 (43.7%) had the typical 45,X karyotype and the remaining individuals (56.3%) were found to be mosaics. Fifteen TS patients (10.5%) carried a structural abnormality of the Y chromosome and presented with the mosaic 45,X/46,XY karyotype. From these, 4 TS cases were investigated further. Karyotyping revealed that 1 patient carried a small supernumerary marker chromosome, whereas cytogenetic and molecular analyses showed that 3 patients carried 2 copies of the SRY gene. Further analysis by SRY sequencing revealed no mutations within the gene. The analyzed patients were found to be phenotypically either females or males, depending on the predominance of the cell line carrying the Y chromosome. This study demonstrates the importance of detailed cytogenetic analysis (such as FISH) in TS patients, and it also emphasizes the need for molecular analysis (such as PCR and sequencing) when fragments of the Y chromosome are present.

  14. Impact of sperm genome decay on Day-3 embryo chromosomal abnormalities from advanced-maternal-age patients.

    PubMed

    Kaarouch, Ismail; Bouamoud, Nouzha; Louanjli, Noureddine; Madkour, Aicha; Copin, Henri; Benkhalifa, Moncef; Sefrioui, Omar

    2015-10-01

    Infertile male patients often exhibit unconventional semen parameters, including DNA fragmentation, chromatin dispersion, and aneuploidy-collectively referred to as sperm genome decay (SGD). We investigated the correlation of SGD to embryo chromosomal abnormalities and its effect on clinical pregnancy rates in patients with advanced maternal age (AMA) (>40 years) who were undergoing intracytoplasmic sperm injection-preimplantation genetic screening (ICSI-PGS). Three groups were assessed: patients with AMA and male partners with normal sperm (AMA-N); AMA patients and male partners presenting with SGD (AMA-SGD); and young fertile female patients and male partners with SGD (Y-SGD). We found a significant increase in embryonic chromosomal abnormalities-polyploidy, nullisomy, mosaicism, and chaotic anomaly rates-when semen parameters are altered (76% vs. 67% and 66% in AMA-SGD vs. AMA-N and Y-SGD groups, respectively). Statistical analysis showed a correlation between SGD and aneuploidies of embryonic chromosomes 13, 16, 21, X, and Y, as well as negative clinical outcomes. Incorporation of molecular sperm analyses should therefore significantly minimize the risk of transmission of chromosomal anomalies from spermatozoa to embryos, and may provide better predictors of pregnancy than conventional sperm analyses. We also demonstrated that an ICSI-PGS program should be implemented for SGD patients in order to limit transmission of chromosomal paternal anomalies and to improve clinical outcome.

  15. Rare chromosome abnormalities, prevalence and prenatal diagnosis rates from population-based congenital anomaly registers in Europe.

    PubMed

    Wellesley, Diana; Dolk, Helen; Boyd, Patricia A; Greenlees, Ruth; Haeusler, Martin; Nelen, Vera; Garne, Ester; Khoshnood, Babak; Doray, Berenice; Rissmann, Anke; Mullaney, Carmel; Calzolari, Elisa; Bakker, Marian; Salvador, Joaquin; Addor, Marie-Claude; Draper, Elizabeth; Rankin, Judith; Tucker, David

    2012-05-01

    The aim of this study is to quantify the prevalence and types of rare chromosome abnormalities (RCAs) in Europe for 2000-2006 inclusive, and to describe prenatal diagnosis rates and pregnancy outcome. Data held by the European Surveillance of Congenital Anomalies database were analysed on all the cases from 16 population-based registries in 11 European countries diagnosed prenatally or before 1 year of age, and delivered between 2000 and 2006. Cases were all unbalanced chromosome abnormalities and included live births, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly. There were 10,323 cases with a chromosome abnormality, giving a total birth prevalence rate of 43.8/10,000 births. Of these, 7335 cases had trisomy 21,18 or 13, giving individual prevalence rates of 23.0, 5.9 and 2.3/10,000 births, respectively (53, 13 and 5% of all reported chromosome errors, respectively). In all, 473 cases (5%) had a sex chromosome trisomy, and 778 (8%) had 45,X, giving prevalence rates of 2.0 and 3.3/10,000 births, respectively. There were 1,737 RCA cases (17%), giving a prevalence of 7.4/10,000 births. These included triploidy, other trisomies, marker chromosomes, unbalanced translocations, deletions and duplications. There was a wide variation between the registers in both the overall prenatal diagnosis rate of RCA, an average of 65% (range 5-92%) and the prevalence of RCA (range 2.4-12.9/10,000 births). In all, 49% were liveborn. The data provide the prevalence of families currently requiring specialised genetic counselling services in the perinatal period for these conditions and, for some, long-term care.

  16. Mitotic Spindle Defects and Chromosome Mis-Segregation Induced by LDL/Cholesterol—Implications for Niemann-Pick C1, Alzheimer’s Disease, and Atherosclerosis

    PubMed Central

    Granic, Antoneta; Potter, Huntington

    2013-01-01

    Elevated low-density lipoprotein (LDL)-cholesterol is a risk factor for both Alzheimer’s disease (AD) and Atherosclerosis (CVD), suggesting a common lipid-sensitive step in their pathogenesis. Previous results show that AD and CVD also share a cell cycle defect: chromosome instability and up to 30% aneuploidy–in neurons and other cells in AD and in smooth muscle cells in atherosclerotic plaques in CVD. Indeed, specific degeneration of aneuploid neurons accounts for 90% of neuronal loss in AD brain, indicating that aneuploidy underlies AD neurodegeneration. Cell/mouse models of AD develop similar aneuploidy through amyloid-beta (Aß) inhibition of specific microtubule motors and consequent disruption of mitotic spindles. Here we tested the hypothesis that, like upregulated Aß, elevated LDL/cholesterol and altered intracellular cholesterol homeostasis also causes chromosomal instability. Specifically we found that: 1) high dietary cholesterol induces aneuploidy in mice, satisfying the hypothesis’ first prediction, 2) Niemann-Pick C1 patients accumulate aneuploid fibroblasts, neurons, and glia, demonstrating a similar aneugenic effect of intracellular cholesterol accumulation in humans 3) oxidized LDL, LDL, and cholesterol, but not high-density lipoprotein (HDL), induce chromosome mis-segregation and aneuploidy in cultured cells, including neuronal precursors, indicating that LDL/cholesterol directly affects the cell cycle, 4) LDL-induced aneuploidy requires the LDL receptor, but not Aß, showing that LDL works differently than Aß, with the same end result, 5) cholesterol treatment disrupts the structure of the mitotic spindle, providing a cell biological mechanism for its aneugenic activity, and 6) ethanol or calcium chelation attenuates lipoprotein-induced chromosome mis-segregation, providing molecular insights into cholesterol’s aneugenic mechanism, specifically through its rigidifying effect on the cell membrane, and potentially explaining why ethanol

  17. Moderate Ovarian Stimulation Does Not Increase the Incidence of Human Embryo Chromosomal Abnormalities in in Vitro Fertilization Cycles

    PubMed Central

    Bosch, Ernesto; Alamá, Pilar; Rubio, Carmen; Rodrigo, Lorena; Pellicer, Antonio

    2012-01-01

    Context: A high chromosomal abnormalities rate has been observed in human embryos derived from in vitro fertilization (IVF) treatments. The real incidence in natural cycles has been poorly studied, so whether this frequency may be induced by external factors, such as use of gonadotropins for ovarian stimulation, remains unknown. Design: We conducted a prospective cohort study in a University-affiliated private infertility clinic with a comparison between unstimulated and stimulated ovarian cycles in the same women. Preimplantation genetic screening by fluorescence in situ hybridization was performed in all viable d 3 embryos. Objective: The primary objective was to compare the incidence of embryo chromosomal abnormalities in an unstimulated cycle and in an ulterior moderate ovarian stimulated cycle. Secondary outcome measures were embryo quality, blastocyst rate of biopsied embryos, number of normal blastocysts per donor, type of chromosomal abnormalities, and clinical outcome. Results: One hundred eighty-five oocyte donors were initially recruited for the unstimulated cycle, and preimplantation genetic screening could be performed in 51 of them, showing 35.3% of embryo chromosomal abnormalities. Forty-six of them later completed a stimulated cycle. The sperm donor sample was the same for both cycles. The proportion of embryos displaying abnormalities in the unstimulated cycle was 34.8% (16 of 46), whereas it was 40.6% (123 of 303) in the stimulated cycle with risk difference = 5.8 [95% confidence interval (CI) = −20.6–9.0], and relative risk = 1.17 (95% CI = 0.77–1.77) (P = 0.45). When an intrasubject comparison was made, the abnormalities rate was 34.8% (95% CI = 20.5–49.1) in the unstimulated cycle and 38.2% (95% CI = 30.5–45.8) in the stimulated cycle [risk difference = 3.4 (95% CI = −17.9–11.2); P = 0.64]. No differences were observed for embryo quality and type of chromosomal abnormalities. Conclusions: Moderate ovarian stimulation in young

  18. Increased likelihood of post-polycythemia vera myelofibrosis in Ph-negative MPN patients with chromosome 12 abnormalities

    PubMed Central

    Benton, Christopher B; Tanaka, Maria; Wilson, Catherine; Pierce, Sherry; Zhou, Lingsha; Cortes, Jorge; Kantarjian, Hagop; Verstovsek, Srdan

    2016-01-01

    Chromosome 12 (Chr12) abnormalities have been described for individual patients with Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-neg MPN), however the frequency, characteristics, and outcomes of such patients as a whole have not been investigated. We reviewed a database of 1787 consecutive Ph-neg MPN patients seen at our institution and determined that 2% of Ph-neg MPN patients harbored an alteration involving Chr12 by cytogenetic evaluation. Retrospective chart review revealed that patients with Chr12 abnormalities had a higher likelihood of having myelofibrosis (MF) compared to patients without a Chr12 abnormality, and were more likely to have post-polycythemia vera MF. The most common alterations in Chr12 in MF patients involved 12q13, 12q15, 12q24, and trisomy 12, and >40% of Chr12 Ph-neg MPN patients had cytogenetic evolution. Chr12 abnormalities did not significantly correlate with JAK2 status, progression to acute myeloid leukemia, or survival, however patients with 12q24 abnormalities trended towards poorer outcomes. PMID:25687833

  19. Automated identification of abnormal metaphase chromosome cells for the detection of chronic myeloid leukemia using microscopic images

    NASA Astrophysics Data System (ADS)

    Wang, Xingwei; Zheng, Bin; Li, Shibo; Mulvihill, John J.; Chen, Xiaodong; Liu, Hong

    2010-07-01

    Karyotyping is an important process to classify chromosomes into standard classes and the results are routinely used by the clinicians to diagnose cancers and genetic diseases. However, visual karyotyping using microscopic images is time-consuming and tedious, which reduces the diagnostic efficiency and accuracy. Although many efforts have been made to develop computerized schemes for automated karyotyping, no schemes can get be performed without substantial human intervention. Instead of developing a method to classify all chromosome classes, we develop an automatic scheme to detect abnormal metaphase cells by identifying a specific class of chromosomes (class 22) and prescreen for suspicious chronic myeloid leukemia (CML). The scheme includes three steps: (1) iteratively segment randomly distributed individual chromosomes, (2) process segmented chromosomes and compute image features to identify the candidates, and (3) apply an adaptive matching template to identify chromosomes of class 22. An image data set of 451 metaphase cells extracted from bone marrow specimens of 30 positive and 30 negative cases for CML is selected to test the scheme's performance. The overall case-based classification accuracy is 93.3% (100% sensitivity and 86.7% specificity). The results demonstrate the feasibility of applying an automated scheme to detect or prescreen the suspicious cancer cases.

  20. Selective chromatid segregation mechanism proposed for the human split hand/foot malformation development by chromosome 2 translocations: A perspective.

    PubMed

    Klar, Amar J S

    2015-12-01

    Three unrelated chromosome 2q14.1-14.2 region translocations caused the split hand/foot limb malformation development in humans by an unknown mechanism. Their etiology was described by the autosomal dominant inheritance with incomplete penetrance genetic model although authors stated, "the understanding of the genotype-to-phenotype relationship has been most challenging". The conundrums are that no mutation was found in known genes located at or near the translocation breakpoints, some limbs were malformed while others were not in the same patient and surprisingly breakpoints lie at relatively large distance of more than 2.5 million bases to have caused disorder-causing gene mutations in a single gene. To help understand translocations etiology for limb development, we invoke the selective DNA strand/chromatid-specific epigenetic imprinting and segregation mechanism employed by the two highly diverged fission yeasts to produce daughter cells of different cell types by mitosis. By this mechanism, an anterior- and posterior-limb-tissues-generating pair of daughter cells is produced by a single deterministic cell dividing in the anlagen of the limb bud. Accordingly, malformation develops simply because translocations hinder the proper distribution of chromatid-specific epialleles of a limb developmental gene during the deterministic cell's mitosis. It is tempting to speculate that such a mechanism might involve the HOXD-cluster genes situated centromere-distal to the translocation breakpoints many million bases away at the 2q31.1 region. Further genetic tests of the hypothesis are proposed for the human and mouse limb development. In sum, genetic analysis of translocations suggests that the sequence asymmetry of strands in the double-helical DNA structure of a developmental gene forms the physical basis of daughter cells' developmental asymmetry, thus opposing the morphogen-gradient research paradigm of limb development.

  1. Are unpaired chromosomes spermicidal?: A maximum-likelihood analysis of segregation and meiotic drive in Drosophila melanogaster males deficient for the ribosomal-dna.

    PubMed Central

    Robbins, L G

    1999-01-01

    Meiosis in Drosophila melanogaster males is achiasmate and requires special systems to ensure normal segregation. Several situations that yield frequent nondisjunction also produce high levels of chromatin-dependent sperm lethality, suggesting the possibility of a simple and direct connection between defective disjunction and defective sperm development. One hypothesis that has been offered is that pairing not only ensures disjunction, but also changes the physical state of chromosomes so that they can be packaged in sperm. Here, I present an analysis of extensive data on disjunction and sperm survival in rDNA-deficient males collected by B. McKee and D. Lindsley. This analysis demonstrates that, although nondisjunction and sperm lethality are indeed correlated, the basis of this is not the presence of unpaired chromosomes in the sperm. Chromosomes that have failed to disjoin are not themselves spermicidal. PMID:9872964

  2. Are unpaired chromosomes spermicidal?: A maximum-likelihood analysis of segregation and meiotic drive in Drosophila melanogaster males deficient for the ribosomal-dna.

    PubMed

    Robbins, L G

    1999-01-01

    Meiosis in Drosophila melanogaster males is achiasmate and requires special systems to ensure normal segregation. Several situations that yield frequent nondisjunction also produce high levels of chromatin-dependent sperm lethality, suggesting the possibility of a simple and direct connection between defective disjunction and defective sperm development. One hypothesis that has been offered is that pairing not only ensures disjunction, but also changes the physical state of chromosomes so that they can be packaged in sperm. Here, I present an analysis of extensive data on disjunction and sperm survival in rDNA-deficient males collected by B. McKee and D. Lindsley. This analysis demonstrates that, although nondisjunction and sperm lethality are indeed correlated, the basis of this is not the presence of unpaired chromosomes in the sperm. Chromosomes that have failed to disjoin are not themselves spermicidal.

  3. Hyponatremia secondary to reset osmostat in a child with a central nervous system midline defect and a chromosomal abnormality.

    PubMed

    Gupta, P; Mick, G; Fong, C T; Jospe, N; McCormick, K

    2000-01-01

    A newborn with a CNS midline defect and persistent hyponatremia was diagnosed with a "reset" osmostat using a 3% hypertonic saline test. The diagnosis was established by measuring urinary arginine vasopressin (UAVP) and plasma osmolality (P(Osmoil)). In this infant a chromosome abnormality with the karyotype 46, X, -X, +der(X) t(X;13) (p22.1;q22) was associated with the midline defect and a reset osmostat.

  4. Congenital abnormality effect of methamphetamine on histological, cellular and chromosomal defects in fetal mice

    PubMed Central

    Mirjalili, Tahereh; Kalantar, Seyed Mehdi; Shams Lahijani, Maryam; Sheikhha, Mohamad Hasan; Talebi, Alireza

    2013-01-01

    Background: Methamphetamine (MA) is a potent psychomotor stimulant with high abuse and addictive potential. MA is a neurotoxic drug which is widely abused by females of childbearing age, raising serious public health concerns in terms of exposure of the fetus to the drug. Neurotoxic effects of MA on adult are well known, such as dopaminergic nerve terminal degeneration and cell death in regions of brain in some doses. Objective: In the present study, we examined effect of prenatal MA exposure on mouse fetuses. Materials and Methods: In this study, forty 8-12 week-old NMRI female mice were used which were mated with male mice in serial days. When sperm plug was observed it was designated as gestational day (GD) 0. Pregnant mice were individually housed in plastic cages. Pregnant mice were divided into four groups: in first group 10 mg/kg /day MA, in second group 5 mg/kg /day MA and in third group saline were injected subcutaneously from GD 6 to GD 14, corresponding to organogenesis period, while fourth or control group were without injection. On GD 14 fetuses were removed and accomplished chromosome preparation from fetal liver. Then fetal were fixed in formalin for brain hematoxilin and eosine staining and TUNEL assay. Results: We observed morphological abnormality including exencephal fetus in 5mg/kg MA group and premature fetuses in 10 mg/kg MA group. Also brain histological study showed subarachnoid hemorrhage in fetal brain in both experimental groups. Fetal liver karyotyping analysis was normal in fetuses of all groups and TUNEL assay in fetal striatum did not show significant difference in number of apoptotic cells between groups. Conclusion: From our results, it could be concluded that chronic abuse of MA by pregnant females during organogenesis period can cause teratogenic effect and brain hemorrage in fetus. PMID:24639691

  5. Detection of numerical chromosomal abnormalities (chr. 1 and 18) before and after photodynamic therapy of human bladder carcinoma cells in vitro

    NASA Astrophysics Data System (ADS)

    Bachor, Ruediger; Reich, Ella D.; Kleinschmidt, Klaus; Hautmann, Richard E.

    1997-12-01

    The application of nonradioactive in situ hybridization with chromosome-specific probes for cytogenetic analysis has increased significantly in recent years. In the field of photodynamic therapy (PDT) the hypothesis is that after PDT the remaining viable malignant cells are potentially metastatic cells. Therefore, we performed in vitro experiments on human bladder carcinoma cells to evaluate numerical chromosomal abnormalities before and after PDT. The possible genotoxic effect of PDT with porphycene (AamTPPn) appears to be small based on criteria such as numerical chromosomal abnormalities for chromosome 1 and 18.

  6. Delineation of candidate genes responsible for structural brain abnormalities in patients with terminal deletions of chromosome 6q27

    PubMed Central

    Peddibhotla, Sirisha; Nagamani, Sandesh CS; Erez, Ayelet; Hunter, Jill V; Holder Jr, J Lloyd; Carlin, Mary E; Bader, Patricia I; Perras, Helene MF; Allanson, Judith E; Newman, Leslie; Simpson, Gayle; Immken, LaDonna; Powell, Erin; Mohanty, Aaron; Kang, Sung-Hae L; Stankiewicz, Pawel; Bacino, Carlos A; Bi, Weimin; Patel, Ankita; Cheung, Sau W

    2015-01-01

    Patients with terminal deletions of chromosome 6q present with structural brain abnormalities including agenesis of corpus callosum, hydrocephalus, periventricular nodular heterotopia, and cerebellar malformations. The 6q27 region harbors genes that are important for the normal development of brain and delineation of a critical deletion region for structural brain abnormalities may lead to a better genotype–phenotype correlation. We conducted a detailed clinical and molecular characterization of seven unrelated patients with deletions involving chromosome 6q27. All patients had structural brain abnormalities. Using array comparative genomic hybridization, we mapped the size, extent, and genomic content of these deletions. The smallest region of overlap spans 1.7 Mb and contains DLL1, THBS2, PHF10, and C6orf70 (ERMARD) that are plausible candidates for the causation of structural brain abnormalities. Our study reiterates the importance of 6q27 region in normal development of brain and helps identify putative genes in causation of structural brain anomalies. PMID:24736736

  7. Sexual maldevelopment and sex reversal, chromosomal causes.

    PubMed

    Magenis, R Ellen

    2006-01-01

    The SRY gene on the Y chromosome is the testis determining factor (TDF). It is therefore the initial male determining factor. However, phenotypic sex determination includes a cascade of genes located on autosomes as well as sex chromosomes. Aberrations of these genes may cause sexual maldevelopment or sex reversal. Abnormalities may include single gene mutations and gene loss or gain-changes may involve only sex organs or may be part of syndromes. These changes may also arise as chromosome abnormalities involving contiguous genes. Eight cases with chromosomal abnormalities involving different causative mechanisms are described herein. The most common cause is nondisjunction, including loss or gain of sex chromosomes. Less common causes are mispairing and crossing over in meiosis, chromosome breaks with repair, nonhomologous pairing due to low copy repeats and crossing over, and translocation (familial or de novo) with segregation. Cases include: [see: text].

  8. Analysis of the evolution of chromosome abnormalities in human embryos from Day 3 to 5 using CGH and FISH.

    PubMed

    Daphnis, D D; Fragouli, E; Economou, K; Jerkovic, S; Craft, I L; Delhanty, J D A; Harper, J C

    2008-02-01

    The use of interphase fluorescent in situ hybridization (FISH) has shown that a large number of human embryos exhibit chromosomal abnormalities in vitro. The most common abnormality is mosaicism which is seen in up to 50% of preimplantation embryos at all stages of development. In this study, comparative genomic hybridization (CGH) was used to analyse 1-2 cells biopsied on Day 3 of development while the rest of the embryo was cultured until Day 5. Embryos were spread on Day 5 and analysed by FISH using probe combinations that varied depending on the CGH result, to investigate the progress of any abnormalities detected on Day 3. A total of 37 frozen-thawed embryos were analysed in this study. One gave no CGH or FISH results and was excluded from analysis. Six embryos failed to give any FISH result as they were degenerating on Day 5. Thirty embryos provided results from both techniques. According to the CGH results, the embryos were divided into two groups; Group 1 had a normal CGH result (13 embryos) and Group 2 an abnormal CGH result (17 embryos). For Group 1, three embryos showed normal CGH and FISH results, while 10 embryos were mosaic after FISH analysis, with various levels of abnormalities. For Group 2, FISH showed that all embryos were mosaic or completely chaotic. The combination of CGH and FISH enabled the thorough investigation of the evolution of mosaicism and of the mechanisms by which it is generated. The main two mechanisms identified were whole or partial chromosome loss and gain. These were observed in embryos examined on both Day 3 and 5.

  9. Identification of FISH biomarkers to detect chromosome abnormalities associated with prostate adenocarcinoma in tumour and field effect environment

    PubMed Central

    2014-01-01

    Background To reduce sampling error associated with cancer detection in prostate needle biopsies, we explored the possibility of using fluorescence in situ hybridisation (FISH) to detect chromosomal abnormalities in the histologically benign prostate tissue from patients with adenocarcinoma of prostate. Methods Tumour specimens from 33 radical prostatectomy (RP) cases, histologically benign tissue from 17 of the 33 RP cases, and 26 benign prostatic hyperplasia (BPH) control cases were evaluated with Locus Specific Identifier (LSI) probes MYC (8q24), LPL (8p21.22), and PTEN (10q23), as well as with centromere enumerator probes CEP8, CEP10, and CEP7. A distribution of FISH signals in the tumour and histologically benign adjacent tissue was compared to that in BPH specimens using receiver operating characteristic curve analysis. Results The combination of MYC gain, CEP8 Abnormal, PTEN loss or chromosome 7 aneusomy was positive in the tumour area of all of the 33 specimens from patients with adenocarcinomas, and in 88% of adjacent histologically benign regions (15 out of 17) but in only 15% (4 out of 26) of the benign prostatic hyperplasia control specimens. Conclusions A panel of FISH markers may allow detection of genomic abnormalities that associate with adenocarcinoma in the field adjacent to and surrounding the tumour, and thus could potentially indicate the presence of cancer in the specimen even if the cancer focus itself was missed by biopsy and histology review. PMID:24568597

  10. Abnormal pairing of X and Y sex chromosomes during meiosis I in interspecific hybrids of Phodopus campbelli and P. sungorus

    PubMed Central

    Ishishita, Satoshi; Tsuboi, Kazuma; Ohishi, Namiko; Tsuchiya, Kimiyuki; Matsuda, Yoichi

    2015-01-01

    Hybrid sterility plays an important role in the maintenance of species identity and promotion of speciation. Male interspecific hybrids from crosses between Campbell's dwarf hamster (Phodopus campbelli) and the Djungarian hamster (P. sungorus) exhibit sterility with abnormal spermatogenesis. However, the meiotic phenotype of these hybrids has not been well described. In the present work, we observed the accumulation of spermatocytes and apoptosis of spermatocyte-like cells in the testes of hybrids between P. campbelli females and P. sungorus males. In hybrid spermatocytes, a high frequency of asynapsis of X and Y chromosomes during the pachytene-like stage and dissociation of these chromosomes during metaphase I (MI) was observed. No autosomal univalency was observed during pachytene-like and MI stages in the hybrids; however, a low frequency of synapsis between autosomes and X or Y chromosomes, interlocking and partial synapsis between autosomal pairs, and γ-H2AFX staining in autosomal chromatin was observed during the pachytene-like stage. Degenerated MI-like nuclei were frequently observed in the hybrids. Most of the spermatozoa in hybrid epididymides exhibited head malformation. These results indicate that the pairing of X and Y chromosomes is more adversely affected than that of autosomes in Phodopus hybrids. PMID:25801302

  11. Abnormal meiotic recombination with complex chromosomal rearrangement in an azoospermic man.

    PubMed

    Wang, Liu; Iqbal, Furhan; Li, Guangyuan; Jiang, Xiaohua; Bukhari, Ihtisham; Jiang, Hanwei; Yang, Qingling; Zhong, Liangwen; Zhang, Yuanwei; Hua, Juan; Cooke, Howard J; Shi, Qinghua

    2015-06-01

    Spermatocyte spreading and immunostaining were applied to detect meiotic prophase I progression, homologous chromosome pairing, synapsis and recombination in an azoospermic reciprocal translocation 46, XY, t(5;7;9;13)(5q11;7p11;7p15;9q12;13p12) carrier. Histological examination of the haematoxylin and eosin stained testicular sections revealed reduced germ cells with no spermatids or sperm in the patient. TdT (terminal deoxynucleotidyl transferase)-mediated dUDP nick-end labelling assay showed apoptotic cells in testicular sections of translocation carrier. Immnunofluorescence analysis indicated the presence of an octavalent in all the pachytene spermatocytes analysed in the patient. Meiotic progression was disturbed, as an increase in zygotene (P < 0.001) and decrease in the pachytene spermatocytes (P < 0.001) were observed in the t(5;7;9;13) carrier compared with controls. It was further observed that 93% of octavalents were found partially asynapsed between homologous chromosomes. A significant decrease in the recombination frequency was observed on 5p, 5q, 7q, 9p and 13q in the translocation carrier compared with the reported controls. A significant reduction in XY recombination frequency was also found in the participants. Our results indicated that complex chromosomal rearrangements can impair synaptic integrity of translocated chromosomes, which may reduce chromosomal recombination on translocated as well as non-translocated chromosomes, a phenomenon commonly known as interchromosomal effect.

  12. Parental decisions following prenatal diagnosis of chromosomal abnormalities: implications for genetic counseling practice in Japan.

    PubMed

    Suzumori, Nobuhiro; Kumagai, Kyoko; Goto, Shinobu; Nakamura, Akira; Sugiura-Ogasawara, Mayumi

    2015-02-01

    Parental decision-making to terminate or continue a pregnancy was studied after prenatal diagnosis of a chromosome aneuploidy among a sample of patients around the city of Nagoya, Japan. A total of 1,051 amniocentesis cases at 15-18 weeks of gestation were analyzed. Of these, 60 cases of chromosomal anomalies with aneuploidies were diagnosed by conventional cytogenetic analysis. Of the 45 diagnoses of autosomal chromosome aneuploidies, pregnancy was terminated in 93.3 % of the cases. Of the 15 cases diagnosed with sex chromosome aneuploidy, pregnancy was terminated in 46.7 %. Differences in parental decisions with respect to maternal age, gestational week at diagnosis, number of pregnancies per individual and existing number of children were not significant in patients diagnosed either with autosomal or sex chromosome aneuploidy. The findings indicate that when diagnosed with a chromosome aneuploidy in which a severe prognosis was expected, most couples decided to terminate the pregnancy in Japan. Implications of these findings for expanding the profession of genetic counseling are discussed and research recommendations are provided.

  13. The maize (Zea mays) desynaptic (dy) mutation defines a pathway for meiotic chromosome segregation, linking nuclear morphology, telomere distribution and synapsis.

    PubMed

    Murphy, Shaun P; Bass, Hank W

    2012-08-01

    Meiosis involves a dramatic reorganization of the genetic material, along with changes in the architecture of the nucleoplasm and cytoplasm. In the opisthokonts, nuclear envelope and meiotic chromosome behavior are coordinated by forces generated in the cytoplasm and transferred to the nucleus by the nuclear-envelope protein linkers SUN and KASH. During meiotic prophase I, the telomere bouquet arrangement has roles in interhomolog recognition, pairing, synapsis, interlock resolution and homologous chromosome recombination. The maize desynaptic (dy) mutant is defective in homologous chromosome synapsis, recombination, telomere-nuclear envelope interactions and chromosome segregation. A detailed three-dimensional cytological analysis of dy revealed telomere misplacement during the bouquet stage, synaptic irregularities, nuclear envelope distortion and chromosome bridges at anaphase I. Using linkage and B-A translocation mapping, we placed dy on the long arm of chromosome 3, genetic bin 3.06. SSR marker analysis narrowed the mapping interval to 9 cM. Candidate genes in this region include a PM3-type SUN domain protein, ZmSUN3. No obvious genetic lesions were found in the ZmSUN3 allele of dy, but a conspicuous splice variant, ZmSUN3-sv1, was observed in mRNA from dy. The variant message is predicted to result in the synthesis of a truncated ZmSUN3 protein lacking two C-terminal transmembrane domains. Other potential candidate genes relevant to the documented phenotypes were also considered. In summary, this study reveals that dy causes disruption of a central meiotic pathway connecting nuclear envelope integrity to telomere localization and synapsis during meiotic prophase.

  14. Analysis of chromosomal abnormalities by CGH-array in patients with dysmorphic and intellectual disability with normal karyotype

    PubMed Central

    Pratte-Santos, Rodrigo; Ribeiro, Katyanne Heringer; Santos, Thainá Altoe; Cintra, Terezinha Sarquis

    2016-01-01

    ABSTRACT Objective To investigate chromosomal abnormalities by CGH-array in patients with dysmorphic features and intellectual disability with normal conventional karyotype. Methods Retrospective study, carried out from January 2012 to February 2014, analyzing the CGH-array results of 39 patients. Results Twenty-six (66.7%) patients had normal results and 13 (33.3%) showed abnormal results - in that, 6 (15.4%) had pathogenic variants, 6 (15.4%) variants designated as uncertain and 1 (2.5%) non-pathogenic variants. Conclusion The characterization of the genetic profile by CGH-array in patients with intellectual disability and dysmorphic features enabled making etiologic diagnosis, followed by genetic counseling for families and specific treatment. PMID:27074231

  15. Nonstructural NSs protein of rift valley fever virus interacts with pericentromeric DNA sequences of the host cell, inducing chromosome cohesion and segregation defects.

    PubMed

    Mansuroglu, Z; Josse, T; Gilleron, J; Billecocq, A; Leger, P; Bouloy, M; Bonnefoy, E

    2010-01-01

    Rift Valley fever virus (RVFV) is an emerging, highly pathogenic virus; RVFV infection can lead to encephalitis, retinitis, or fatal hepatitis associated with hemorrhagic fever in humans, as well as death, abortions, and fetal deformities in animals. RVFV nonstructural NSs protein, a major factor of the virulence, forms filamentous structures in the nuclei of infected cells. In order to further understand RVFV pathology, we investigated, by chromatin immunoprecipitation, immunofluorescence, fluorescence in situ hybridization, and confocal microscopy, the capacity of NSs to interact with the host genome. Our results demonstrate that even though cellular DNA is predominantly excluded from NSs filaments, NSs interacts with some specific DNA regions of the host genome such as clusters of pericentromeric gamma-satellite sequence. Targeting of these sequences by NSs was correlated with the induction of chromosome cohesion and segregation defects in RVFV-infected murine, as well as sheep cells. Using recombinant nonpathogenic virus rZHDeltaNSs210-230, expressing a NSs protein deleted of its region of interaction with cellular factor SAP30, we showed that the NSs-SAP30 interaction was essential for NSs to target pericentromeric sequences, as well as for induction of chromosome segregation defects. The effect of RVFV upon the inheritance of genetic information is discussed with respect to the pathology associated with fetal deformities and abortions, highlighting the main role played by cellular cofactor SAP30 on the establishment of NSs interactions with host DNA sequences and RVFV pathogenesis.

  16. Chromosome

    MedlinePlus

    Chromosomes are structures found in the center (nucleus) of cells that carry long pieces of DNA. DNA ... is the building block of the human body. Chromosomes also contain proteins that help DNA exist in ...

  17. Sexual and individual foraging segregation in Gentoo penguins Pygoscelis papua from the Southern Ocean during an abnormal winter.

    PubMed

    Xavier, José C; Trathan, Philip N; Ceia, Filipe R; Tarling, Geraint A; Adlard, Stacey; Fox, Derren; Edwards, Ewan W J; Vieira, Rui P; Medeiros, Renata; De Broyer, Claude; Cherel, Yves

    2017-01-01

    Knowledge about sexual segregation and gender-specific, or indeed individual specialization, in marine organisms has improved considerably in the past decade. In this context, we tested the "Intersexual Competition Hypothesis" for penguins by investigating the feeding ecology of Gentoo penguins during their austral winter non-breeding season. We considered this during unusual environmental conditions (i.e. the year 2009 had observations of high sea surface and air temperatures) in comparison with the long term average at Bird Island, South Georgia. Through conventional (i.e. stomach contents) and stable isotopic values from red blood cells, plasma and feathers of both male and female Gentoo penguins, we showed that there were significant differences between sexes, with males feeding mainly on fish (54% by mass) followed by crustaceans (38%) whereas females fed mainly on crustaceans (89% by mass) followed by fish (4%). Themisto gaudichaudii was the most important crustacean prey for males (64% by mass; 82% by number; 53% by frequency of occurrence) and females (63% by mass; 77% by number; 89% by frequency of occurrence), contrasting with all previous studies that found Antarctic krill Euphausia superba were generally the main prey. Stable isotopic data showed that, in terms of habitat use (based on δ 13C), there were significant differences in short-term carbon signatures between males and females (based on plasma and red blood cells), suggesting that both sexes explored different habitats, with females exploring more offshore pelagic waters and males feeding more in coastal benthic waters. Based on δ 15N, males fed on significantly higher trophic level than females (based on plasma and red blood cells), in agreement with our diet results., Thus, Gentoo penguins behave in a similar manner to other non-breeding penguins species (e.g. king, macaroni and rockhopper penguins), albeit at a smaller spatial scale (as they do not disperse as these other penguins do), in

  18. Sexual and individual foraging segregation in Gentoo penguins Pygoscelis papua from the Southern Ocean during an abnormal winter

    PubMed Central

    Trathan, Philip N.; Ceia, Filipe R.; Tarling, Geraint A.; Adlard, Stacey; Fox, Derren; Edwards, Ewan W. J.; Vieira, Rui P.; Medeiros, Renata; De Broyer, Claude; Cherel, Yves

    2017-01-01

    Knowledge about sexual segregation and gender-specific, or indeed individual specialization, in marine organisms has improved considerably in the past decade. In this context, we tested the “Intersexual Competition Hypothesis” for penguins by investigating the feeding ecology of Gentoo penguins during their austral winter non-breeding season. We considered this during unusual environmental conditions (i.e. the year 2009 had observations of high sea surface and air temperatures) in comparison with the long term average at Bird Island, South Georgia. Through conventional (i.e. stomach contents) and stable isotopic values from red blood cells, plasma and feathers of both male and female Gentoo penguins, we showed that there were significant differences between sexes, with males feeding mainly on fish (54% by mass) followed by crustaceans (38%) whereas females fed mainly on crustaceans (89% by mass) followed by fish (4%). Themisto gaudichaudii was the most important crustacean prey for males (64% by mass; 82% by number; 53% by frequency of occurrence) and females (63% by mass; 77% by number; 89% by frequency of occurrence), contrasting with all previous studies that found Antarctic krill Euphausia superba were generally the main prey. Stable isotopic data showed that, in terms of habitat use (based on δ 13C), there were significant differences in short-term carbon signatures between males and females (based on plasma and red blood cells), suggesting that both sexes explored different habitats, with females exploring more offshore pelagic waters and males feeding more in coastal benthic waters. Based on δ 15N, males fed on significantly higher trophic level than females (based on plasma and red blood cells), in agreement with our diet results., Thus, Gentoo penguins behave in a similar manner to other non-breeding penguins species (e.g. king, macaroni and rockhopper penguins), albeit at a smaller spatial scale (as they do not disperse as these other penguins do

  19. Characterization of the temporal persistence of chromosomal abnormalities in the semen of Hodkin`s disease patients after treatment with NOVP chemotherapy using multi-chromosome fluorescence in situ hybridization

    SciTech Connect

    Cassel, M.J.; Robbins, W.A.; Wyrobek, A.J.; Meistrich, M.L.

    1994-12-31

    Three-chromosome fluorescence in situ hybridization (FISH) was applied to sperm of men with Hodgkin`s disease to measure the persistence of chromosomally abnormal sperm within the time interval of 3 to 33 months after the end of treatment. NOVP chemotherapy includes the agents novantrone, oncovin, vinblastine, and prednisone, two of which are spindle poisons expected to induce aneuploidy. Semen samples were evaluated for the frequencies of fluorescence phenotypes representing hyperhaploidy, hypohaploidy, and genomic duplications using DNA probes specific for repetitive sequences on chromosomes X,Y, and 8. Using this procedure, NOVP was previously shown to induce chromosomally abnormal sperm in treated patients. In a longitudinal assessment of 11 semen samples from 2 men, frequencies of abnormal sperm appeared to return to pre-treatment levels at {approximately}6 months after the end of treatment and remained at these levels up to 33 months after the end of treatment. However, pre-treatment frequencies of chromosomally abnormal cells in Hodgkin`s patients were elevated above those found in normal healthy men. Additional patients are being evaluated to determine how long after therapy Hodgkin`s disease patients remain at increased risk for producing chromosomally abnormal sperm.

  20. Chromosome rearrangements, recombination suppression, and limited segregation distortion in hybrids between Yellowstone cutthroat trout (Oncorhynchus clarkii bouvieri) and rainbow trout (O. mykiss)

    PubMed Central

    2013-01-01

    Background Introgressive hybridization is an important evolutionary process that can lead to the creation of novel genome structures and thus potentially new genetic variation for selection to act upon. On the other hand, hybridization with introduced species can threaten native species, such as cutthroat trout (Oncorhynchus clarkii) following the introduction of rainbow trout (O. mykiss). Neither the evolutionary consequences nor conservation implications of rainbow trout introgression in cutthroat trout is well understood. Therefore, we generated a genetic linkage map for rainbow-Yellowstone cutthroat trout (O. clarkii bouvieri) hybrids to evaluate genome processes that may help explain how introgression affects hybrid genome evolution. Results The hybrid map closely aligned with the rainbow trout map (a cutthroat trout map does not exist), sharing all but one linkage group. This linkage group (RYHyb20) represented a fusion between an acrocentric (Omy28) and a metacentric chromosome (Omy20) in rainbow trout. Additional mapping in Yellowstone cutthroat trout indicated the two rainbow trout homologues were fused in the Yellowstone genome. Variation in the number of hybrid linkage groups (28 or 29) likely depended on a Robertsonian rearrangement polymorphism within the rainbow trout stock. Comparison between the female-merged F1 map and a female consensus rainbow trout map revealed that introgression suppressed recombination across large genomic regions in 5 hybrid linkage groups. Two of these linkage groups (RYHyb20 and RYHyb25_29) contained confirmed chromosome rearrangements between rainbow and Yellowstone cutthroat trout indicating that rearrangements may suppress recombination. The frequency of allelic and genotypic segregation distortion varied among parents and families, suggesting few incompatibilities exist between rainbow and Yellowstone cutthroat trout genomes. Conclusions Chromosome rearrangements suppressed recombination in the hybrids. This result

  1. Specific gene expression profiles and chromosomal abnormalities are associated with infant disseminated neuroblastoma

    PubMed Central

    2009-01-01

    Background Neuroblastoma (NB) tumours have the highest incidence of spontaneous remission, especially among the stage 4s NB subgroup affecting infants. Clinical distinction of stage 4s from lethal stage 4 can be difficult, but critical for therapeutic decisions. The aim of this study was to investigate chromosomal alterations and differential gene expression amongst infant disseminated NB subgroups. Methods Thirty-five NB tumours from patients diagnosed at < 18 months (25 stage 4 and 10 stage 4s), were evaluated by allelic and gene expression analyses. Results All stage 4s patients underwent spontaneous remission, only 48% stage 4 patients survived despite combined modality therapy. Stage 4 tumours were 90% near-diploid/tetraploid, 44% MYCN amplified, 77% had 1p LOH (50% 1p36), 23% 11q and/or 14q LOH (27%) and 47% had 17q gain. Stage 4s were 90% near-triploid, none MYCN amplified and LOH was restricted to 11q. Initial comparison analyses between stage 4s and 4 < 12 months tumours revealed distinct gene expression profiles. A significant portion of genes mapped to chromosome 1 (P < 0.0001), 90% with higher expression in stage 4s, and chromosome 11 (P = 0.0054), 91% with higher expression in stage 4. Less definite expression profiles were observed between stage 4s and 4 < 18m, yet, association with chromosomes 1 (P < 0.0001) and 11 (P = 0.005) was maintained. Distinct gene expression profiles but no significant association with specific chromosomal region localization was observed between stage 4s and stage 4 < 18 months without MYCN amplification. Conclusion Specific chromosomal aberrations are associated with distinct gene expression profiles which characterize spontaneously regressing or aggressive infant NB, providing the biological basis for the distinct clinical behaviour. PMID:19192278

  2. Diversity of sex chromosome abnormalities in a cohort of 95 Indonesian patients with monosomy X

    PubMed Central

    2011-01-01

    Background Monosomy × or 45,X is a cytogenetic characteristic for Turner syndrome. This chromosome anomaly is encountered in around 50% of cases, but wide variations of other anomalies have been found. This report is to describe the cytogenetic characteristics of 45,X individuals. To the best of our knowledge, there were no large series of 45,X cases has been reported from Indonesia. Results Ninety five cases with 45,X cell line found, of which 60 were detected by karyotyping, 4 by FISH for sex chromosomes, and 31 by both karyotyping and FISH. Using karyotyping 37 out of 91 cases(40.6%) were identified as 45,X individuals, while cases who underwent FISH only 4 out of 35 cases (11.4%) showed 45,X result, resulting in total of 39 45,X cases (41.1%), and the rest 56 (58.9%) cases are mosaic. Among these cases, 21 out of 95 (22.1%) have Y or part of Y as the second or third sex chromosome in their additional cell lines. Result discrepancies revealed in 22 out of 31 cases who underwent both FISH and karyotyping, of which 7 showed normal 46,XX or 46,XY karyotypes, but by FISH, additional monosomy × cell line was found. Most of the cases were referred at the age of puberty (8-13 years old) or after that (14-18 years old), 31 and 21 cases respectively, and there were 14 cases were sent in adulthood. Conclusion Wide variations of sex chromosome aberrations have been detected using the combination of conventional cytogenetic and FISH, including detection of low level of mosaicism and Y-chromosome fragments. Result discrepancies using both techniques were found in 22/31 cases, and in order to obtain a more details of sex chromosome constitution of individuals with 45,X cell line both FISH and karyotyping should be carried out simultaneously. PMID:21992692

  3. Chromosome fragility and the abnormal replication of the FMR1 locus in fragile X syndrome.

    PubMed

    Yudkin, Dmitry; Hayward, Bruce E; Aladjem, Mirit I; Kumari, Daman; Usdin, Karen

    2014-06-01

    Fragile X Syndrome (FXS) is a learning disability seen in individuals who have >200 CGG•CCG repeats in the 5' untranslated region of the X-linked FMR1 gene. Such alleles are associated with a fragile site, FRAXA, a gap or constriction in the chromosome that is coincident with the repeat and is induced by folate stress or thymidylate synthase inhibitors like fluorodeoxyuridine (FdU). The molecular basis of the chromosome fragility is unknown. Previous work has suggested that the stable intrastrand structures formed by the repeat may be responsible, perhaps via their ability to block DNA synthesis. We have examined the replication dynamics of normal and FXS cells with and without FdU. We show here that an intrinsic problem with DNA replication exists in the FMR1 gene of individuals with FXS even in the absence of FdU. Our data suggest a model for chromosome fragility in FXS in which the repeat impairs replication from an origin of replication (ORI) immediately adjacent to the repeat. The fact that the replication problem occurs even in the absence of FdU suggests that this phenomenon may have in vivo consequences, including perhaps accounting for the loss of the X chromosome containing the fragile site that causes Turner syndrome (45, X0) in female carriers of such alleles. Our data on FRAXA may also be germane for the other FdU-inducible fragile sites in humans, that we show here share many common features with FRAXA.

  4. Effects of age on segregation of the X and Y chromosomes in cultured lymphocytes from Chinese men.

    PubMed

    Song, Yaxian; Chen, Qian; Zhang, Zhen; Hou, Heli; Zhang, Ding; Shi, Qinghua

    2009-08-01

    Chromosome malsegregation in binucleated lymphocytes is a useful endpoint to evaluate age effect on genetic stability. However, the investigations on chromosome malsegregation in binucleated lymphocytes from Chinese are scarce. In this study, peripheral blood lymphocytes were collected from 14 old (60-70 years) and 10 young (22-26 years) healthy Chinese men. To detect malsegregation of the sex chromosomes, multi-color fluorescence in situ hybridization (FISH) was performed on binucleated lymphocytes, cytokinesis-blocked by cytochalasin B at the first mitosis after phytohaemagglutinin stimulation. Compared with that in young men, a significant increase in frequencies of loss of chromosome X (9.2 +/- 3.2 per thousand vs. 1.1 +/- 0.9 per thousand, P < 0.001) and Y (2.5 +/- 1.9 per thousand vs. 0.2 +/- 0.3 per thousand, P < 0.001) was found in old men. Similarly, nondisjunction of chromosome X (16.5 +/- 3.4 per thousand vs. 3.5 +/- 1.1 per thousand, P < 0.001) and Y (7.2 +/- 2.6 per thousand vs. 2.4 +/- 1.3 per thousand, P < 0.001) occurred more frequently in old men than in young men. Regardless of donor's age, nondisjunction is more prevalent than loss for both chromosome X and Y. The frequencies of observed simultaneous malsegregation were relatively higher than the expected, suggesting an association between malsegregation. These results indicated that in Chinese men, malsegregation of the sex chromosomes increases with age in an associated fashion, and nondisjunction accounts for the majority of spontaneous chromosome malsegregation.

  5. HPV-16 E2 gene disruption and sequence variation in CIN 3 lesions and invasive squamous cell carcinomas of the cervix: relation to numerical chromosome abnormalities

    PubMed Central

    Graham, D A; Herrington, C S

    2000-01-01

    Aim—To test the hypothesis that, because the human papillomavirus (HPV) E2 protein represses viral early gene transcription, E2 gene sequence variation or disruption could play a part in the induction of the numerical chromosome abnormalities that have been described in squamous cervical lesions. Methods—The integrity and sequence of the E2 gene from 11 cervical intraepithelial neoplasia (CIN) grade 3 lesions and 14 invasive squamous cell carcinomas, all of which contained HPV-16, were analysed by the polymerase chain reaction (PCR). The E2 gene was amplified in three overlapping fragments and PCR products sequenced directly. Chromosome abnormalities were identified by interphase cytogenetics using chromosome specific probes for chromosomes 1, 3, 11, 17, 18, and X. Results—E2 gene disruption was present in significantly more invasive carcinomas (eight of 14) than CIN 3 lesions (one of 11) (p = 0.03). No association was found between E2 disruption and the presence of a numerical chromosome abnormality. The E2 gene from the non-disrupted isolates was sequenced and wild-type (n = 5) and variant (n = 11) sequences identified. Variant sequences belonged to European and African classes and contained from one to 15 amino acid substitutions. Although numerical chromosome abnormalities were significantly more frequent in invasive squamous cell carcinoma than CIN 3 (p = 0.04), there was no significant relation between the presence of sequence variation and either histological diagnosis or chromosome abnormality. Conclusions—These data do not support the hypothesis that E2 gene disruption or variation is important in the induction of chromosome imbalance in these lesions. However, there is a relation between E2 gene disruption and the presence of invasive disease. PMID:11040943

  6. Structural and functional conservation of the human homolog of the Schizosaccharomyces pombe rad2 gene, which is required for chromosome segregation and recovery from DNA damage.

    PubMed Central

    Murray, J M; Tavassoli, M; al-Harithy, R; Sheldrick, K S; Lehmann, A R; Carr, A M; Watts, F Z

    1994-01-01

    The rad2 mutant of Schizosaccharomyces pombe is sensitive to UV irradiation and deficient in the repair of UV damage. In addition, it has a very high degree of chromosome loss and/or nondisjunction. We have cloned the rad2 gene and have shown it to be a member of the Saccharomyces cerevisiae RAD2/S. pombe rad13/human XPG family. Using degenerate PCR, we have cloned the human homolog of the rad2 gene. Human cDNA has 55% amino acid sequence identity to the rad2 gene and is able to complement the UV sensitivity of the rad2 null mutant. We have thus isolated a novel human gene which is likely to be involved both in controlling the fidelity of chromosome segregation and in the repair of UV-induced DNA damage. Its involvement in two fundamental processes for maintaining chromosomal integrity suggests that it is likely to be an important component of cancer avoidance mechanisms. Images PMID:8007985

  7. Eosinophilic fasciitis associated with hypereosinophilia, abnormal bone-marrow karyotype and inversion of chromosome 5.

    PubMed

    Ferguson, J S; Bosworth, J; Min, T; Mercieca, J; Holden, C A

    2014-03-01

    We report the case of a male patient presenting with eosinophilia, pulmonary oedema and eosinophilic fasciitis (EF). He had the classic clinical appearance and magnetic resonance imaging of EF. Cytogenetic analysis of the bone marrow revealed a previously undescribed pericentric inversion of chromosome 5. Overall, the presentation was consistent with a diagnosis of chronic eosinophilic leukaemia, not otherwise specified (CEL-NOS). Dermatologists should consult a haematologist in cases of EF, in order to rule out possible haematological malignancies.

  8. The Dicentric Chromosome dic(20;22) Is a Recurrent Abnormality in Myelodysplastic Syndromes and Is a Product of Telomere Fusion.

    PubMed

    MacKinnon, Ruth N; Duivenvoorden, Hendrika M; Campbell, Lynda J; Wall, Meaghan

    2017-03-04

    We describe a recurrent dicentric chromosome formed by telomere fusion between chromosome 20 and chromosome 22 in 4 cases of myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML). In particular, the presence of residual telomere sequences at the site of translocation in 3 of the 4 cases makes a compelling case for telomere fusion. This is the first description of a recurrent telomere fusion event in any malignant condition. The 20q subtelomeric region was retained in all 4 examples despite deletion of the 20q12 region closer to the centromere. The original dicentric chromosome in all 4 cases contained nucleolus organiser region material from the short arm of chromosome 22 and had also undergone secondary rearrangements that produced amplification of the common gained region on 20q. We propose that the sequence of events producing this chromosome abnormality is: degradation of the telomeres, formation of an unstable dicentric chromosome by 20q and 22p telomere fusion, breakage-fusion-bridge cycles causing copy number aberration between the centromeres, selection of cells with 20q12 deletion, and further selection of cells with 20q11.2 gain. The last 2 steps are driver events responsible for the abnormal chromosomes found in the malignant cells. Finding recurrent patterns in the complex genome reorganisation events that characterise poor-prognosis, complex-karyotype AML and MDS will help us understand the mechanisms and oncogenic driver mutations in these poorly understood malignancies.

  9. Meiotic abnormalities

    SciTech Connect

    1993-12-31

    Chapter 19, describes meiotic abnormalities. These include nondisjunction of autosomes and sex chromosomes, genetic and environmental causes of nondisjunction, misdivision of the centromere, chromosomally abnormal human sperm, male infertility, parental age, and origin of diploid gametes. 57 refs., 2 figs., 1 tab.

  10. Marker chromosomes.

    PubMed

    Rao, Kiran Prabhaker; Belogolovkin, Victoria

    2013-04-01

    Marker chromosomes are a morphologically heterogeneous group of structurally abnormal chromosomes that pose a significant challenge in prenatal diagnosis. Phenotypes associated with marker chromosomes are highly variable and range from normal to severely abnormal. Clinical outcomes are very difficult to predict when marker chromosomes are detected prenatally. In this review, we outline the classification, etiology, cytogenetic characterization, and clinical consequences of marker chromosomes, as well as practical approaches to prenatal diagnosis and genetic counseling.

  11. Effects of oocyte quality, incubation time and maturation environment on the number of chromosomal abnormalities in IVF-derived early bovine embryos.

    PubMed

    Demyda-Peyrás, Sebastian; Dorado, Jesus; Hidalgo, Manuel; Anter, Jaouad; De Luca, Leonardo; Genero, Enrique; Moreno-Millán, Miguel

    2013-01-01

    Chromosomal aberrations are one of the major causes of embryo developmental failures in mammals. The occurrence of these types of abnormalities is higher in in vitro-produced (IVP) embryos. The aim of the present study was to investigate the effect of oocyte morphology and maturation conditions on the rate of chromosomal abnormalities in bovine preimplantational embryos. To this end, 790 early cattle embryos derived from oocytes with different morphologies and matured under different conditions, including maturation period (24 v. 36h) and maturation media (five different serum supplements in TCM-199), were evaluated cytogenetically in three sequential experiments. The rates of normal diploidy and abnormal haploidy, polyploidy and aneuploidy were determined in each embryo. Throughout all the experiments, the rate of chromosomal abnormalities was significantly (P<0.05) affected by oocyte morphology and maturation conditions (maturation time and culture medium). Lower morphological quality was associated with a high rate of chromosome abnormalities (P<0.05). Moreover, polyploidy was associated with increased maturation time (P<0.01), whereas the maturation medium significantly (P<0.05) affected the rates of haploidy and polyploidy. In general, supplementing the maturation medium with oestrous cow serum or fetal calf serum resulted in higher rates of chromosomal aberrations (P<0.05) compared with the other serum supplements tested (bovine steer serum, anoestroues cow serum, bovine amniotic fluid and bovine serum albumin). On the basis of the results of the present study, we conclude that the morphological quality of oocytes and the maturation conditions affect the rate of chromosomal abnormalities in IVP bovine embryos.

  12. Delineation of a deletion region critical for corpus callosal abnormalities in chromosome 1q43-q44.

    PubMed

    Nagamani, Sandesh C Sreenath; Erez, Ayelet; Bay, Carolyn; Pettigrew, Anjana; Lalani, Seema R; Herman, Kristin; Graham, Brett H; Nowaczyk, Malgorzata Jm; Proud, Monica; Craigen, William J; Hopkins, Bobbi; Kozel, Beth; Plunkett, Katie; Hixson, Patricia; Stankiewicz, Pawel; Patel, Ankita; Cheung, Sau Wai

    2012-02-01

    Submicroscopic deletions involving chromosome 1q43-q44 result in cognitive impairment, microcephaly, growth restriction, dysmorphic features, and variable involvement of other organ systems. A consistently observed feature in patients with this deletion are the corpus callosal abnormalities (CCAs), ranging from thinning and hypoplasia to complete agenesis. Previous studies attempting to delineate the critical region for CCAs have yielded inconsistent results. We conducted a detailed clinical and molecular characterization of seven patients with deletions of chromosome 1q43-q44. Using array comparative genomic hybridization, we mapped the size, extent, and genomic content of these deletions. Four patients had CCAs, and shared the smallest region of overlap that contains only three protein coding genes, CEP170, SDCCAG8, and ZNF238. One patient with a small deletion involving SDCCAG8 and AKT3, and another patient with an intragenic deletion of AKT3 did not have any CCA, implying that the loss of these two genes is unlikely to be the cause of CCA. CEP170 is expressed extensively in the brain, and encodes for a protein that is a component of the centrosomal complex. ZNF238 is involved in control of neuronal progenitor cells and survival of cortical neurons. Our results rule out the involvement of AKT3, and implicate CEP170 and/or ZNF238 as novel genes causative for CCA in patients with a terminal 1q deletion.

  13. American College of Medical Genetics and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in neoplastic disorders.

    PubMed

    Cooley, Linda D; Lebo, Matthew; Li, Marilyn M; Slovak, Marilyn L; Wolff, Daynna J

    2013-06-01

    Microarray methodologies, to include array comparative genomic hybridization and single-nucleotide polymorphism-based arrays, are innovative methods that provide genomic data. These data should be correlated with the results from the standard methods, chromosome and/or fluorescence in situ hybridization, to ascertain and characterize the genomic aberrations of neoplastic disorders, both liquid and solid tumors. Over the past several decades, standard methods have led to an accumulation of genetic information specific to many neoplasms. This specificity is now used for the diagnosis and classification of neoplasms. Cooperative studies have revealed numerous correlations between particular genetic aberrations and therapeutic outcomes. Molecular investigation of chromosomal abnormalities identified by standard methods has led to discovery of genes, and gene function and dysfunction. This knowledge has led to improved therapeutics and, in some disorders, targeted therapies. Data gained from the higher-resolution microarray methodologies will enhance our knowledge of the genomics of specific disorders, leading to more effective therapeutic strategies. To assist clinical laboratories in validation of the methods, their consistent use, and interpretation and reporting of results from these microarray methodologies, the American College of Medical Genetics and Genomics has developed the following professional standard and guidelines.

  14. Prenatal diagnosis of a small supernumerary, XIST-negative, mosaic ring X chromosome identified by fluorescence in situ hybridization in an abnormal male fetus.

    PubMed

    Le Caignec, C; Boceno, M; Joubert, M; Winer, N; Aubron, F; Fallet-Bianco, C; Rival, J M

    2003-02-01

    Marker or ring X [r(X)] chromosomes of varying size are often found in patients with Turner syndrome. Patients with very small r(X) chromosomes that did not include the X-inactivation locus (XIST) have been described with a more severe phenotype. Small r(X) chromosomes are rare in males and there are only five previous reports of such cases. We report the identification of a small supernumerary X chromosome in an abnormal male fetus. Cytogenetic analysis from chorionic villus sampling was performed because of fetal nuchal translucency thickness and it showed mosaicism 46,XY/47,XY,+r(X)/48,XY,+r(X),+r(X). Fluorescence in situ hybridizations (FISH) showed the marker to be of X-chromosome origin and not to contain the XIST locus. Additional specific probes showed that the r(X) included a euchromatic region in proximal Xq. At 20 weeks gestation, a second ultrasound examination revealed cerebral abnormalities. After genetic counselling, the pregnancy was terminated. The fetus we describe is the first male with a mosaic XIST-negative r(X) chromosome identified at prenatal diagnosis. The phenotype we observed was probably the result of functional disomy of the genes in the r(X) chromosome, secondary to loss of the XIST locus.

  15. Mapping the Flavor Contributing Traits on "Fengwei Melon" (Cucumis melo L.) Chromosomes Using Parent Resequencing and Super Bulked-Segregant Analysis.

    PubMed

    Zhang, Hong; Yi, Hongping; Wu, Mingzhu; Zhang, Yongbin; Zhang, Xuejin; Li, Meihua; Wang, Guangzhi

    2016-01-01

    We used a next-generation high-throughput sequencing platform to resequence the Xinguowei and Shouxing melon cultivars, the parents of Fengwei melon. We found 84% of the reads (under a coverage rate of "13×") placed on the reference genome DHL92. There were 2,550,000 single-nucleotide polymorphisms and 140,000 structural variations in the two genomes. We also identified 1,290 polymorphic genes between Xinguowei and Shouxing. We combined specific length amplified fragment sequencing (SLAF-seq) and bulked-segregant analysis (super-BSA) to analyze the two parents and the F2 extreme phenotypes. This combined method yielded 12,438,270 reads, 46,087 SLAF tags, and 4,480 polymorphic markers (average depth of 161.81×). There were six sweet trait-related regions containing 13 differential SLAF markers, and 23 sour trait-related regions containing 48 differential SLAF markers. We further fine-mapped the sweet trait to the genomic regions on chromosomes 6, 10, 11, and 12. Correspondingly, we mapped the sour trait-related genomic regions to chromosomes 2, 3, 4, 5, 9, and 12. Finally, we positioned nine of the 61 differential markers in the sweet and sour trait candidate regions on the parental genome. These markers corresponded to one sweet and eight sour trait-related genes. Our study provides a basis for marker-assisted breeding of desirable sweet and sour traits in Fengwei melons.

  16. Mapping the Flavor Contributing Traits on "Fengwei Melon" (Cucumis melo L.) Chromosomes Using Parent Resequencing and Super Bulked-Segregant Analysis

    PubMed Central

    Zhang, Hong; Yi, Hongping; Wu, Mingzhu; Zhang, Yongbin; Zhang, Xuejin; Li, Meihua; Wang, Guangzhi

    2016-01-01

    We used a next-generation high-throughput sequencing platform to resequence the Xinguowei and Shouxing melon cultivars, the parents of Fengwei melon. We found 84% of the reads (under a coverage rate of “13×”) placed on the reference genome DHL92. There were 2,550,000 single-nucleotide polymorphisms and 140,000 structural variations in the two genomes. We also identified 1,290 polymorphic genes between Xinguowei and Shouxing. We combined specific length amplified fragment sequencing (SLAF-seq) and bulked-segregant analysis (super-BSA) to analyze the two parents and the F2 extreme phenotypes. This combined method yielded 12,438,270 reads, 46,087 SLAF tags, and 4,480 polymorphic markers (average depth of 161.81×). There were six sweet trait-related regions containing 13 differential SLAF markers, and 23 sour trait-related regions containing 48 differential SLAF markers. We further fine-mapped the sweet trait to the genomic regions on chromosomes 6, 10, 11, and 12. Correspondingly, we mapped the sour trait-related genomic regions to chromosomes 2, 3, 4, 5, 9, and 12. Finally, we positioned nine of the 61 differential markers in the sweet and sour trait candidate regions on the parental genome. These markers corresponded to one sweet and eight sour trait-related genes. Our study provides a basis for marker-assisted breeding of desirable sweet and sour traits in Fengwei melons. PMID:26840947

  17. Structure–function relationships of two paralogous single-stranded DNA-binding proteins from Streptomyces coelicolor: implication of SsbB in chromosome segregation during sporulation

    PubMed Central

    Paradzik, Tina; Ivic, Nives; Filic, Zelimira; Manjasetty, Babu A.; Herron, Paul; Luic, Marija; Vujaklija, Dusica

    2013-01-01

    The linear chromosome of Streptomyces coelicolor contains two paralogous ssb genes, ssbA and ssbB. Following mutational analysis, we concluded that ssbA is essential, whereas ssbB plays a key role in chromosome segregation during sporulation. In the ssbB mutant, ∼30% of spores lacked DNA. The two ssb genes were expressed differently; in minimal medium, gene expression was prolonged for both genes and significantly upregulated for ssbB. The ssbA gene is transcribed as part of a polycistronic mRNA from two initiation sites, 163 bp and 75 bp upstream of the rpsF translational start codon. The ssbB gene is transcribed as a monocistronic mRNA, from an unusual promoter region, 73 bp upstream of the AUG codon. Distinctive DNA-binding affinities of single-stranded DNA-binding proteins monitored by tryptophan fluorescent quenching and electrophoretic mobility shift were observed. The crystal structure of SsbB at 1.7 Å resolution revealed a common OB-fold, lack of the clamp-like structure conserved in SsbA and previously unpublished S-S bridges between the A/B and C/D subunits. This is the first report of the determination of paralogous single-stranded DNA-binding protein structures from the same organism. Phylogenetic analysis revealed frequent duplication of ssb genes in Actinobacteria, whereas their strong retention suggests that they are involved in important cellular functions. PMID:23393191

  18. Lack of the H-NS Protein Results in Extended and Aberrantly Positioned DNA during Chromosome Replication and Segregation in Escherichia coli

    PubMed Central

    Helgesen, Emily; Fossum-Raunehaug, Solveig

    2016-01-01

    ABSTRACT The architectural protein H-NS binds nonspecifically to hundreds of sites throughout the chromosome and can multimerize to stiffen segments of DNA as well as to form DNA-protein-DNA bridges. H-NS has been suggested to contribute to the orderly folding of the Escherichia coli chromosome in the highly compacted nucleoid. In this study, we investigated the positioning and dynamics of the origins, the replisomes, and the SeqA structures trailing the replication forks in cells lacking the H-NS protein. In H-NS mutant cells, foci of SeqA, replisomes, and origins were irregularly positioned in the cell. Further analysis showed that the average distance between the SeqA structures and the replisome was increased by ∼100 nm compared to that in wild-type cells, whereas the colocalization of SeqA-bound sister DNA behind replication forks was not affected. This result may suggest that H-NS contributes to the folding of DNA along adjacent segments. H-NS mutant cells were found to be incapable of adopting the distinct and condensed nucleoid structures characteristic of E. coli cells growing rapidly in rich medium. It appears as if H-NS mutant cells adopt a “slow-growth” type of chromosome organization under nutrient-rich conditions, which leads to a decreased cellular DNA content. IMPORTANCE It is not fully understood how and to what extent nucleoid-associated proteins contribute to chromosome folding and organization during replication and segregation in Escherichia coli. In this work, we find in vivo indications that cells lacking the nucleoid-associated protein H-NS have a lower degree of DNA condensation than wild-type cells. Our work suggests that H-NS is involved in condensing the DNA along adjacent segments on the chromosome and is not likely to tether newly replicated strands of sister DNA. We also find indications that H-NS is required for rapid growth with high DNA content and for the formation of a highly condensed nucleoid structure under such

  19. Distal Deletion of Chromosome 11q Encompassing Jacobsen Syndrome without Platelet Abnormality.

    PubMed

    Sheth, Frenny J; Datar, Chaitanya; Andrieux, Joris; Pandit, Anand; Nayak, Darshana; Rahman, Mizanur; Sheth, Jayesh J

    2014-01-01

    Terminal 11q deletion, known as Jacobsen syndrome (JBS), is a rare genetic disorder associated with numerous dysmorphic features. We studied two cases with multiple congenital anomalies that were cytogenetically detected with deletions on 11q encompassing JBS region: 46,XX,der(11) del(11)(q24). Array comparative genomic hybridization (aCGH) analysis confirmed partial deletion of 11.8-11.9 Mb at 11q24.1q25 (case 1) and 13.9-14 Mb deletion at 11q23.3q25 together with 7.3-7.6 Mb duplication at 12q24.32q24.33 (case 2). Dysmorphism because of the partial duplication of 12q was not overtly decipherable over the Jacobsen phenotype except for a triangular facial profile. Aberrant chromosome 11 was inherited from phenotypically normal father, carrier of balanced translocation 46,XY,t(11;12)(q23.3; q24.32). In the present study, both cases had phenotypes that were milder than the ones described in literature despite having large deletion size. Most prominent features in classical JBS is thrombocytopenia, which was absent in both these cases. Therefore, detailed functional analysis of terminal 11q region is warranted to elucidate etiology of JBS and their clinical presentation.

  20. Monosomal karyotype predicts poor survival after allogeneic stem cell transplantation in chromosome 7 abnormal myelodysplastic syndrome and secondary acute myeloid leukemia.

    PubMed

    van Gelder, M; de Wreede, L C; Schetelig, J; van Biezen, A; Volin, L; Maertens, J; Robin, M; Petersen, E; de Witte, T; Kröger, N

    2013-04-01

    Treatment algorithms for poor cytogenetic-risk myelodysplastic syndrome (MDS), defined by chromosome 7 abnormalities or complex karyotype (CK), include allogeneic stem cell transplantation (alloSCT). We studied outcome of alloSCT in chromosome 7 abnormal MDS patients as this data are scarce in literature. We specifically focused on the impact of the extra presence of CK and monosomal karyotype (MK). The European Group for Blood and Marrow Transplantation database contained data on 277 adult MDS patients with a chromosome 7 abnormality treated with alloSCT. Median age at alloSCT was 45 years. Median follow-up of patients alive was 5 years. Five-year progression-free survival (PFS) and overall survival (OS) were 22% and 28%, respectively. In multivariate analysis, statistically significant predictors for worse PFS were higher MDS stages treated, but not in complete remission (CR) (hazards ratio (HR) 1.7), and the presence of CK (HR 1.5) or MK (HR 1.8). Negative predictive factors for OS were higher MDS stages treated, but not in CR (HR 1.8), and the presence of CK (HR 1.6) or MK (HR 1.7). By means of the cross-validated log partial likelihood, MK showed to have a better predictive value than CK. The results are relevant when considering alloSCT for higher-stage MDS patients having MK including a chromosome 7 abnormality.

  1. Simultaneous formation of inv dup(15) and dup(15q) in a girl with developmental delay: origin of the abnormal chromosomes.

    PubMed

    Abeliovich, D; Dagan, J; Werner, M; Lerer, I; Shapira, Y; Meiner, V

    1995-01-01

    Two de novo abnormal derivatives of chromosome 15, inv dup(15) and dup(15q) were found in a girl with developmental delay and mild dysmorphological signs. Fluorescence in situ hybridization, using DNA probes of the Prader-Willi/Angelman syndromes (PWS/AS) critical region and chromosome-15-specific alpha-satellite, combined with molecular analysis using dinucleotide repeat polymorphisms within the PWS/AS region and the parent-of-origin specific methylation sites at the locus D15S63, shed light on how the abnormal karyotype was formed. We suggest that a translocation between the two homologues of maternal chromosomes 15 resulted in the formation of dup(15q) and two reciprocal products: an acentric fragment of 15q that was lost and a centric fragment that underwent U-type reunion to form inv dup(15).

  2. Live births after simultaneous avoidance of monogenic diseases and chromosome abnormality by next-generation sequencing with linkage analyses.

    PubMed

    Yan, Liying; Huang, Lei; Xu, Liya; Huang, Jin; Ma, Fei; Zhu, Xiaohui; Tang, Yaqiong; Liu, Mingshan; Lian, Ying; Liu, Ping; Li, Rong; Lu, Sijia; Tang, Fuchou; Qiao, Jie; Xie, X Sunney

    2015-12-29

    In vitro fertilization (IVF), preimplantation genetic diagnosis (PGD), and preimplantation genetic screening (PGS) help patients to select embryos free of monogenic diseases and aneuploidy (chromosome abnormality). Next-generation sequencing (NGS) methods, while experiencing a rapid cost reduction, have improved the precision of PGD/PGS. However, the precision of PGD has been limited by the false-positive and false-negative single-nucleotide variations (SNVs), which are not acceptable in IVF and can be circumvented by linkage analyses, such as short tandem repeats or karyomapping. It is noteworthy that existing methods of detecting SNV/copy number variation (CNV) and linkage analysis often require separate procedures for the same embryo. Here we report an NGS-based PGD/PGS procedure that can simultaneously detect a single-gene disorder and aneuploidy and is capable of linkage analysis in a cost-effective way. This method, called "mutated allele revealed by sequencing with aneuploidy and linkage analyses" (MARSALA), involves multiple annealing and looping-based amplification cycles (MALBAC) for single-cell whole-genome amplification. Aneuploidy is determined by CNVs, whereas SNVs associated with the monogenic diseases are detected by PCR amplification of the MALBAC product. The false-positive and -negative SNVs are avoided by an NGS-based linkage analysis. Two healthy babies, free of the monogenic diseases of their parents, were born after such embryo selection. The monogenic diseases originated from a single base mutation on the autosome and the X-chromosome of the disease-carrying father and mother, respectively.

  3. Multicolor fluorescence in situ hybridization analysis of meiotic chromosome segregation in a 47,XYY male and a review of the literature.

    PubMed

    Shi, Q; Martin, R H

    2000-07-03

    The frequencies of aneuploid and diploid sperm were determined in a 47,XYY male using multi-color fluorescence in situ hybridization (FISH) analysis, and compared with those from 10 control donors. A total of 30,078 sperm from the patient was scored, 15,044 by two-color FISH for chromosomes 13 and 21, and 15,034 by three-color FISH for the sex chromosomes using chromosome 1 as an internal autosomal control for diploidy and lack of hybridization. The frequencies of X-bearing (49.73%) and Y-bearing sperm (49.46%) in control males were not significantly different from the expected 50% (chi(2)-test for goodness of fit). The ratio of 24,X (50.60%) to 24, Y sperm (48.35%) in the patient, however, was significantly different from the controls (P = 0.0144, chi(2)-test for independence) and from the expected 1:1 ratio (P = 0.0055, chi(2)-test for goodness of fit). There was no significant increase in the frequency of diploid sperm when compared with the controls (chi(2)-test for independence). Significantly increased frequencies were found for 24,YY (0.07% vs. 0.02%, P = 0.0009) and 24,XY (0.44% vs. 0.29%, P = 0.0025), but not for 24,XX (0.05% vs. 0.05%, P > 0. 05), 24,+13 (0.07% vs. 0.07%, P > 0.05) or 24,+21 sperm (0.21% vs. 0. 18%, P > 0.05) in the 47,XYY male when compared with control donors (chi(2)-test for independence). Our results support the theory that loss of the extra Y chromosome occurs during spermatogenesis in most cells. In this XYY patient there was a significant increase in the frequency of sperm with sex chromosomal abnormalities but no suggestion of an inter-chromosomal effect on autosomes. All 3-color FISH studies in the literature demonstrate a significantly increased risk of gonosomal aneuploidy in XYY males, with the risk being on the order of 1%.

  4. Karyotypes, B-chromosomes and meiotic abnormalities in 13 populations of Alebra albostriella and A. wahlbergi (Hemiptera, Auchenorrhyncha, Cicadellidae) from Greece.

    PubMed

    Kuznetsova, Valentina G; Golub, Natalia V; Aguin-Pombo, Dora

    2013-11-26

    In this work 13 populations of the leafhopper species Alebra albostriella (Fallén, 1826) (6 populations) and A. wahlbergi (Boheman, 1845) (7 populations) (Cicadellidae: Typhlocybinae) from Greece were studied cytogenetically. We examined chromosomal complements and meiosis in 41 males of A. albostriella sampled from Castanea sativa, Fagus sylvatica and Quercus cerris and in 21 males of A. wahlbergi sampled from C. sativa, Acer opalus and Ulmus sp. The species were shown to share 2n = 22 + X(0) and male meiosis of the chiasmate preductional type typical for Auchenorrhyncha. In all populations of A. albostriella and in all but two populations of A. wahlbergi B chromosomes and/or different meiotic abnormalities including the end-to-end non-homologous chromosomal associations, translocation chains, univalents, anaphasic laggards besides aberrant sperms were encountered. This study represents the first chromosomal record for the genus Alebra and one of the few population-cytogenetic studies in the Auchenorrhyncha.

  5. An improved, non-isotopic method of screening cells from patients with abnormalities of sexual differentiation for Y chromosomal DNA content.

    PubMed Central

    Witt, M; Michalczak, K; Latos-Bielenska, A; Jaruzelska, J; Kuczora, I; Lopez, M

    1993-01-01

    The detection of 45,X/46,XY mosaicism in patients with abnormalities of sexual differentiation is of crucial diagnostic importance. Here we present application of a PCR based method of detection of alphoid repeats of Y chromosomal origin. The method detects 0.01% of male DNA on a female DNA background. Out of 28 patients studied, in all cases where the Y chromosome or a part of it containing centromeric sequences was present, a positive amplification signal of Y chromosomal alphoid repeats was detected. In five cases the Y origin of marker chromosomes was diagnosed. The pattern of amplification signal distribution of the SRY gene was identical to that of Y specific alphoid primers, which confirms applicability of this method in the molecular diagnostic laboratory. The other diagnostic advantage is the ability to use dried blood specimens as an easy to handle and efficient source of DNA. Images PMID:8487276

  6. An improved, non-isotopic method of screening cells from patients with abnormalities of sexual differentiation for Y chromosomal DNA content.

    PubMed

    Witt, M; Michalczak, K; Latos-Bielenska, A; Jaruzelska, J; Kuczora, I; Lopez, M

    1993-04-01

    The detection of 45,X/46,XY mosaicism in patients with abnormalities of sexual differentiation is of crucial diagnostic importance. Here we present application of a PCR based method of detection of alphoid repeats of Y chromosomal origin. The method detects 0.01% of male DNA on a female DNA background. Out of 28 patients studied, in all cases where the Y chromosome or a part of it containing centromeric sequences was present, a positive amplification signal of Y chromosomal alphoid repeats was detected. In five cases the Y origin of marker chromosomes was diagnosed. The pattern of amplification signal distribution of the SRY gene was identical to that of Y specific alphoid primers, which confirms applicability of this method in the molecular diagnostic laboratory. The other diagnostic advantage is the ability to use dried blood specimens as an easy to handle and efficient source of DNA.

  7. Chromosome numbers and meiotic analysis in the pre-breeding of Brachiaria decumbens (Poaceae).

    PubMed

    Ricci, Gléia Cristina Laverde; De Souza-Kaneshima, Alice Maria; Felismino, Mariana Ferrari; Mendes-Bonato, Andrea Beatriz; Pagliarini, Maria Suely; Do Valle, Cacilda Borges

    2011-08-01

    A total of 44 accessions of Brachiaria decumbens were analysed for chromosome count and meiotic behaviour in order to identify potential progenitors for crosses. Among them, 15 accessions presented 2n = 18; 27 accessions, 2n = 36; and 2 accessions, 2n = 45 chromosomes. Among the diploid accessions, the rate of meiotic abnormalities was low, ranging from 0.82% to 7.93%. In the 27 tetraploid accessions, the rate of meiotic abnormalities ranged from 18.41% to 65.83%. The most common meiotic abnormalities were related to irregular chromosome segregation, but chromosome stickiness and abnormal cytokinesis were observed in low frequency. All abnormalities can compromise pollen viability by generating unbalanced gametes. Based on the chromosome number and meiotic stability, the present study indicates the apomictic tetraploid accessions that can act as male genitor to produce interspecific hybrids with B. ruziziensis or intraspecific hybrids with recently artificially tetraploidized accessions.

  8. Alteration/Deficiency in Activation 3 (ADA3) Protein, a Cell Cycle Regulator, Associates with the Centromere through CENP-B and Regulates Chromosome Segregation.

    PubMed

    Mohibi, Shakur; Srivastava, Shashank; Wang-France, Jun; Mirza, Sameer; Zhao, Xiangshan; Band, Hamid; Band, Vimla

    2015-11-20

    ADA3 (alteration/deficiency in activation 3) is a conserved component of several transcriptional co-activator and histone acetyltransferase (HAT) complexes. Recently, we generated Ada3 knock-out mice and demonstrated that deletion of Ada3 leads to early embryonic lethality. The use of Ada3(FL/FL) mouse embryonic fibroblasts with deletion of Ada3 using adenovirus Cre showed a critical role of ADA3 in cell cycle progression through mitosis. Here, we demonstrate an association of ADA3 with the higher order repeat region of the α-satellite region on human X chromosome centromeres that is consistent with its role in mitosis. Given the role of centromere proteins (CENPs) in mitosis, we next analyzed whether ADA3 associates with the centromere through CENPs. Both an in vivo proximity ligation assay and immunofluorescence studies confirmed the association of ADA3 with CENP-B protein, a highly conserved centromeric protein that binds to the 17-bp DNA sequences on α-satellite DNA. Deletional analysis showed that ADA3 directly associates with CENP-B through its N terminus, and a CENP-B binding-deficient mutant of ADA3 was incompetent in cell proliferation rescue. Notably, knockdown of ADA3 decreased binding of CENP-B onto the centromeres, suggesting that ADA3 is required for the loading of CENP-B onto the centromeres. Finally, we show that deletion of Ada3 from Ada3(FL/FL) mouse embryonic fibroblasts exhibited various chromosome segregation defects. Taken together, we demonstrate a novel ADA3 interaction with CENP-B-centromere that may account for its previously known function in mitosis. This study, together with its known function in maintaining genomic stability and its mislocalization in cancers, suggests an important role of ADA3 in mitosis.

  9. Alteration/Deficiency in Activation 3 (ADA3) Protein, a Cell Cycle Regulator, Associates with the Centromere through CENP-B and Regulates Chromosome Segregation*

    PubMed Central

    Mohibi, Shakur; Srivastava, Shashank; Wang-France, Jun; Mirza, Sameer; Zhao, Xiangshan; Band, Hamid; Band, Vimla

    2015-01-01

    ADA3 (alteration/deficiency in activation 3) is a conserved component of several transcriptional co-activator and histone acetyltransferase (HAT) complexes. Recently, we generated Ada3 knock-out mice and demonstrated that deletion of Ada3 leads to early embryonic lethality. The use of Ada3FL/FL mouse embryonic fibroblasts with deletion of Ada3 using adenovirus Cre showed a critical role of ADA3 in cell cycle progression through mitosis. Here, we demonstrate an association of ADA3 with the higher order repeat region of the α-satellite region on human X chromosome centromeres that is consistent with its role in mitosis. Given the role of centromere proteins (CENPs) in mitosis, we next analyzed whether ADA3 associates with the centromere through CENPs. Both an in vivo proximity ligation assay and immunofluorescence studies confirmed the association of ADA3 with CENP-B protein, a highly conserved centromeric protein that binds to the 17-bp DNA sequences on α-satellite DNA. Deletional analysis showed that ADA3 directly associates with CENP-B through its N terminus, and a CENP-B binding-deficient mutant of ADA3 was incompetent in cell proliferation rescue. Notably, knockdown of ADA3 decreased binding of CENP-B onto the centromeres, suggesting that ADA3 is required for the loading of CENP-B onto the centromeres. Finally, we show that deletion of Ada3 from Ada3FL/FL mouse embryonic fibroblasts exhibited various chromosome segregation defects. Taken together, we demonstrate a novel ADA3 interaction with CENP-B-centromere that may account for its previously known function in mitosis. This study, together with its known function in maintaining genomic stability and its mislocalization in cancers, suggests an important role of ADA3 in mitosis. PMID:26429915

  10. Safety evaluation of a triazine compound nitromezuril by assessing bacterial reverse mutation, sperm abnormalities, micronucleus and chromosomal aberration.

    PubMed

    Fei, Chenzhong; Zhang, Jie; Lin, Yang; Wang, Xiaoyang; Zhang, Keyu; Zhang, Lifang; Zheng, Wenli; Wang, Mi; Li, Tao; Xiao, Sui; Xue, Feiqun; Wang, Chunmei

    2015-04-01

    Nitromezuril (NZL) is a novel triazine compound that exhibits remarkable anticoccidial activity. However, mutagenicity and genotoxicity of NZL have not been evaluated to date. This study evaluated the potential risks of NZL by testing for bacterial reverse mutation (Ames), mouse sperm abnormality (SA), bone marrow micronucleus (MN) and chromosomal aberration (CA). Mice were orally administered with NZL at 385, 192 and 96 mg/kg, corresponding to 0.5 ×, 0.25 × and 0.125 × the LD50 of NZL, respectively. No significant increases in SA and CA were found in mice treated with NZL for 5d and 3d, respectively (P>0.05). NZL at 96-385 mg/kg did not have significant influence on micronucleated polychromatic erythrocyte counts (P>0.05). These results suggest that NZL is not genotoxic. However, Ames test results were positive both with and without the S9 system for Salmonella typhimurium TA98 and TA100, suggesting that NZL may be mutagenic. The mutagenic effects of NZL were different in in vitro and in vivo assays. Further studies should be conducted to confirm the safety of using and developing NZL as a novel anticoccidial drug.

  11. Widespread chromosomal abnormalities in high-grade ductal carcinoma in situ of the breast. Comparative genomic hybridization study of pure high-grade DCIS.

    PubMed

    Moore, E; Magee, H; Coyne, J; Gorey, T; Dervan, P A

    1999-03-01

    For a variety of technical reasons it is rarely possible to study cytogenetic abnormalities in ductal carcinoma in situ (DCIS) using traditional techniques. However, by combining molecular biology and computerized image analysis it is possible to carry out cytogenetic analyses on formalin-fixed, paraffin-embedded tissue, using comparative genomic hybridization (CGH). The purpose of this study was to identify the prevalence of chromosomal amplifications and deletions in high-grade DCIS and to look specifically for unique or consistent abnormalities in this pre-invasive cancer. Twenty-three cases of asymptomatic, non-palpable, screen-detected, high-grade DCIS were examined using CGH on tumour cells obtained from histology slides. All cases showed chromosomal abnormalities. A wide variety of amplifications and deletions were spread across the genome. The most frequent changes were gains of chromosomes 17 (13 of 23), 16p (13 of 23), and 20q (9 of 23) and amplifications of 11q13 (22 of 23), 12q 24.1-24.2 (12 of 23), 6p21.3 (11 of 23), and 1q31-qter (6 of 23). The most frequent deletions were on 13q 21.3-q33 (7 of 23), 9p21 (4 of 23), and 6q16.1 (4 of 23). These findings indicate that high-grade DCIS is, from a cytogenetic viewpoint, an advanced lesion. There was no absolutely consistent finding in every case, but amplification of 11q13 was found in 22 of the 23 cases. The precise significance of this is unknown at present. This region of chromosome 11q harbours a number of known oncogenes, including cyclin D1 andINT2. It is likely that many of these findings are the result of accumulated chromosomal abnormalities, reflecting an unstable genome in established malignancy.

  12. Influence of sperm fertilising concentration, sperm selection method and sperm capacitation procedure on the incidence of numerical chromosomal abnormalities in IVF early bovine embryos.

    PubMed

    Demyda-Peyrás, Sebastián; Dorado, Jesús; Hidalgo, Manuel; Moreno-Millán, Miguel

    2015-01-01

    The occurrence of numerical chromosomal aberrations, widely described as a major cause of mortality in in vitro-produced (IVP) embryos, has been linked to several factors. In the present study we investigated the effect of sperm fertilising concentration and semen handling (sperm selection and capacitation) before IVF on the rate of numerical chromosomal abnormalities in bovine embryos. In all, 466 IVP cattle embryos were karyotyped throughout three sequential experiments, analysing the effects of sperm fertilising concentration (0.1, 1.0 or 10×10(6) spermatozoa mL(-1)), selection method (unselected or Percoll-selected spermatozoa) and capacitation medium (bovine serum albumin (BSA), heparin or their combination). The percentage of normal (diploid) and aberrant (haploid, polyploid or aneuploid) embryos was noted in each experiment. The rate of numerical chromosomal abnormalities was mainly affected by sperm fertilising concentration (P<0.01) and, to a lesser extent, by the sperm capacitation medium (P<0.05). Polyploidy and haploidy rates were only affected by sperm fertilising concentration (P<0.05). Interestingly, the sperm selection technique used in the present study did not reduce the incidence of chromosome abnormalities in IVP cattle embryos (P>0.05). Finally, aneuploidy rates were not affected during the experiments (P>0.05), which suggests that they are not related to sperm-related factors. On the basis of these results, we conclude that sperm fertilising concentration is the 'paternal' key factor that affects the rate of numerical chromosomal abnormalities in IVP bovine embryos. By making small adjustments to fertilising protocols, the rate of cytogenetically aberrant embryos can be markedly reduced.

  13. Regional deletion and amplification on chromosome 6 in a uveal melanoma case without abnormalities on chromosomes 1p, 3 and 8.

    PubMed

    van Gils, Walter; Kilic, Emine; Brüggenwirth, Hennie T; Vaarwater, Jolanda; Verbiest, Michael M; Beverloo, Berna; van Til-Berg, Marjan E; Paridaens, Dion; Luyten, Gregorius P; de Klein, Annelies

    2008-02-01

    Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Loss of the long arm and gain of the short arm of chromosome 6 are frequently observed chromosomal aberrations in UM, together with loss of chromosome 1p36, loss of chromosome 3 and gain of chromosome 8. This suggests the presence of one or more oncogenes on 6p and tumor suppressor genes at 6q that are involved in UM development. Both regions, however, have not been well defined yet. Furthermore in other neoplasms gain of 6p and loss of 6q are frequently occurring events. In this case report, we describe the delineation of a partial gain on chromosome 6p and a partial deletion on 6q in a UM with the objective to pinpoint smaller candidate regions on chromosome 6 involved in UM development. Conventional cytogenetics, comparative genomic hybridization (CGH) and fluorescence in-situ hybridization (FISH) were used to delineate regions of loss and gain on chromosome 6 in this UM patient. With conventional cytogenetics a deleted region was found on chromosome 6q that was further delineated to a region ranging from 6q16.1 to 6q22 using CGH and FISH. A region of gain from 6pter to 6p21.2 was also demarcated with CGH and FISH. No other deletions or amplifications on recurrently involved chromosomes were found in this patient. This study indicates the presence of one or more tumor suppressor genes on chromosomal region 6q16.1-6q22 and the presence of one or more oncogenes on chromosomal region 6pter-6p21.2, which are likely to be important in UM and other tumors.

  14. The spatio-temporal dynamics of PKA activity profile during mitosis and its correlation to chromosome segregation.

    PubMed

    Vandame, Pauline; Spriet, Corentin; Trinel, Dave; Gelaude, Armance; Caillau, Katia; Bompard, Coralie; Biondi, Emanuele; Bodart, Jean-François

    2014-01-01

    The cyclic adenosine monophosphate dependent kinase protein (PKA) controls a variety of cellular processes including cell cycle regulation. Here, we took advantages of genetically encoded FRET-based biosensors, using an AKAR-derived biosensor to characterize PKA activity during mitosis in living HeLa cells using a single-cell approach. We measured PKA activity changes during mitosis. HeLa cells exhibit a substantial increase during mitosis, which ends with telophase. An AKAREV T>A inactive form of the biosensor and H89 inhibitor were used to ascertain for the specificity of the PKA activity measured. On a spatial point of view, high levels of activity near to chromosomal plate during metaphase and anaphase were detected. By using the PKA inhibitor H89, we assessed the role of PKA in the maintenance of a proper division phenotype. While this treatment in our hands did not impaired cell cycle progression in a drastic manner, inhibition of PKA leads to a dramatic increase in chromososme misalignement on the spindle during metaphase that could result in aneuploidies. Our study emphasizes the insights that can be gained with genetically encoded FRET-based biosensors, which enable to overcome the shortcomings of classical methologies and unveil in vivo PKA spatiotemporal profiles in HeLa cells.

  15. Evolution and tinkering: what do a protein kinase, a transcriptional regulator and chromosome segregation/cell division proteins have in common?

    PubMed

    Derouiche, Abderahmane; Shi, Lei; Kalantari, Aida; Mijakovic, Ivan

    2016-02-01

    In this study, we focus on functional interactions among multi-domain proteins which share a common evolutionary origin. The examples we develop are four Bacillus subtilis proteins, which all possess an ATP-binding Walker motif: the bacterial tyrosine kinase (BY-kinase) PtkA, the chromosome segregation protein Soj (ParA), the cell division protein MinD and a transcription regulator SalA. These proteins have arisen via duplication of the ancestral ATP-binding domain, which has undergone fusions with other functional domains in the process of divergent evolution. We point out that these four proteins, despite having very different physiological roles, engage in an unusually high number of binary functional interactions. Namely, MinD attracts Soj and PtkA to the cell pole, and in addition, activates the kinase function of PtkA. SalA also activates the kinase function of PtkA, and it gets phosphorylated by PtkA as well. The consequence of this phosphorylation is the activation of SalA as a transcriptional repressor. We hypothesize that these functional interactions remain preserved during divergent evolution and represent a constraint on the process of evolutionary "tinkering", brought about by fusions of different functional domains.

  16. SUMO-interacting motifs (SIMs) in Polo-like kinase 1-interacting checkpoint helicase (PICH) ensure proper chromosome segregation during mitosis.

    PubMed

    Sridharan, Vinidhra; Azuma, Yoshiaki

    2016-08-17

    Polo-like kinase 1 (Plk1)-interacting checkpoint helicase (PICH) localizes at the centromere and is critical for proper chromosome segregation during mitosis. However, the precise molecular mechanism of PICH's centromeric localization and function at the centromere is not yet fully understood. Recently, using Xenopus egg extract assays, we showed that PICH is a promiscuous SUMO binding protein. To further determine the molecular consequence of PICH/SUMO interaction on PICH function, we identified 3 SUMO-interacting motifs (SIMs) on PICH and generated a SIM-deficient PICH mutant. Using the conditional expression of PICH in cells, we found distinct roles of PICH SIMs during mitosis. Although all SIMs are dispensable for PICH's localization on ultrafine anaphase DNA bridges, only SIM3 (third SIM, close to the C-terminus end of PICH) is critical for its centromeric localization. Intriguingly, the other 2 SIMs function in chromatin bridge prevention. With these results, we propose a novel SUMO-dependent regulation of PICH's function on mitotic centromeres.

  17. An unconventional interaction between Dis1/TOG and Mal3/EB1 in fission yeast promotes the fidelity of chromosome segregation

    PubMed Central

    Matsuo, Yuzy; Maurer, Sebastian P.; Yukawa, Masashi; Zakian, Silva; Singleton, Martin R.; Surrey, Thomas

    2016-01-01

    ABSTRACT Dynamic microtubule plus-ends interact with various intracellular target regions such as the cell cortex and the kinetochore. Two conserved families of microtubule plus-end-tracking proteins, the XMAP215, ch-TOG or CKAP5 family and the end-binding 1 (EB1, also known as MAPRE1) family, play pivotal roles in regulating microtubule dynamics. Here, we study the functional interplay between fission yeast Dis1, a member of the XMAP215/TOG family, and Mal3, an EB1 protein. Using an in vitro microscopy assay, we find that purified Dis1 autonomously tracks growing microtubule ends and is a bona fide microtubule polymerase. Mal3 recruits additional Dis1 to microtubule ends, explaining the synergistic enhancement of microtubule dynamicity by these proteins. A non-canonical binding motif in Dis1 mediates the interaction with Mal3. X-ray crystallography shows that this new motif interacts in an unconventional configuration with the conserved hydrophobic cavity formed within the Mal3 C-terminal region that typically interacts with the canonical SXIP motif. Selectively perturbing the Mal3–Dis1 interaction in living cells demonstrates that it is important for accurate chromosome segregation. Whereas, in some metazoans, the interaction between EB1 and the XMAP215/TOG family members requires an additional binding partner, fission yeast relies on a direct interaction, indicating evolutionary plasticity of this critical interaction module. PMID:27872152

  18. Cell division cycle 6, a mitotic substrate of polo-like kinase 1, regulates chromosomal segregation mediated by cyclin-dependent kinase 1 and separase.

    PubMed

    Yim, Hyungshin; Erikson, Raymond L

    2010-11-16

    Defining the links between cell division and DNA replication is essential for understanding normal cell cycle progression and tumorigenesis. In this report we explore the effect of phosphorylation of cell division cycle 6 (Cdc6), a DNA replication initiation factor, by polo-like kinase 1 (Plk1) on the regulation of chromosomal segregation. In mitosis, the phosphorylation of Cdc6 was highly increased, in correlation with the level of Plk1, and conversely, Cdc6 is hypophosphorylated in Plk1-depleted cells, although cyclin A- and cyclin B1-dependent kinases are active. Binding between Cdc6 and Plk1 occurs through the polo-box domain of Plk1, and Cdc6 is phosphorylated by Plk1 on T37. Immunohistochemistry studies reveal that Cdc6 and Plk1 colocalize to the central spindle in anaphase. Expression of T37V mutant of Cdc6 (Cdc6-TV) induces binucleated cells and incompletely separated nuclei. Wild-type Cdc6 but not Cdc6-TV binds cyclin-dependent kinase 1 (Cdk1). Expression of wild-type Plk1 but not kinase-defective mutant promotes the binding of Cdc6 to Cdk1. Cells expressing wild-type Cdc6 display lower Cdk1 activity and higher separase activity than cells expressing Cdc6-TV. These results suggest that Plk1-mediated phosphorylation of Cdc6 promotes the interaction of Cdc6 and Cdk1, leading to the attenuation of Cdk1 activity, release of separase, and subsequent anaphase progression.

  19. A mutation in the FHA domain of Coprinus cinereus Nbs1 Leads to Spo11-independent meiotic recombination and chromosome segregation.

    PubMed

    Crown, K Nicole; Savytskyy, Oleksandr P; Malik, Shehre-Banoo; Logsdon, John; Williams, R Scott; Tainer, John A; Zolan, Miriam E

    2013-11-06

    Nbs1, a core component of the Mre11-Rad50-Nbs1 complex, plays an essential role in the cellular response to DNA double-strand breaks (DSBs) and poorly understood roles in meiosis. We used the basidiomycete Coprinus cinereus to examine the meiotic roles of Nbs1. We identified the C. cinereus nbs1 gene and demonstrated that it corresponds to a complementation group previously known as rad3. One allele, nbs1-2, harbors a point mutation in the Nbs1 FHA domain and has a mild spore viability defect, increased frequency of meiosis I nondisjunction, and an altered crossover distribution. The nbs1-2 strain enters meiosis with increased levels of phosphorylated H2AX, which we hypothesize represent unrepaired DSBs formed during premeiotic replication. In nbs1-2, there is no apparent induction of Spo11-dependent DSBs during prophase. We propose that replication-dependent DSBs, resulting from defective replication fork protection and processing by the Mre11-Rad50-Nbs1 complex, are competent to form meiotic crossovers in C. cinereus, and that these crossovers lead to high levels of faithful chromosome segregation. In addition, although crossover distribution is altered in nbs1-2, the majority of crossovers were found in subtelomeric regions, as in wild-type. Therefore, the location of crossovers in C. cinereus is maintained when DSBs are induced via a Spo11-independent mechanism.

  20. Knockdown of UCHL5IP causes abnormalities in γ-tubulin localisation, spindle organisation and chromosome alignment in mouse oocyte meiotic maturation.

    PubMed

    Wang, Ya-Peng; Qi, Shu-Tao; Wei, Yanchang; Ge, Zhao-Jia; Chen, Lei; Hou, Yi; Ouyang, Ying-Chun; Schatten, Heide; Zhao, Jian-Guo; Sun, Qing-Yuan

    2013-01-01

    UCHL5IP is one of the subunits of the haus complex, which is important for microtubule generation, spindle bipolarity and accurate chromosome segregation in Drosophila and human mitotic cells. In this study, the expression and localisation of UCHL5IP were explored, as well as its functions in mouse oocyte meiotic maturation. The results showed that the UCHL5IP protein level was consistent during oocyte maturation and it was localised to the meiotic spindle in MI and MII stages. Knockdown of UCHL5IP led to spindle defects, chromosome misalignment and disruption of γ-tubulin localisation in the spindle poles. These results suggest that UCHL5IP plays critical roles in spindle formation during mouse oocyte meiotic maturation.

  1. Presence of XIST specific sequences and apparent failure of X dosage compensation by inactivation in a patient with a severe Turner phenotype and mosaicism for X chromosome abnormalities

    SciTech Connect

    Bent-Williams, A.H.; Felton, S.M.; Driscoll, D.J.

    1994-09-01

    An XIST FISH analysis and a late replication chromosome study was performed for a 10 year old female with Turner stigmata, mental retardation, multiple congenital anomalies and a cytogenetic mosaicism of 45,X,inv(9)(p11q13)/46,X,del(X)(q22),inv(9)(p11q13)/46,X,+mar,inv(9)(p11q13). The X chromosomes from a cell line in which one was deleted for the distal long arm segment (breakpoint of Xq22), observed in 6% of metaphase cells from peripheral blood and 23.3% of metaphase cells from skin fibroblasts, did not demonstrate an asynchronous or differential staining pattern by BrDU techniques. However, both the normal X chromosome and the deleted X chromosome were demonstrated to contain XIST specific sequences by FISH analysis. A very small marker chromosome, observed in 6% of metaphase cells from peripheral blood and 3.3% of metaphase cells from skin fibroblasts, appeared to consist exclusively of X chromosome alpha satellite centromeric material (DXZ1). This finding was consistent with the morphology of the marker chromosome as observed by conventional G-banding. Due to its small size and low level frequency, analysis by late replication BrDU techniques was not possible. The predominate cell line containing a signal X chromosome was observed in 88% of metaphase cells from peripheral blood and 73.3% of metaphase cells from skin fibroblasts. This case is significant because: (1) it represents another case of an X chromosome abnormality in which XIST is apparently present but not expressed; and (2) the more severe phenotype expressed is probably attributable to the failure of X gene dosage compensation by inactivation.

  2. Linking topology of tethered polymer rings with applications to chromosome segregation and estimation of the knotting length

    NASA Astrophysics Data System (ADS)

    Marko, John F.

    2009-05-01

    The Gauss linking number (Ca) of two flexible polymer rings which are tethered to one another is investigated. For ideal random walks, mean linking-squared varies with the square root of polymer length while for self-avoiding walks, linking-squared increases logarithmically with polymer length. The free-energy cost of linking of polymer rings is therefore strongly dependent on degree of self-avoidance, i.e., on intersegment excluded volume. Scaling arguments and numerical data are used to determine the free-energy cost of fixed linking number in both the fluctuation and large-Ca regimes; for ideal random walks, for |Ca|>N1/4 , the free energy of catenation is found to grow ∝|Ca/N1/4|4/3 . When excluded volume interactions between segments are present, the free energy rapidly approaches a linear dependence on Gauss linking (dF/dCa≈3.7kBT) , suggestive of a novel “catenation condensation” effect. These results are used to show that condensation of long entangled polymers along their length, so as to increase excluded volume while decreasing number of statistical segments, can drive disentanglement if a mechanism is present to permit topology change. For chromosomal DNA molecules, lengthwise condensation is therefore an effective means to bias topoisomerases to eliminate catenations between replicated chromatids. The results for mean-square catenation are also used to provide a simple approximate estimate for the “knotting length,” or number of segments required to have a knot along a single circular polymer, explaining why the knotting length ranges from ≈300 for an ideal random walk to 106 for a self-avoiding walk.

  3. Chromosomal breakage in human spermatozoa, a heterozygous effect of the bloom syndrome mutation

    SciTech Connect

    Martin, R.H.; Rademaker, A.; German, J.

    1994-12-01

    The chromosome complements of 662 spermatozoa produced by the three fathers of individuals with Bloom syndrome (BS) were analyzed to determine whether the BS mutation could affect chromosome segregation and the frequency of aneuploidy in sperm. The frequency of numerical abnormalities was not significantly different from that in normal controls studied in our laboratory, but the frequencies of structural abnormalities were significantly increased in two of the men, 14.3% and 15.9%, versus 8.6% in controls. More striking was the increase in these two men of cells with multiple structural abnormalities: 8.1% and 6.7% with multiple abnormalities, versus 2.3% in controls.

  4. Epigenetic abnormality of SRY gene in the adult XY female with pericentric inversion of the Y chromosome.

    PubMed

    Mitsuhashi, Tomoko; Warita, Katsuhiko; Sugawara, Teruo; Tabuchi, Yoshiaki; Takasaki, Ichiro; Kondo, Takashi; Hayashi, Fumio; Wang, Zhi-Yu; Matsumoto, Yoshiki; Miki, Takanori; Takeuchi, Yoshiki; Ebina, Yasuhiko; Yamada, Hideto; Sakuragi, Noriaki; Yokoyama, Toshifumi; Nanmori, Takashi; Kitagawa, Hiroshi; Kant, Jeffrey A; Hoshi, Nobuhiko

    2010-06-01

    In normal ontogenetic development, the expression of the sex-determining region of the Y chromosome (SRY) gene, involved in the first step of male sex differentiation, is spatiotemporally regulated in an elaborate fashion. SRY is expressed in germ cells and Sertoli cells in adult testes. However, only few reports have focused on the expressions of SRY and the other sex-determining genes in both the classical organ developing through these genes (gonad) and the peripheral tissue (skin) of adult XY females. In this study, we examined the gonadal tissue and fibroblasts of a 17-year-old woman suspected of having disorders of sexual differentiation by cytogenetic, histological, and molecular analyses. The patient was found to have the 46,X,inv(Y)(p11.2q11.2) karyotype and streak gonads with abnormally prolonged SRY expression. The sex-determining gene expressions in the patient-derived fibroblasts were significantly changed relative to those from a normal male. Further, the acetylated histone H3 levels in the SRY region were significantly high relative to those of the normal male. As SRY is epistatic in the sex-determination pathway, the prolonged SRY expression possibly induced a destabilizing effect on the expressions of the downstream sex-determining genes. Collectively, alterations in the sex-determining gene expressions persisted in association with disorders of sexual differentiation not only in the streak gonads but also in the skin of the patient. The findings suggest that correct regulation of SRY expression is crucial for normal male sex differentiation, even if SRY is translated normally.

  5. Meiotic abnormalities in metaphase I human spermatocytes from infertile males: frequencies, chromosomes involved, and the relationships with polymorphic karyotype and seminal parameters.

    PubMed

    Sarrate, Zaida; Vidal, Francesca; Blanco, Joan

    2014-01-01

    The aim of this study was to look in depth at the relationship between meiotic anomalies and male infertility, such as the determination of the chromosomes involved or the correlation with patient features. For this purpose, a total of 31 testicular tissue samples from individuals consulting for fertility problems were analyzed. Metaphase I cells were evaluated using a sequential methodology combining Leishman stained procedures and multiplex fluorescence in situ hybridization protocols. The number of chromosomal units and chiasmata count per bivalent were established and a hierarchical cluster analysis of the individuals was performed. The relationship of the seminogram and the karyotype over recombination were evaluated using Poisson regression models. Results obtained in this study show a significant percentage of infertile individuals with altered meiotic behavior, mostly specified as a reduction in chiasmata count in medium and large chromosomes, the presence of univalents, and the observation of tetraploid metaphases. Moreover, the number and the type of anomalies were found to be different between cells of the same individual, suggesting the coexistence of cell lines with normal meiotic behavior and cell lines with abnormalities. In addition, chromosomal abnormalities in metaphase I are significantly associated with oligozoospermia and/or polymorphic karyotype variants.

  6. Identification and molecular characterization of a small chromosome 10q duplication [dir dup (10) (q24.2-24.3)] inherited from a mother mosaic for the abnormality

    SciTech Connect

    Tonk, V.; Schneider, N.R.; Schultz, R.A.

    1994-09-01

    Inheritance of a cytogenetic abnormality from a clinically normal parent who is mosaic for the anomaly is rare event, although recent data suggest that such events may be more frequent than originally thought. The identification of such cases can have important implications for genetic counseling and can offer valuable resources for the mapping and analysis of genes involved in human disease and development. We describe a family in which two siblings exhibited developmental delay and very specific neurological abnormalities which included normal muscle mass but reduced muscle tone and mild muscle weakness. Cytogenetic evaluation revealed that both children had inherited a tandem duplication of a small portion of the long arm of chromosome 10 [dir dup (10) (q24.2-24.3)]. The clinically normal mother was found to be mosaic for the duplication which was identified in only two of the twenty metaphases examined. Fluorescence in situ hybridization approaches, including total chromosome painting and the use of previously characterized regional-specific cosmid probes, were used to confirm and characterize the chromosome 10q origin of the duplicated material. This represents the smallest confirmed duplication of distal chromosome 10q reported to date.

  7. Molecular analysis of chromosomal rearrangements using pulsed field gel electrophoresis and somatic cell hybrids

    SciTech Connect

    Davis, L.M. )

    1991-01-01

    Many human genetic diseases, including some cancers, are characterized by consistent chromosome abnormalities, such as deletions and translocations. Analyses of these mutations often prove crucial to the eventual cloning and characterization of the gene(s) responsible for the disease. Two methods for analyzing these chromosome abnormalities have been developed in recent years: somatic cell hybridization and pulsed field gel electrophoresis (PFGE). Somatic cell hybridization is a technique for segregating an aberrant chromosome from its normal homologue in a cell derived from an unrelated species, which is usually a rodent. Demonstrations of these analytic techniques are presented, using as an example chromosomal abnormalities involving human chromosome band 11p13, the locus for the Wilms' tumor, aniridia, genitourinary abnormality, and mental retardation (WAGR) syndrome.

  8. Reversible phosphorylation and regulation of mammalian oocyte meiotic chromatin remodeling and segregation.

    PubMed

    Swain, J E; Smith, G D

    2007-01-01

    The mammalian oocyte is notorious for high rates of chromosomal abnormalities. This results in subsequent embryonic aneuploidy, resulting in infertility and congenital defects. Therefore, understanding regulatory mechanisms involved in chromatin remodeling and chromosome segregation during oocyte meiotic maturation is imperative to fully understand the complex process and establish potential therapies. This review will focus on major events occurring during oocyte meiosis, critical to ensure proper cellular ploidy. Mechanistic and cellular events such as chromosome condensation, meiotic spindle formation, as well as cohesion of homologues and sister chromatids will be discussed, focusing on the role of reversible phosphorylation in control of these processes.

  9. Mutations reducing replication from R-loops suppress the defects of growth, chromosome segregation and DNA supercoiling in cells lacking topoisomerase I and RNase HI activity.

    PubMed

    Usongo, Valentine; Martel, Makisha; Balleydier, Aurélien; Drolet, Marc

    2016-04-01

    R-loop formation occurs when the nascent RNA hybridizes with the template DNA strand behind the RNA polymerase. R-loops affect a wide range of cellular processes and their use as origins of replication was the first function attributed to them. In Escherichia coli, R-loop formation is promoted by the ATP-dependent negative supercoiling activity of gyrase (gyrA and gyrB) and is inhibited by topoisomerase (topo) I (topA) relaxing transcription-induced negative supercoiling. RNase HI (rnhA) degrades the RNA moiety of R-loops. The depletion of RNase HI activity in topA null mutants was previously shown to lead to extensive DNA relaxation, due to DNA gyrase inhibition, and to severe growth and chromosome segregation defects that were partially corrected by overproducing topo III (topB). Here, DNA gyrase assays in crude cell extracts showed that the ATP-dependent activity (supercoiling) of gyrase but not its ATP-independent activity (relaxation) was inhibited in topA null cells lacking RNase HI. To characterize the cellular event(s) triggered by the absence of RNase HI, we performed a genetic screen for suppressors of the growth defect of topA rnhA null cells. Suppressors affecting genes in replication (holC2::aph and dnaT18::aph) nucleotide metabolism (dcd49::aph), RNA degradation (rne59::aph) and fimbriae synthesis (fimD22::aph) were found to reduce replication from R-loops and to restore supercoiling, thus pointing to a correlation between R-loop-dependent replication in topA rnhA mutants and the inhibition of gyrase activity and growth. Interestingly, the position of fimD on the E. coli chromosome corresponds to the site of one of the five main putative origins of replication from R-loops in rnhA null cells recently identified by next-generation sequencing, thus suggesting that the fimD22::aph mutation inactivated one of these origins. Furthermore, we show that topo III overproduction is unable to complement the growth defect of topA rnhA null mutants at low

  10. Identification of the CIMP-like subtype and aberrant methylation of members of the chromosomal segregation and spindle assembly pathways in esophageal adenocarcinoma

    PubMed Central

    Krause, Lutz; Nones, Katia; Loffler, Kelly A.; Nancarrow, Derek; Oey, Harald; Tang, Yue Hang; Wayte, Nicola J.; Patch, Ann Marie; Patel, Kalpana; Brosda, Sandra; Manning, Suzanne; Lampe, Guy; Clouston, Andrew; Thomas, Janine; Stoye, Jens; Hussey, Damian J.; Watson, David I.; Lord, Reginald V.; Phillips, Wayne A.; Gotley, David; Smithers, B.Mark; Whiteman, David C.; Hayward, Nicholas K.; Grimmond, Sean M.; Waddell, Nicola; Barbour, Andrew P.

    2016-01-01

    The incidence of esophageal adenocarcinoma (EAC) has risen significantly over recent decades. Although survival has improved, cure rates remain poor, with <20% of patients surviving 5 years. This is the first study to explore methylome, transcriptome and ENCODE data to characterize the role of methylation in EAC. We investigate the genome-wide methylation profile of 250 samples including 125 EAC, 19 Barrett’s esophagus (BE), 85 squamous esophagus and 21 normal stomach. Transcriptome data of 70 samples (48 EAC, 4 BE and 18 squamous esophagus) were used to identify changes in methylation associated with gene expression. BE and EAC showed similar methylation profiles, which differed from squamous tissue. Hypermethylated sites in EAC and BE were mainly located in CpG-rich promoters. A total of 18575 CpG sites associated with 5538 genes were differentially methylated, 63% of these genes showed significant correlation between methylation and mRNA expression levels. Pathways involved in tumorigenesis including cell adhesion, TGF and WNT signaling showed enrichment for genes aberrantly methylated. Genes involved in chromosomal segregation and spindle formation were aberrantly methylated. Given the recent evidence that chromothripsis may be a driver mechanism in EAC, the role of epigenetic perturbation of these pathways should be further investigated. The methylation profiles revealed two EAC subtypes, one associated with widespread CpG island hypermethylation overlapping H3K27me3 marks and binding sites of the Polycomb proteins. These subtypes were supported by an independent set of 89 esophageal cancer samples. The most hypermethylated tumors showed worse patient survival. PMID:26905591

  11. Roles of cohesin and condensin in chromosome dynamics during mammalian meiosis.

    PubMed

    Lee, Jibak

    2013-10-01

    Meiosis is a key step for sexual reproduction in which chromosome number is halved by two successive meiotic divisions after a single round of DNA replication. In the first meiotic division (meiosis I), homologous chromosomes pair, synapse, and recombine with their partners in prophase I. As a result, homologous chromosomes are physically connected until metaphase I and then segregated from each other at the onset of anaphase I. In the subsequent second meiotic division (meiosis II), sister chromatids are segregated. Chromosomal abnormality arising during meiosis is one of the major causes of birth defects and congenital disorders in mammals including human and domestic animals. Hence understanding of the mechanism underlying these unique chromosome behavior in meiosis is of great importance. This review focuses on the roles of cohesin and condensin, and their regulation in chromosome dynamics during mammalian meiosis.

  12. Structurally abnormal human autosomes

    SciTech Connect

    1993-12-31

    Chapter 25, discusses structurally abnormal human autosomes. This discussion includes: structurally abnormal chromosomes, chromosomal polymorphisms, pericentric inversions, paracentric inversions, deletions or partial monosomies, cri du chat (cat cry) syndrome, ring chromosomes, insertions, duplication or pure partial trisomy and mosaicism. 71 refs., 8 figs.

  13. The long-term clinical implications of clonal chromosomal abnormalities in newly diagnosed chronic phase chronic myeloid leukemia patients treated with imatinib mesylate.

    PubMed

    Lee, Sung-Eun; Choi, Soo Young; Bang, Ju-Hee; Kim, Soo-Hyun; Jang, Eun-Jung; Byeun, Ji-Young; Park, Jin Eok; Jeon, Hye-Rim; Oh, Yun Jeong; Kim, Myungshin; Kim, Dong-Wook

    2012-11-01

    The aim of this study was to evaluate the long-term clinical significance of an additional chromosomal abnormality (ACA), variant Philadelphia chromosome (vPh) at diagnosis, and newly developed other chromosomal abnormalities (OCA) in patients with chronic myeloid leukemia (CML) on imatinib (IM) therapy. Sequential cytogenetic data from 281 consecutive new chronic phase CML patients were analyzed. With a median follow-up of 78.6 months, the 22 patients with vPh (P = 0.034) or ACA (P = 0.034) at diagnosis had more events of IM failure than did the patients with a standard Ph. The 5-year overall survival (OS), event-free survival (EFS), and failure-free survival (FFS) rates for patients with vPh at diagnosis were 77.8%, 75.0%, and 53.3%, respectively; for patients with ACA at diagnosis, 100%, 66.3%, and 52.1%, respectively; and for patients with a standard Ph, 96.0%, 91.3%, and 83.7%, respectively. During IM therapy, eight patients developed an OCA, which had no impact on outcomes as a time-dependent covariate in our Cox proportional hazards regression models. This study showed that vPh was associated with poor OS and FFS and that ACA had adverse effects on EFS and FFS. In addition, no OCA, except monosomy 7, had any prognostic impact, suggesting that the development of OCA may not require a change in treatment strategy.

  14. Detection of Chromosomal Abnormalities with Different In Situ Hybridisation Techniques--the Usefulness in the Qualification of Cancer Patients for Molecularly-Targeted Therapies.

    PubMed

    Nicoś, Marcin; Wojas-Krawczyk, Kamila; Krawczyk, Paweł; Milanowski, Janusz

    2015-01-01

    Proper qualification of patients with cancer for an effective treatment regiment is essential to rationalize therapy benefit and costs. The early detection of genetic disorders that are responsible for the stimulation of uncontrolled cancer cells proliferation makes it possible to select a group of patients with a high probability of response to molecularly-targeted therapy. Data has shown that careful analysis of genes mutation using different PCR and sequencing techniques or chromosomal aberrations using in situ hybridization (ISH) techniques have a predictive value for drug targeted therapy. Overexpression of receptors and gene amplification has been reported in various cancers. Their detection is still a considerable challenge, which is connected with the unsatisfactory quality of DNA and low mutated cells percentage compared to cells with no genetic abnormalities in tested material. Different techniques of standardization were performed to prevent false negative results and to increase the sensitivity of qualitative and quantitative evaluation of chromosomal abnormalities. Immunohistochemistry (IHC) technique is useful in the screening of receptor expression in paraffin-embedded tissue samples in different malignant diseases. Whereas ISH techniques, especially fluorescence in situ hybridization (FISH), are now considered the diagnostic gold standard method in detection chromosomal aberrations. Moreover, molecular biology techniques, which are using molecular probes and real-time PCR and quantitative PCR techniques, were also applied for the detection of chromosomal changes. In order to identify the best genetic marker for treatment regiment, it is important to compare results of different studies, which are evaluating the sensitivity of diagnostic techniques and treatment response after a suitable selection factors based on genetic aberrations profile.

  15. Distal 8p deletion (8) (p23.1): An easily missed chromosomal abnormality that may be associated with congenital heart defect and mental retardation

    SciTech Connect

    Wu, Bai-Lin; Schneider, G.H.; Sabatino, D.E.

    1996-03-01

    We describe the clinical manifestations and molecular cytogenetic analyses of three patients with a similar distal deletion of chromosome 8. Each child had mild developmental delay and subtle minor anomalies. Two had cardiac anomalies but no other major congenital anomalies were present. High resolution G and R banding showed in all three patients del(8)(p23.1), but the breakpoint in case 1 was distal to 8p23.1, in case 2 was in the middle of 8p23.1, and in case 3 proximal to 8p23.1. Fluorescence in situ hybridization (FISH) studies with a chromosome 8 paint probe confirmed that no other rearrangement had occurred. FISH with a chromosome 8-specific telomere probe indicated that two patients had terminal deletions. Chromosome analysis of the parents of case 1 and mother of case 2 were normal; the remaining parents were not available for study. Thirteen individual patients including the three in this study, and three relatives in one family with del(8)(p23.1), have been reported in the past 5 years. Major congenital anomalies, especially congenital heart defects, are most often associated with a breakpoint proximal to 8p23.1. Three patients were found within a 3-year period in this study and five cases were found within 4 years by another group, indicating that distal 8p deletion might be a relatively common chromosomal abnormality. This small deletion is easily overlooked (i.e., cases 1 and 2 were reported as normal at amniocentesis) and can be associated with few or no major congenital anomalies. 31 refs., 4 figs., 2 tabs.

  16. Persistence of histone H2AX phosphorylation after meiotic chromosome synapsis and abnormal centromere cohesion in Poly (ADP-ribose) polymerase (Parp-1) null oocytes

    PubMed Central

    Yang, Feikun; Baumann, Claudia; De La Fuente, Rabindranath

    2009-01-01

    In spite of the impact of aneuploidy on human health little is known concerning the molecular mechanisms involved in the formation of structural or numerical chromosome abnormalities during meiosis. Here, we provide novel evidence indicating that lack of PARP-1 function during oogenesis predisposes the female gamete to genome instability. During prophase I of meiosis, a high proportion of Parp-1 (−/−) mouse oocytes exhibit a spectrum of meiotic defects including incomplete homologous chromosome synapsis or persistent histone H2AX phosphorylation in fully synapsed chromosomes at the late pachytene stage. Moreover, the X chromosome bivalent is also prone to exhibit persistent double strand DNA breaks (DSBs). In striking contrast, such defects were not detected in mutant pachytene spermatocytes. In fully-grown wild type oocytes at the germinal vesicle stage, PARP-1 protein associates with nuclear speckles and upon meiotic resumption, undergoes a striking re-localization towards spindle poles as well as pericentric heterochromatin domains at the metaphase II stage. Notably, a high proportion of in vivo matured Parp-1 (−/−) oocytes show lack of recruitment of the kinetochore-associated protein BUB3 to centromeric domains and fail to maintain metaphase II arrest. Defects in chromatin modifications in the form of persistent histone H2AX phosphorylation during prophase I of meiosis and deficient sister chromatid cohesion during metaphase II predispose mutant oocytes to premature anaphase II onset upon removal from the oviductal environment. Our results indicate that PARP-1 plays a critical role in the maintenance of chromosome stability at key stages of meiosis in the female germ line. Moreover, in the metaphase II stage oocyte PARP-1 is required for the regulation of centromere structure and function through a mechanism that involves the recruitment of BUB3 protein to centromeric domains. PMID:19463809

  17. Identification of chromosome abnormalities in screening of a family with manic depression and psoriasis: predisposition to aneuploidy.

    PubMed

    Demirhan, Osman; Demirbek, Bülent; Tunç, Erdal; Uslu, Inayet Nur; Çetiner, Salih; Serin, Ayşe

    2012-06-01

    Cytogenetic analysis is an important stage in understanding the genetic background of manic depression (MD), and may provide a valuable clue to the identification of target loci and successful search for major genes. In order to identify chromosomal regions we aimed to detect the relationships between chromosomal aberrations (CAs) and immunological markers in a family with MD and psoriasis. We used the cell cultivation and conventional G-banding. We found predominantly numerical aberrations. The most common aneuploidy was chromosome 8, followed by chromosome 22, 21, 15, X and Y. However, structural aberrations consisted of duplications, deletions, translocations and breaks, with a focus on: loci on del(1)(q12-q23), del(1)(q21.1-q24), del(1)(q21.1-q23), del(10)(p11.2-pter), der(2)t(2;4)(p25;p12), t(2;22)(p14;p13), t(19;Y)? and dup(10)(q26). The susceptibility genes of MD or psoriasis may be located on these loci. Numerical sex CAs included 4(5.8%) with 45,X, 3(4.3%) with 47,XXY, and 4(5.8%) with structural chromosome X; del(X)(q13); del(X)(p11-pter) del(X)(q21.3) and inv(Y)(q11.2). We also conducted an immunological study. According results of this study, the percentage of CD2+, CD4+ and CD8+ lymphocytes of the father were significantly higher, whereas CD4+ lymphocytes were decreased in the mother, when compared the healthy persons. The percentage of CD4 level of the son was decreased, whereas CD8+ lymphocytes were higher. The CD4/CD8 ratio of the father and the son was found to be significantly high. These results may suggest that MD and psoriasis have a significant impact on both genetic and immunological parameters.

  18. Characterization of a 5.8-Mb interstitial deletion of chromosome 3p in a girl with 46,XX,inv(7)dn karyotype and phenotypic abnormalities.

    PubMed

    Morales, C; Mademont-Soler, I; Armengol, L; Milà, M; Badenas, C; Andrés, S; Soler, A; Sánchez, A

    2009-01-01

    Interstitial deletions of the short arm of chromosome 3 are rare, and a specific clinical phenotype has not been defined. We report the first isolated cryptic proximal interstitial 3p deletion, del(3)(p12.3p13), assessed by array-based comparative genomic hybridization in a girl with an inversion of chromosome 7, whose phenotype includes neurodevelopmental delay, growth retardation, dysmorphic facial features, hypophysis hypoplasia, gastroesophageal reflux, clinodactyly, preauricular appendix, and myopia. Her features are similar to those observed in the previously reported cases of proximal 3p deletions overlapping with our imbalance, indicating that her clinical manifestations are likely to be due to the deletion. As our patient's imbalance is the first non-cytogenetically visible proximal interstitial 3p deletion uncomplicated by other imbalances, its characterization has allowed us to narrow the minimal deletion interval associated with growth retardation and neurodevelopmental delay to the 3p12.3-p13 region. Among the genes found in this region, ROBO1, ROBO2, PDZRN3 and CNTN3 might play a role in the neurodevelopmental delay of the patient. This study provides additional evidence that cryptic imbalances anywhere along the genome can be found in patients with phenotypic abnormalities and a balanced chromosome rearrangement.

  19. Dual colour FISH in paraffin wax embedded bone trephines for identification of numerical and structural chromosomal abnormalities in acute myeloid leukaemia and myelodysplasia

    PubMed Central

    Le Maitre, C L; Byers, R; Liu, Y; Hoyland, J; Freemont, A

    2001-01-01

    Aims/Background—The advent of new treatments for haematological malignancies has led to the need for a correlation between cytogenetic and morphological abnormalities. This study aimed to achieve this by the application of interphase cytogenetics to marrow trephine sections, a technique not previously reported for formalin fixed, paraffin wax embedded trephine biopsies. Methods—Dual colour fluorescence in situ hybridisation (FISH) was used to detect numerical and structural abnormalities in routinely processed paraffin wax embedded trephine biopsies. Three cases with t(8;21) and three with t(15;17) were analysed, together with a case of trisomy 8. Chromosome specific probes were hybridised with sections and disclosed by fluorescein isothiocyanate and rhodamine/Texas red labelled antidigoxigenin and antibiotin amplification; translocations were identified by colocalisation of probes using a double wavelength bypass filter. Results—A translocation signal was present in 12% and 11.5% of the cells counted in the t(8;21) and t(15;17) cases, respectively, but in none of the normal controls (p < 0.001). In the case of trisomy 8, 9% of the cells counted contained three hybridisation signals for chromosome 8, whereas no cell contained more than two in the normal control (p < 0.001). Conclusions—This technique is useful for archived routinely processed material, enabling it to be used as a research tool but also, and perhaps more importantly, in clinical practice. Key Words: acute myeloid leukaemia • paraffin wax embedded bone trephines • cytogenetic abnormalities • myelodysplasia • fluorescence in situ hybridisation PMID:11533086

  20. Induction of mitotic and chromosomal abnormalities on Allium cepa cells by pesticides imidacloprid and sulfentrazone and the mixture of them.

    PubMed

    Bianchi, Jaqueline; Fernandes, Thais Cristina Casimiro; Marin-Morales, Maria Aparecida

    2016-02-01

    To evaluate the cytotoxic and genotoxic effects of low concentrations of pesticides in non-target organisms, seeds of Allium cepa were exposed for 24 h to the imidacloprid insecticide, sulfentrazone herbicide and to the mixture of them, followed by recovery periods of 48 and 72 h. Imidacloprid results indicated an indirect genotoxic effect by inducing different types of chromosome aberration (CA), mainly bridges and chromosomal adherences. Cells with micronucleus (MN) were not significant in the analyzed meristems. Moreover, the 72-h recovery tests indicated that the two lower concentrations of the insecticide (0.036 and 0.36 g L(-1)) had their genotoxic effects minimized after discontinuation of treatment, differently to the observed for the field concentration (3.6 g L(-1)). Sulfentrazone herbicide at field concentration (6 g L(-1)) caused cytotoxic effects by inducing nuclear fragmentation and inhibition of cell division. The other concentrations (0.06, 0.6 and 1.2 g L(-1)) indicated genotoxic effects for this herbicide. The concentration of 0.06 g L(-1) induced persistent effects that could be visualized both by the induction of CA in the recovery times as by the presence of MN in meristematic and F1 cells. The induction of MN by this lowest concentration was associated with the great amount of breakage, losses and chromosomal bridges. The mixture of pesticides induced genotoxic and cytotoxic effects, by reducing the MI of the cells. The chromosomal damage induced by the mixture of pesticides was not persistent to the cells, since such damage was minimized 72 h after the interruption of the exposure.

  1. Cloning a balanced t(9;11)(p24;q23.1) chromosomal translocation breakpoint segregating with bipolar affective disorder in a small pedigree

    SciTech Connect

    Duggan, D.J.; Baysal, B.E.; Gollin, S.M.

    1994-09-01

    A small multigenerational pedigree was previously identified in which a balanced 9;11 chromosomal translocation was cosegregating with bipolar affective disorder. We hypothesize that genes or gene regulatory sequences disrupted by the translocation are contributing to bipolar affective disorder in a dominant fashion. The general strategy involves (1) using somatic cell hybrids containing the derivative 9 or 11 chromosomes to identify the closest chromosome 9 and 11 flanking markers, (2) using the nearest markers as PCR and hybridization probes to isolate both normal DNA (YAC) and patient DNA (cosmid) adjacent to and incorporating the translocation breakpoint, and (3) identifying expressed sequences in the genomic DNA that may be disrupted by the translocation. From a fusion of the translocation patient cell line and a recipient hamster cell line, somatic cell hybrids were isolated which contain either the human derivative 9 or derivative 11 chromosome. Using PCR-based STS assays with these hybrids, the location of the translocation breakpoint was localized to an estimated 500 kb region at chromosome 11 band q23.1 and a 1 cM region in 9 band p24 (more telomeric than originally reported). From a large set of CEPH and Roswell Park yeast artificial chromosomes (YACs), six chromosome 11 YACs spanning the 11q23.1 breakpoint have now been identified. A combination of pulsed field gel eletrophoresis and YAC mapping has narrowed the chromosome 11 region to less than 430 kb. Current efforts are focused on generating new chromosome 11 probes within the flanking markers, mapping these probes back to the der(9) and der(11) containing hybrids and the chromosome 11 YAC mapping panel. As the region is physically narrowed, we will identify candidate genes whose expression may be altered by this t(9:11) translocation.

  2. Possible influences on the expression of X chromosome-linked dystrophin abnormalities by heterozygosity for autosomal recessive Fukuyama congenital muscular dystrophy

    SciTech Connect

    Beggs, A.H.; Neumann, P.E.; Anderson, M.S.; Kunkel, L.M. ); Arahata, Kiichi; Arikawa, Eri; Nonaka, Ikuya )

    1992-01-15

    Abnormalities of dystrophin, a cytoskeletal protein of muscle and nerve, are generally considered specific for Duchenne and Becker muscular dystrophy. However, several patients have recently been identified with dystrophin deficiency who, before dystrophin testing, were considered to have Fukuyama congenital muscular dystrophy (FCMD) on the basis of clinical findings. Epidemiologic data suggest that only 1/3,500 males with autosomal recessive FCMD should have abnormal dystrophin. To explain the observation of 3/23 FCMD males with abnormal dystrophin, the authors propose that dystrophin and the FCMD gene product interact and that the earlier onset and greater severity of these patients' phenotype (relative to Duchenne muscular dystrophy) are due to their being heterozygous for the FCMD mutation in addition to being hemizygous for Duchenne muscular dystrophy, a genotype that is predicted to occur in 1/175,000 Japanese males. This model may help explain the genetic basis for some of the clinical and pathological variability seen among patients with FCMD, and it has potential implications for understanding the inheritance of other autosomal recessive disorders in general. For example, sex ratios for rare autosomal recessive disorders caused by mutations in proteins that interact with X chromosome-linked gene products may display predictable deviation from 1:1.

  3. [Distribution of abnormal cell clone with deletion of chromosome 20q in marrow cell lineages and apoptosis cells in myelodysplastic syndrome].

    PubMed

    Qin, Ling; Wang, Chun; Qin, You-Wen; Xie, Kuang-Cheng; Yan, Shi-Ke; Gao, Yan-Rong; Wang, Xiao-Rui; Zhao, Chu-Xian

    2008-06-01

    This study was aimed to investigate the distribution of abnormal clone in marrow cell lineages and apoptosis cells in myelodysplastic syndrome (MDS) with deletion of chromosome 20q. Monoclonal antibodies recognizing myeloid precursors (CD15), erythroid precursors (GPA), T cells (CD3(+)CD56(-)CD16(-)), B cells (CD19), NK cells (CD3(-)CD56(+)CD16(+)) were used to sort bone marrow cells in a MDS patient with del (20q) by fluorescence activated cell sorting (FACS). Annexin V-FITC and PI were used to sort bone marrow Annexin V(+)PI(-) and Annexin V(-)PI(-) cells by FACS. The sorted positive cells were detected by interphase dual-color fluorescence in situ hybridization (D-FISH) using a LSI D20S108 probe (Spectrum Orange) and a Telvysion TM 20p probe (Spectrum Green). FACS and FISH analysis were also performed on the samples from 4 cases with normal karyotype. The results showed that the proportions of MDS clone in the myeloid and erythroid precursors were 70.50% and 93.33% respectively, in the RAEB-1 patient with del (20q) and were obviously higher than that in control group (5.39% and 6.17%). The proportions of abnormal clone in T, B and NK cells were 3.23%, 4.32% and 5.77% respectively and were less than that in control group (5.76%, 4.85%, 6.36%). The percentage of apoptotic cells in the bone marrow nucleated cells was 16.09%. The proportions of MDS clone in Annexin V(+)PI(-) and Annexin V(-)PI(-) cells were 32.48% and 70.11%, respectively. It is concluded that most myeloid and erythroid precursors are originated from the abnormal clone in MDS with del (20q). A little part of apoptotic cells are derived from the abnormal clone.

  4. Mitotic chromosome structure

    SciTech Connect

    Heermann, Dieter W.

    2012-07-15

    Mounting evidence is compiling linking the physical organizational structure of chromosomes and the nuclear structure to biological function. At the base of the physical organizational structure of both is the concept of loop formation. This implies that physical proximity within chromosomes is provided for otherwise distal genomic regions and thus hierarchically organizing the chromosomes. Together with entropy many experimental observations can be explained with these two concepts. Among the observations that can be explained are the measured physical extent of the chromosomes, their shape, mechanical behavior, the segregation into territories (chromosomal and territories within chromosomes), the results from chromosome conformation capture experiments, as well as linking gene expression to structural organization.

  5. Balancing acts of two HEAT subunits of condensin I support dynamic assembly of chromosome axes.

    PubMed

    Kinoshita, Kazuhisa; Kobayashi, Tetsuya J; Hirano, Tatsuya

    2015-04-06

    Condensin I is a five-subunit protein complex that plays a central role in mitotic chromosome assembly and segregation in eukaryotes. To dissect its mechanism of action, we reconstituted wild-type and mutant complexes from recombinant subunits and tested their abilities to assemble chromosomes in Xenopus egg cell-free extracts depleted of endogenous condensins. We find that ATP binding and hydrolysis by SMC subunits have distinct contributions to the action of condensin I and that continuous ATP hydrolysis is required for structural maintenance of chromosomes. Mutant complexes lacking either one of two HEAT subunits produce abnormal chromosomes with highly characteristic defects and have contrasting structural effects on chromosome axes preassembled with the wild-type complex. We propose that balancing acts of the two HEAT subunits support dynamic assembly of chromosome axes under the control of the SMC ATPase cycle, thereby governing construction of rod-shaped chromosomes in eukaryotic cells.

  6. [Meiotic abnormalities as expression of nuclear-cytoplasmic incompatibility in crosses of Pisum sativum subspecies].

    PubMed

    Bogdanova, V S; Galieva, E R

    2009-05-01

    Meiosis in anthers and mitosis in somatic cells were studied in reciprocal F1 hybrids of the accession VIR320, which belonged to wild Pisum sativum ssp. elatius (Bieb.) Schmal., and the laboratory line Sprint-1. When VIR320 was used as a maternal form, the hybrids displayed nuclear-cytoplasmic conflict, which caused chlorophyll defects and meiotic abnormalities. One or two chromosomes lagged in the equatorial region during chromosome segregation to the poles, distorting cytokinesis and yielding abnormal microspores. Chlorophyll defects were not observed, and meiotic abnormalities were far less frequent in reciprocal hybrids and in the case of an abnormal paternal inheritance of plastids from Sprint-1. Mitosis lacked overt abnormalities in all of the hybrids.

  7. Enhanced conversion of induced neuronal cells (iN cells) from human fibroblasts: Utility in uncovering cellular deficits in mental illness-associated chromosomal abnormalities.

    PubMed

    Passeri, Eleonora; Wilson, Ashley M; Primerano, Amedeo; Kondo, Mari A; Sengupta, Srona; Srivastava, Rupali; Koga, Minori; Obie, Cassandra; Zandi, Peter P; Goes, Fernando S; Valle, David; Rapoport, Judith L; Sawa, Akira; Kano, Shin-ichi; Ishizuka, Koko

    2015-12-01

    The novel technology of induced neuronal cells (iN cells) is promising for translational neuroscience, as it allows the conversion of human fibroblasts into cells with postmitotic neuronal traits. However, a major technical barrier is the low conversion rate. To overcome this problem, we optimized the conversion media. Using our improved formulation, we studied how major mental illness-associated chromosomal abnormalities may impact the characteristics of iN cells. We demonstrated that our new iN cell culture protocol enabled us to obtain more precise measurement of neuronal cellular phenotypes than previous iN cell methods. Thus, this iN cell culture provides a platform to efficiently obtain possible cellular phenotypes caused by genetic differences, which can be more thoroughly studied in research using other human cell models such as induced pluripotent stem cells.

  8. Mammalian chromosomes contain cis-acting elements that control replication timing, mitotic condensation, and stability of entire chromosomes.

    PubMed

    Thayer, Mathew J

    2012-09-01

    Recent studies indicate that mammalian chromosomes contain discrete cis-acting loci that control replication timing, mitotic condensation, and stability of entire chromosomes. Disruption of the large non-coding RNA gene ASAR6 results in late replication, an under-condensed appearance during mitosis, and structural instability of human chromosome 6. Similarly, disruption of the mouse Xist gene in adult somatic cells results in a late replication and instability phenotype on the X chromosome. ASAR6 shares many characteristics with Xist, including random mono-allelic expression and asynchronous replication timing. Additional "chromosome engineering" studies indicate that certain chromosome rearrangements affecting many different chromosomes display this abnormal replication and instability phenotype. These observations suggest that all mammalian chromosomes contain "inactivation/stability centers" that control proper replication, condensation, and stability of individual chromosomes. Therefore, mammalian chromosomes contain four types of cis-acting elements, origins, telomeres, centromeres, and "inactivation/stability centers", all functioning to ensure proper replication, condensation, segregation, and stability of individual chromosomes.

  9. Structural chromosome abnormalities, increased DNA strand breaks and DNA strand break repair deficiency in dermal fibroblasts from old female human donors

    PubMed Central

    Kalfalah, Faiza; Seggewiß, Sabine; Walter, Regina; Tigges, Julia; Moreno-Villanueva, María; Bürkle, Alexander; Ohse, Sebastian; Busch, Hauke; Boerries, Melanie; Hildebrandt, Barbara; Royer-Pokora, Brigitte; Boege, Fritz

    2015-01-01

    Dermal fibroblasts provide a paradigmatic model of cellular adaptation to long-term exogenous stress and ageing processes driven thereby. Here we addressed whether fibroblast ageing analysed ex vivo entails genome instability. Dermal fibroblasts from human female donors aged 20–67 years were studied in primary culture at low population doubling. Under these conditions, the incidence of replicative senescence and rates of age-correlated telomere shortening were insignificant. Genome-wide gene expression analysis revealed age-related impairment of mitosis, telomere and chromosome maintenance and induction of genes associated with DNA repair and non-homologous end-joining, most notably XRCC4 and ligase 4. We observed an age-correlated drop in proliferative capacity and age-correlated increases in heterochromatin marks, structural chromosome abnormalities (deletions, translocations and chromatid breaks), DNA strand breaks and histone H2AX-phosphorylation. In a third of the cells from old and middle-aged donors repair of X-ray induced DNA strand breaks was impaired despite up-regulation of DNA repair genes. The distinct phenotype of genome instability, increased heterochromatinisation and (in 30% of the cases futile) up-regulation of DNA repair genes was stably maintained over several cell passages indicating that it represents a feature of geroconversion that is distinct from cellular senescence, as it does not encompass a block of proliferation. PMID:25678531

  10. Diagnosis of chromosomal abnormalities in a patient with thanatophoric dysplasia (TD) type I: The first report describing an important association between cytogenetic findings and TD

    PubMed Central

    Turgut, Mehmet; Demirhan, Osman; Tunc, Erdal; Bucak, Ibrahim Hakan; Canoz, Perihan Yasemen; Temiz, Fatih; Tumgor, Gokhan

    2012-01-01

    Summary Background: Thanatophoric dysplasia (TD) is the most lethal and most severe type of dysplasia. It has distinct features, the most important of which is short tubular bones and short ribs with platyspondyly, allowing a precise radiologic and prenatal ultrasonographic diagnosis. It has been reported to be caused by mutations in the FGFR3 gene, but exactly how cytogenetic abnormalities might lead to TD is unclear. Case Report: We report a case of TD with different prenatal sonographic features compatible with the classification of type I. In the result of cytogenetic examination, we found de novo CAs in 28% of cells analyzed from the affected infant; 75% of the abnormalities were numerical, and of those, 25% were structural aberrations; 21% of cells revealed predominantly numerical aberrations. Monosomy 18, 21 and 22 was observed in 4% of cells, monosomy 20 in 2%, and monosomy 7, 8, 14, 17 and 19 in 1%. Structural changes were observed in 7% of cells. Conclusions: It appears that these chromosomes may be preferentially involved in and important for TD development. PMID:23569503

  11. Chromosomal Abnormalities Are Major Prognostic Factors in Elderly Patients With Multiple Myeloma: The Intergroupe Francophone du Myélome Experience

    PubMed Central

    Avet-Loiseau, Hervé; Hulin, Cyrille; Campion, Loic; Rodon, Philippe; Marit, Gerald; Attal, Michel; Royer, Bruno; Dib, Mamoun; Voillat, Laurent; Bouscary, Didier; Caillot, Denis; Wetterwald, Marc; Pegourie, Brigitte; Lepeu, Gerard; Corront, Bernadette; Karlin, Lionel; Stoppa, Anne-Marie; Fuzibet, Jean-Gabriel; Delbrel, Xavier; Guilhot, Francois; Kolb, Brigitte; Decaux, Olivier; Lamy, Thierry; Garderet, Laurent; Allangba, Olivier; Lifermann, Francois; Anglaret, Bruno; Moreau, Philippe; Harousseau, Jean-Luc; Facon, Thierry

    2013-01-01

    Purpose Chromosomal abnormalities, especially t(4;14) and del(17p), are major prognostic factors in patients with multiple myeloma (MM). However, this has been especially demonstrated in patients age < 66 years treated with intensive approaches. The goal of this study was to address this issue in elderly patients treated with conventional-dose chemotherapy. Patients and Methods To answer this important question, we retrospectively analyzed a series of 1,890 patients (median age, 72 years; range, 66 to 94 years), including 1,095 with updated data on treatment modalities and survival. Results This large study first showed that the incidence of t(4;14) was not uniform over age, with a marked decrease in the oldest patients. Second, it showed that both t(4;14) and del(17p) retained their prognostic value in elderly patients treated with melphalan and prednisone–based chemotherapy. Conclusion t(4;14) and del(17p) are major prognostic factors in elderly patients with MM, both for progression-free and overall survival, indicating that these two abnormalities should be investigated at diagnosis of MM, regardless of age. PMID:23796999

  12. A theory explaining the abnormality in 45,X/46,XY mosaicism with non-fluorescent Y chromosome. presentation of three cases.

    PubMed

    Kaluzewski, B; Jokinen, A; Hortling, H; de la Chapelle, A

    1978-03-01

    Three patients with male habitus, short stature and testicular differentiation are described. All had mos 45,X/46,XY, the ratio of the two stemlines varying between the patients and between different tissues. The Y chromosome was abnormal, lacking the brilliant QFQ fluorescence and dark CGB staining characteristic of the distal part of the normal Y. Detailed banding studies suggested that the short arm and proximal part of the long arm were normal, while the distal part of the long arm was molecularly or otherwise altered, resulting in abnormal staining properties. Two of the patients were tested for H-Y antigen and found to be positive. These data and those collected from the literature are compatible with a model in which the primary lesion in X/XY mosaicism is a molecular alteration in the reiterated Y-specific DNA sequences (and possibly neighbouring sequences) of a 46,XY zygote resulting in the frequent mitotic loss of the Y and the emergence of a 45,X line. Provided the testis-determining gene(s) near the centromere are normal, testes are formed and the patient is H-Y antigen-positive. The extent of male or female differentiation depends in part on the prevalence, time of occurence, and distribution of the 45,X line and possibly in part on the alteration of other genes involved in sex differentiation and located on Yq further from the centromere.

  13. Additional cytogenetic abnormalities in adults with Philadelphia chromosome-positive acute lymphoblastic leukaemia: a study of the Cancer and Leukaemia Group B.

    PubMed

    Wetzler, Meir; Dodge, Richard K; Mrózek, Krzysztof; Stewart, Carleton C; Carroll, Andrew J; Tantravahi, Ramana; Vardiman, James W; Larson, Richard A; Bloomfield, Clara D

    2004-02-01

    We analysed the nature and prognostic significance of secondary cytogenetic changes in 111 newly diagnosed adults with acute lymphoblastic leukaemia (ALL) and t(9;22)(q34;q11.2) or its variants. Secondary aberrations were seen in 75 (68%) patients. They included, in order of descending frequency: +der(22)t(9;22), +21, abnormalities of 9p, high hyperdiploidy (>50 chromosomes), +8, -7, +X and abnormalities resulting in loss of material from 8p, gain of 8q, gain of 1q and loss of 7p. Eighty patients (72%) had > or =1 normal metaphase in their karyotype. There were four balanced and 12 unbalanced translocations previously unreported in ALL with t(9;22). The t(2;7)(p11;p13) and der(18)t(8;18)(q11.2;p11.2) were seen in two cases each, and have never before been reported in haematological malignancy. All but four patients were treated on front-line Cancer and Leukaemia Group B clinical protocols. The presence of -7 as a sole secondary abnormality was associated with a lower complete remission (CR) rate (P = 0.004), while the presence of > or =3 aberrations was associated with a higher CR rate (P = 0.009) and +der(22)t(9;22) with a higher cumulative incidence of relapse (P = 0.02). It will be of interest to see if newly diagnosed t(9;22)-positive adult ALL patients with these and other secondary aberrations respond differently to treatment regimens that include imatinib mesylate.

  14. Ethanol alters proliferation and differentiation of normal and chromosomally abnormal human embryonic stem cell-derived neurospheres.

    PubMed

    Krishnamoorthy, Malini; Gerwe, Brian A; Scharer, Christopher D; Sahasranaman, Vanita; Eilertson, Carmen D; Nash, Rachel J; Usta, Sümeyra Naz; Kelly, Shasmine; Rose, Matthew; Peraza, Rene; Arumugham, Jagan; Stewart, Bethany; Stice, Steven L; Nash, Rodney J

    2013-06-01

    Ethanol is a powerful substance and, when consumed during pregnancy, has significant psychoactive and developmental effects on the developing fetus. These abnormalities include growth retardation, neurological deficits, and behavioral and cognitive deficiencies, commonly referred to as fetal alcohol spectrum disorder. The effect of ethanol has been reported to affect cellular development on the embryonic level, however, not much is known about mutations contributing to the influence of ethanol. The purpose of our study was to determine if mutation contribute to changes in differentiation patterning, cell-cycle regulatory gene expression, and DNA methylation in human embryonic stem cells after ethanol exposure. We exposed human embryonic stem cells (with and without know DNA mutations) to a low concentration (20 mM) of ethanol and measured neurosphere proliferation and differentiation, glial protein levels, expression of various cell-cycle genes, and DNA methylation. Ethanol altered cell-cycle gene expression between the two cell lines; however, gene methylation was not affected in ether lines.

  15. Reproductive outcomes in men with karyotype abnormalities: Case report and review of the literature

    PubMed Central

    Kohn, Taylor P.; Clavijo, Raul; Ramasamy, Ranjith; Hakky, Tariq; Candrashekar, Aravind; Lamb, Dolores J.; Lipshultz, Larry I.

    2015-01-01

    Reciprocal translocations of autosomal chromosomes are present in about 1/625 men, yet often there are no symptoms except primary infertility. Abnormal segregation during meiosis often produces sperm and subsequent embryos with unbalanced translocations that often ultimately result in spontaneous abortions. We report on a 37-year-old man and his 39-year-old wife who complained of primary infertility. Previous in vitro fertilization (IVF) had resulted in pregnancy, but two spontaneous abortions. Upon chromosomal testing, the man was diagnosed with a reciprocal translocation and his wife was diagnosed with mosaic Turner’s syndrome. Through testicular sperm extraction (TESE) and IVF with preimplantation genetic screening (PGS), they succeeded in having two healthy children. Since men with different karyotype abnormalities can have male infertility, we reviewed the literature and summarized the reproductive outcomes for men with both autosome and sex chromosomal karyotype abnormalities. PMID:26425238

  16. Segregation of a paternal insertional translocation results in partial 4q monosomy or 4q trisomy in two siblings

    SciTech Connect

    Hegmann, K.M.; Spikes, A.S.; Orr-Urtreger, A.; Shaffer, L.G.

    1996-01-02

    A genetics evaluation was requested for a 6-week-old infant with multiple congenital malformations including mild craniofacial anomalies, truncal hypotonia, hypospadias, and a ventriculoseptal defect. Blood obtained for chromosome analysis revealed an abnormal chromosome 4. Paternal chromosome analysis showed a 46,XY, inv ins (3;4)(p21.32;q25q21.2), inv(4)(p15.3q21.2) karyotype. Therefore, the proband`s chromosome 4 was the unbalanced product of this insertional translocation from the father resulting in partial monosomy 4q. Additionally, the derivative 4 had a pericentric inversion which was also seen in the father`s chromosome 4. During genetic counseling, the proband`s 2-year-old brother was evaluated. He was not felt to be abnormal in appearance, but was described as having impulsive behavior. Chromosome analysis on this child revealed 46, XY, der(3) inv ins(3;4)(p21.32;q25q21.2)pat. This karyotype results in partial trisomy 4q. FISH using two-color {open_quotes}painting{close_quotes} probes for chromosomes 3 and 4 confirmed the G-banded interpretation in this family. The segregation seen in this family resulted in both reciprocal products being observed in the two children, with partial 4q monosomy showing multiple congenital anomalies, and partial 4q trisomy showing very few phenotypic abnormalities. 13 refs., 5 figs.

  17. Whole Exome Sequencing and Segregation Analysis Confirms That a Mutation in COL17A1 Is the Cause of Epithelial Recurrent Erosion Dystrophy in a Large Dominant Pedigree Previously Mapped to Chromosome 10q23-q24

    PubMed Central

    Le, Derek J.; Chen, Yabin; Wang, Qiwei; Chung, D. Doug; Frausto, Ricardo F.; Croasdale, Christopher; Yee, Richard W.; Hejtmancik, Fielding J.; Aldave, Anthony J.

    2016-01-01

    Purpose To report identification of a COL17A1 mutation in a family with a corneal dystrophy previously mapped to chromosome 10q23-q24. Methods Whole-exome sequencing was performed on DNA samples from five affected family members and two unrelated, unaffected individuals. Identified variants were filtered for those that were: located in the linked interval on chromosome 10q23-q24; novel or rare (minor allele frequency ≤0.01); heterozygous; present in all affected individuals and not in controls; and present in genes that encode proteins expressed in human corneal epithelial cells (reads per kilobase per million ≥1). Sanger sequencing of identified variants (SNVs) was performed in additional family members. In silico analysis was used to predict the functional impact of non-synonymous variants. Results Three SNVs located in two genes were identified that met the filtering criteria: one rare synonymous c.3156C>T variant in the collagen, type XVII, alpha I (COL17A1) gene; and two rare variants, one synonymous and one missense, in the dynamin binding protein (DNMBP) gene. Sanger sequencing of additional family members determined that only the COL17A1 variant segregates with the affected phenotype. In silico analysis predicts that the missense variant in DNMBP would be tolerated. Conclusions The corneal dystrophy mapped to chromosome 10q23-q24 is associated with the c.3156C>T variant in COL17A1. As this variant has recently been identified in five other families with early onset recurrent corneal erosions, and has been shown in vitro to introduce a cryptic splice donor site, this dystrophy is likely caused by aberrant splicing of COL17A1 and should be classified as epithelial recurrent erosion dystrophy. PMID:27309958

  18. White matter microstructural abnormalities in girls with chromosome 22q11.2 deletion syndrome, Fragile X or Turner syndrome as evidenced by diffusion tensor imaging.

    PubMed

    Villalon-Reina, Julio; Jahanshad, Neda; Beaton, Elliott; Toga, Arthur W; Thompson, Paul M; Simon, Tony J

    2013-11-01

    Children with chromosome 22q11.2 deletion syndrome (22q11.2DS), Fragile X syndrome (FXS), or Turner syndrome (TS) are considered to belong to distinct genetic groups, as each disorder is caused by separate genetic alterations. Even so, they have similar cognitive and behavioral dysfunctions, particularly in visuospatial and numerical abilities. To assess evidence for common underlying neural microstructural alterations, we set out to determine whether these groups have partially overlapping white matter abnormalities, relative to typically developing controls. We scanned 101 female children between 7 and 14years old: 25 with 22q11.2DS, 18 with FXS, 17 with TS, and 41 aged-matched controls using diffusion tensor imaging (DTI). Anisotropy and diffusivity measures were calculated and all brain scans were nonlinearly aligned to population and site-specific templates. We performed voxel-based statistical comparisons of the DTI-derived metrics between each disease group and the controls, while adjusting for age. Girls with 22q11.2DS showed lower fractional anisotropy (FA) than controls in the association fibers of the superior and inferior longitudinal fasciculi, the splenium of the corpus callosum, and the corticospinal tract. FA was abnormally lower in girls with FXS in the posterior limbs of the internal capsule, posterior thalami, and precentral gyrus. Girls with TS had lower FA in the inferior longitudinal fasciculus, right internal capsule and left cerebellar peduncle. Partially overlapping neurodevelopmental anomalies were detected in all three neurogenetic disorders. Altered white matter integrity in the superior and inferior longitudinal fasciculi and thalamic to frontal tracts may contribute to the behavioral characteristics of all of these disorders.

  19. White matter microstructural abnormalities in girls with chromosome 22q11.2 deletion syndrome, Fragile X or Turner syndrome as evidenced by diffusion tensor imaging

    PubMed Central

    Villalon, Julio; Jahanshad, Neda; Beaton, Elliott; Toga, Arthur W.; Thompson, Paul M.; Simon, Tony J.

    2014-01-01

    Children with chromosome 22q11.2 Deletion Syndrome (22q11.2DS), Fragile X Syndrome (FXS), or Turner Syndrome (TS) are considered to belong to distinct genetic groups, as each disorder is caused by separate genetic alterations. Even so, they have similar cognitive and behavioral dysfunctions, particularly in visuospatial and numerical abilities. To assess evidence for common underlying neural microstructural alterations, we set out to determine whether these groups have partially overlapping white matter abnormalities, relative to typically developing controls. We scanned 101 female children between 7 and 14 years old: 25 with 22q11.2DS, 18 with FXS, 17 with TS, and 41 aged-matched controls using diffusion tensor imaging (DTI). Anisotropy and diffusivity measures were calculated and all brain scans were nonlinearly aligned to population and site-specific templates. We performed voxel-based statistical comparisons of the DTI-derived metrics between each disease group and the controls, while adjusting for age. Girls with 22q11.2DS showed lower fractional anisotropy (FA) than controls in the association fibers of the superior and inferior longitudinal fasciculi, the splenium of the corpus callosum, and the corticospinal tract. FA was abnormally lower in girls with FXS in the posterior limbs of the internal capsule, posterior thalami, and precentral gyrus. Girls with TS had lower FA in the inferior longitudinal fasciculus, right internal capsule and left cerebellar peduncle. Partially overlapping neurodevelopmental anomalies were detected in all three neurogenetic disorders. Altered white matter integrity in the superior and inferior longitudinal fasciculi and thalamic to frontal tracts may contribute to the behavioral characteristics of all of these disorders. PMID:23602925

  20. Histone H3 phosphorylation and elimination of paternal X chromosomes at early cleavages in sciarid flies.

    PubMed

    Escribá, M Carmen; Goday, Clara

    2013-07-15

    In sciarid flies (Diptera, Sciaridae), one or two paternally derived X chromosomes are discarded from the soma at early cleavages to determine the sex of the embryo (XX, females; X0, males). X chromosome(s) elimination is achieved by an abnormal anaphase segregation so that X sister chromatids do not reach the poles and are not included in the daughter nuclei. A cis-acting locus (CE) within the heterochromatin proximal to the centromere is known to regulate X chromosome elimination. By immunofluorescence analysis in early embryos from Sciara ocellaris and Sciara coprophila, we investigated histone H3 phosphorylation at Ser10, Ser28 and Thr3 prior to, and during, the X elimination process. We found that the regular syncytial nuclear divisions are characterized by a gradual loss of H3S10 phosphorylation along the chromosome arms at anaphase. Importantly, the eliminating X chromosomes show a retardation in anaphase chromatid segregation and high levels of H3S10 phosphorylation in the chromosome arms. In the present study, we provide the first evidence linking the hyper-phosphorylated H3 status of the X chromosome with a delay in sister chromatid separation at anaphase. Our findings support the idea that the CE induces a deficiency in H3 dephosphorylation in the paternal X chromosomes to be eliminated.

  1. What`s in a name? Chromosome 22q abnormalities and the DiGeorge, velocardiofacial and conotruncal anomalies face syndromes

    SciTech Connect

    Wulfsberg, E.A.; Leana-Cox, J.; Neri, G.

    1996-11-11

    The recent advances in our understanding of the phenotype associated with deletion of the DiGeorge Chromosome Region (DGCR) at 22q11.2 are in many ways analogous to the fable about the blind men and the elephant. Originally described as three distinct phenotypes (DiGeorge (DG) syndrome, velocardiofacial (VCF) syndrome, and the conotruncal anomalies face (CTAF) syndrome), it is now clear that there is only a single broad and variable phenotype associated with deletion of the DGCR. As in the fable, distinguished clinicians approached this phenotypic {open_quotes}elephant{close_quotes} from different perspectives and provided three separate, although overlapping descriptions. Our analogy to this fable is not to imply some {open_quotes}blindness{close_quotes} on the part of these clinicians, but rather to point out the well-known difficulty in delineating the indistinct phenotypic boundaries of a syndrome until a genetic or biochemical marker for the condition is available. The recent availability of a fluorescent in situ hybridization (FISH) probe to detect deletion of the DGCR now allows delineation of the broad phenotype of our {open_quotes}elephant{close_quotes} which spans from lethal DG phenotypes through the intermediate VCF and CTAF phenotypes to the newly recognized {open_quotes}mild{close_quotes} phenotype consisting of only developmental delays and subtle facial abnormalities. 33 refs.

  2. FISH analysis of 1cen-1q12 breakage, chromosome 1 numerical abnormalities and centromeric content of micronuclei in buccal cells from thyroid cancer and hyperthyroidism patients treated with radioactive iodine.

    PubMed

    Ramírez, M J; Surrallés, J; Galofré, P; Creus, A; Marcos, R

    1999-01-01

    One of the health consequences of the Chernobyl nuclear power plant accident was a radioactive iodine-related increase in the incidence of thyroid cancer in exposed children. This radioisotope is used in the treatment of thyroid cancer and hyperthyroidism patients providing a convenient opportunity to study cytogenetic damage induced by known doses of radioactive iodine in treated patients. We used pancentromeric FISH on micronuclei and chromosome 1 tandem labelling FISH to monitor overall chromosome breakage and loss, 1q12 breakage and decondensation and chromosome 1 numerical abnormalities in buccal cells from 31 radioactive iodine-exposed hyperthyroidism and thyroid cancer patients. The overall outcome of the study, with 250,000 buccal cells analysed, is that there was no radioactive iodine-related increase in the frequency of micronuclei, 1q12 breakage, 1q12 decondensation or chromosome 1 numerical abnormalities. In addition, neither age nor gender, health status nor radioactive iodine dose modulated the frequency of the above cytogenetic end points. Although several uncertainties of these emerging molecular cytogenetic methodologies will require further experimentation, we conclude that, at the reported exposure levels, radioactive iodine did not induce detectable chromosome damage in buccal cells from treated patients.

  3. Digital Quantification of DNA Replication and Chromosome Segregation Enables Determination of Antimicrobial Susceptibility after only 15 Minutes of Antibiotic Exposure.

    PubMed

    Schoepp, Nathan G; Khorosheva, Eugenia M; Schlappi, Travis S; Curtis, Matthew S; Humphries, Romney M; Hindler, Janet A; Ismagilov, Rustem F

    2016-08-08

    Rapid antimicrobial susceptibility testing (AST) would decrease misuse and overuse of antibiotics. The "holy grail" of AST is a phenotype-based test that can be performed within a doctor visit. Such a test requires the ability to determine a pathogen's susceptibility after only a short antibiotic exposure. Herein, digital PCR (dPCR) was employed to test whether measuring DNA replication of the target pathogen through digital single-molecule counting would shorten the required time of antibiotic exposure. Partitioning bacterial chromosomal DNA into many small volumes during dPCR enabled AST results after short exposure times by 1) precise quantification and 2) a measurement of how antibiotics affect the states of macromolecular assembly of bacterial chromosomes. This digital AST (dAST) determined susceptibility of clinical isolates from urinary tract infections (UTIs) after 15 min of exposure for all four antibiotic classes relevant to UTIs. This work lays the foundation to develop a rapid, point-of-care AST and strengthen global antibiotic stewardship.

  4. The Precarious Prokaryotic Chromosome

    PubMed Central

    2014-01-01

    Evolutionary selection for optimal genome preservation, replication, and expression should yield similar chromosome organizations in any type of cells. And yet, the chromosome organization is surprisingly different between eukaryotes and prokaryotes. The nuclear versus cytoplasmic accommodation of genetic material accounts for the distinct eukaryotic and prokaryotic modes of genome evolution, but it falls short of explaining the differences in the chromosome organization. I propose that the two distinct ways to organize chromosomes are driven by the differences between the global-consecutive chromosome cycle of eukaryotes and the local-concurrent chromosome cycle of prokaryotes. Specifically, progressive chromosome segregation in prokaryotes demands a single duplicon per chromosome, while other “precarious” features of the prokaryotic chromosomes can be viewed as compensations for this severe restriction. PMID:24633873

  5. Altered cohesin gene dosage affects Mammalian meiotic chromosome structure and behavior.

    PubMed

    Murdoch, Brenda; Owen, Nichole; Stevense, Michelle; Smith, Helen; Nagaoka, So; Hassold, Terry; McKay, Michael; Xu, Huiling; Fu, Jun; Revenkova, Ekaterina; Jessberger, Rolf; Hunt, Patricia

    2013-01-01

    Based on studies in mice and humans, cohesin loss from chromosomes during the period of protracted meiotic arrest appears to play a major role in chromosome segregation errors during female meiosis. In mice, mutations in meiosis-specific cohesin genes cause meiotic disturbances and infertility. However, the more clinically relevant situation, heterozygosity for mutations in these genes, has not been evaluated. We report here evidence from the mouse that partial loss of gene function for either Smc1b or Rec8 causes perturbations in the formation of the synaptonemal complex (SC) and affects both synapsis and recombination between homologs during meiotic prophase. Importantly, these defects increase the frequency of chromosomally abnormal eggs in the adult female. These findings have important implications for humans: they suggest that women who carry mutations or variants that affect cohesin function have an elevated risk of aneuploid pregnancies and may even be at increased risk of transmitting structural chromosome abnormalities.

  6. Neocentromere-mediated Chromosome Movement in Maize

    PubMed Central

    Yu, Hong-Guo; Hiatt, Evelyn N.; Chan, Annette; Sweeney, Mary; Dawe, R. Kelly

    1997-01-01

    Neocentromere activity is a classic example of nonkinetochore chromosome movement. In maize, neocentromeres are induced by a gene or genes on Abnormal chromosome 10 (Ab10) which causes heterochromatic knobs to move poleward at meiotic anaphase. Here we describe experiments that test how neocentromere activity affects the function of linked centromere/kinetochores (kinetochores) and whether neocentromeres and kinetochores are mobilized on the spindle by the same mechanism. Using a newly developed system for observing meiotic chromosome congression and segregation in living maize cells, we show that neocentromeres are active from prometaphase through anaphase. During mid-anaphase, normal chromosomes move on the spindle at an average rate of 0.79 μm/min. The presence of Ab10 does not affect the rate of normal chromosome movement but propels neocentromeres poleward at rates as high as 1.4 μm/min. Kinetochore-mediated chromosome movement is only marginally affected by the activity of a linked neocentromere. Combined in situ hybridization/immunocytochemistry is used to demonstrate that unlike kinetochores, neocentromeres associate laterally with microtubules and that neocentromere movement is correlated with knob size. These data suggest that microtubule depolymerization is not required for neocentromere motility. We argue that neocentromeres are mobilized on microtubules by the activity of minus end–directed motor proteins that interact either directly or indirectly with knob DNA sequences. PMID:9362502

  7. Spatial ordering of chromosomes enhances the fidelity of chromosome partitioning in cyanobacteria.

    PubMed

    Jain, Isha H; Vijayan, Vikram; O'Shea, Erin K

    2012-08-21

    Many cyanobacteria have been shown to harbor multiple chromosome copies per cell, yet little is known about the organization, replication, and segregation of these chromosomes. Here, we visualize individual chromosomes in the cyanobacterium Synechococcus elongatus via time-lapse fluorescence microscopy. We find that chromosomes are equally spaced along the long axis of the cell and are interspersed with another regularly spaced subcellular compartment, the carboxysome. This remarkable organization of the cytoplasm along with accurate midcell septum placement allows for near-optimal segregation of chromosomes to daughter cells. Disruption of either chromosome ordering or midcell septum placement significantly increases the chromosome partitioning error. We find that chromosome replication is both asynchronous and independent of the position of the chromosome in the cell and that spatial organization is preserved after replication. Our findings on chromosome organization, replication, and segregation in S. elongatus provide a basis for understanding chromosome dynamics in bacteria with multiple chromosomes.

  8. The G⁵¹⁶T CYP2B6 germline polymorphism affects the risk of acute myeloid leukemia and is associated with specific chromosomal abnormalities.

    PubMed

    Daraki, Aggeliki; Zachaki, Sophia; Koromila, Theodora; Diamantopoulou, Paraskevi; Pantelias, Gabriel E; Sambani, Constantina; Aleporou, Vasiliki; Kollia, Panagoula; Manola, Kalliopi N

    2014-01-01

    The etiology of acute myeloid leukemia (AML) underlies the influence of genetic variants in candidate genes. The CYP2B6 enzyme detoxifies many genotoxic xenobiotics, protecting cells from oxidative damage. The CYP2B6 gene is subjected to a single-nucleotide polymorphism (G⁵¹⁶T) with heterozygotes (GT) and homozygotes (TT) presenting decreased enzymatic activity. This case-control study aimed to investigate the association of CYP2B6 G⁵¹⁶T polymorphism with the susceptibility of AML and its cytogenetic and clinical characteristics. Genotyping was performed on 619 AML patients and 430 healthy individuals using RCR-RFLP and a novel LightSNip assay. The major finding was a statistically higher frequency of the variant genotypes (GT and TT) in patients compared to the controls (GT:38.8% vs 29.8% and TT:9.3% vs 5.3% respectively) (p<0.001). More specifically, a significantly higher frequency of GT+TT genotypes in de novo AML patients (46.6%) and an immensely high frequency of TT in secondary AML (s-AML) (20.5%) were observed. The statistical analysis showed that the variant T allele was approximately 1.5-fold and 2.4-fold higher in de novo and s-AML respectively than controls. Concerning FAB subtypes, the T allele presented an almost 2-fold increased in AML-M2. Interestingly, a higher incidence of the TT genotype was observed in patients with abnormal karyotypes. In particular, positive correlations of the mutant allele were found in patients carrying specific chromosomal aberrations [-7/del(7q), -5/del(5q), +8, +21 or t(8;21)], complex or monosomal karyotypes. Finally, a strikingly higher frequency of TT genotype was also observed in patients stratified to the poor risk group. In conclusion, our results provide evidence for the involvement of the CYP2B6 polymorphism in AML susceptibility and suggest a possible role of the CYP2B6 genetic background on the development of specific chromosomal aberrations.

  9. The G516T CYP2B6 Germline Polymorphism Affects the Risk of Acute Myeloid Leukemia and Is Associated with Specific Chromosomal Abnormalities

    PubMed Central

    Daraki, Aggeliki; Zachaki, Sophia; Koromila, Theodora; Diamantopoulou, Paraskevi; Pantelias, Gabriel E.; Sambani, Constantina; Aleporou, Vasiliki; Kollia, Panagoula; Manola, Kalliopi N.

    2014-01-01

    The etiology of acute myeloid leukemia (AML) underlies the influence of genetic variants in candidate genes. The CYP2B6 enzyme detoxifies many genotoxic xenobiotics, protecting cells from oxidative damage. The CYP2B6 gene is subjected to a single-nucleotide polymorphism (G516T) with heterozygotes (GT) and homozygotes (TT) presenting decreased enzymatic activity. This case-control study aimed to investigate the association of CYP2B6 G516T polymorphism with the susceptibility of AML and its cytogenetic and clinical characteristics. Genotyping was performed on 619 AML patients and 430 healthy individuals using RCR-RFLP and a novel LightSNip assay. The major finding was a statistically higher frequency of the variant genotypes (GT and TT) in patients compared to the controls (GT:38.8% vs 29.8% and TT:9.3% vs 5.3% respectively) (p<0.001). More specifically, a significantly higher frequency of GT+TT genotypes in de novo AML patients (46.6%) and an immensely high frequency of TT in secondary AML (s-AML) (20.5%) were observed. The statistical analysis showed that the variant T allele was approximately 1.5-fold and 2.4-fold higher in de novo and s-AML respectively than controls. Concerning FAB subtypes, the T allele presented an almost 2-fold increased in AML-M2. Interestingly, a higher incidence of the TT genotype was observed in patients with abnormal karyotypes. In particular, positive correlations of the mutant allele were found in patients carrying specific chromosomal aberrations [-7/del(7q), -5/del(5q), +8, +21 or t(8;21)], complex or monosomal karyotypes. Finally, a strikingly higher frequency of TT genotype was also observed in patients stratified to the poor risk group. In conclusion, our results provide evidence for the involvement of the CYP2B6 polymorphism in AML susceptibility and suggest a possible role of the CYP2B6 genetic background on the development of specific chromosomal aberrations. PMID:24586425

  10. Zygotes segregate entire parental genomes in distinct blastomere lineages causing cleavage-stage chimerism and mixoploidy

    PubMed Central

    Destouni, Aspasia; Zamani Esteki, Masoud; Catteeuw, Maaike; Tšuiko, Olga; Dimitriadou, Eftychia; Smits, Katrien; Kurg, Ants; Salumets, Andres; Van Soom, Ann; Voet, Thierry; Vermeesch, Joris R.

    2016-01-01

    Dramatic genome dynamics, such as chromosome instability, contribute to the remarkable genomic heterogeneity among the blastomeres comprising a single embryo during human preimplantation development. This heterogeneity, when compatible with life, manifests as constitutional mosaicism, chimerism, and mixoploidy in live-born individuals. Chimerism and mixoploidy are defined by the presence of cell lineages with different parental genomes or different ploidy states in a single individual, respectively. Our knowledge of their mechanistic origin results from indirect observations, often when the cell lineages have been subject to rigorous selective pressure during development. Here, we applied haplarithmisis to infer the haplotypes and the copy number of parental genomes in 116 single blastomeres comprising entire preimplantation bovine embryos (n = 23) following in vitro fertilization. We not only demonstrate that chromosome instability is conserved between bovine and human cleavage embryos, but we also discovered that zygotes can spontaneously segregate entire parental genomes into different cell lineages during the first post-zygotic cleavage division. Parental genome segregation was not exclusively triggered by abnormal fertilizations leading to triploid zygotes, but also normally fertilized zygotes can spontaneously segregate entire parental genomes into different cell lineages during cleavage of the zygote. We coin the term “heterogoneic division” to indicate the events leading to noncanonical zygotic cytokinesis, segregating the parental genomes into distinct cell lineages. Persistence of those cell lines during development is a likely cause of chimerism and mixoploidy in mammals. PMID:27197242

  11. From equator to pole: splitting chromosomes in mitosis and meiosis.

    PubMed

    Duro, Eris; Marston, Adèle L

    2015-01-15

    During eukaryotic cell division, chromosomes must be precisely partitioned to daughter cells. This relies on a mechanism to move chromosomes in defined directions within the parental cell. While sister chromatids are segregated from one another in mitosis and meiosis II, specific adaptations enable the segregation of homologous chromosomes during meiosis I to reduce ploidy for gamete production. Many of the factors that drive these directed chromosome movements are known, and their molecular mechanism has started to be uncovered. Here we review the mechanisms of eukaryotic chromosome segregation, with a particular emphasis on the modifications that ensure the segregation of homologous chromosomes during meiosis I.

  12. Kif2a depletion generates chromosome segregation and pole coalescence defects in animal caps and inhibits gastrulation of the Xenopus embryo

    PubMed Central

    Eagleson, Gerald; Pfister, Katherine; Knowlton, Anne L.; Skoglund, Paul; Keller, Ray; Stukenberg, P. Todd

    2015-01-01

    Kif2a is a member of the kinesin-13 microtubule depolymerases, which tightly regulate microtubule dynamics for many cellular processes. We characterized Kif2a depletion in Xenopus animal caps and embryos. Kif2a depletion generates defects in blastopore closure. These defects are rescued by removing the animal cap, suggesting that Kif2a-depleted animal caps are not compliant enough to allow gastrulation movements. Gastrulation defects are not rescued by a Kif2a mutated in an Aurora kinase phosphorylation site, suggesting that the phenotypes are caused by problems in mitosis. During animal cap mitoses, Kif2a localizes to the spindle poles and centromeres. Depletion of Kif2a generated multipolar spindles in stage 12 embryos. Kif2a-depleted animal caps have anaphase lagging chromosomes in stage 9 and 10 embryos and subsequent cytokinesis failure. Later divisions have greater than two centrosomes, generating extra spindle poles. Kif2a-depleted embryos are also defective at coalescing extra spindle poles into a bipolar spindle. The gastrulation and mitotic phenotypes can be rescued by either human Kif2a or Kif2b, which suggests that the two homologues redundantly regulate mitosis in mammals. These studies demonstrate that defects in mitosis can inhibit large-scale developmental movements in vertebrate tissues. PMID:25568341

  13. Chromosomal Disorders and Autism.

    ERIC Educational Resources Information Center

    Gillberg, Christopher

    1998-01-01

    This paper reviews the literature on chromosomal aberrations in autism, especially possible gene markers. It notes that Chromosome 15 and numerical and structural abnormalities of the sex chromosomes have been most frequently reported as related to the genesis of autism. (Author/DB)

  14. Meiotic drive of chromosomal knobs reshaped the maize genome.

    PubMed Central

    Buckler, E S; Phelps-Durr, T L; Buckler, C S; Dawe, R K; Doebley, J F; Holtsford, T P

    1999-01-01

    Meiotic drive is the subversion of meiosis so that particular genes are preferentially transmitted to the progeny. Meiotic drive generally causes the preferential segregation of small regions of the genome; however, in maize we propose that meiotic drive is responsible for the evolution of large repetitive DNA arrays on all chromosomes. A maize meiotic drive locus found on an uncommon form of chromosome 10 [abnormal 10 (Ab10)] may be largely responsible for the evolution of heterochromatic chromosomal knobs, which can confer meiotic drive potential to every maize chromosome. Simulations were used to illustrate the dynamics of this meiotic drive model and suggest knobs might be deleterious in the absence of Ab10. Chromosomal knob data from maize's wild relatives (Zea mays ssp. parviglumis and mexicana) and phylogenetic comparisons demonstrated that the evolution of knob size, frequency, and chromosomal position agreed with the meiotic drive hypothesis. Knob chromosomal position was incompatible with the hypothesis that knob repetitive DNA is neutral or slightly deleterious to the genome. We also show that environmental factors and transposition may play a role in the evolution of knobs. Because knobs occur at multiple locations on all maize chromosomes, the combined effects of meiotic drive and genetic linkage may have reshaped genetic diversity throughout the maize genome in response to the presence of Ab10. Meiotic drive may be a major force of genome evolution, allowing revolutionary changes in genome structure and diversity over short evolutionary periods. PMID:10471723

  15. Lack of segregation of a Marfan-like phenotype associating marfanoie habitus and mitral valve disease with fibrillin gene on chromosome 15

    SciTech Connect

    VanMaldergen, L.; Hilbert, P.; Gillerot, Y.

    1994-09-01

    Apart from typical Marfan syndrome (MS), several Marfan-like conditions are known. One of those is the MASS syndrome (Mitral involvement, Aortic dilatation, Skin and Skeletal abnormalities) defined by Pyeritz et al. Among these, a dominantly inherited mitral valve prolapse with marfanoid habitus have also been reported. Until now, except for a Marfan-like condition described by Boileau et al., all Marfan families are linked to fib 15. A large Belgian pedigree with 25 affected patients among 62 at risk subjects spanning four generations is described. A syndrome including marfanoid skeletal dysplasia (tall stature, dolichostenomelia, arachnodactyly, pectus carinatum joint dislocation), prolapse and/or myxomatous degeneration of the mitral valve, but without aortic dilatation of eye involvement was observed. Although the phenotype fulfills Berlin diagnostic criteria for MS, it closely resembles MASS syndrome. Preliminary linkage results show discordance aggregation insertion in the fib 15 gene, as evaluated by intragenic microsatellite fib 15. Since Dietz et al. described a similar patient with fib 15 gene, we suggest that this variant of Marfan syndrome is genetically heterogeneous and caused by mutations, some of which are allelic to classical Marfan syndrome plus a subtype, some of which are not. Linkage studies are under way to further characterize the gene involved in the present family.

  16. Meiotic behavior and chromosome number of Urochloa adspersa (Trin.) R. D. Webster from the Brazilian Chaco.

    PubMed

    Felismino, M F; Maior, R L S; Damasceno, G A; Pott, A; Pagliarini, M S

    2015-07-06

    This is the first report of meiotic division in Uro-chloa adspersa (Trin.) collected from the Brazilian Chaco. Meiotic analyses were performed on three specimens of U. adspersa named G10, G15, and G16. Inflorescences were collected and fixed in a mixture of ethanol and acetic acid (3:1, v/v) for 24 h and then stored in 70% alcohol. Diakinesis revealed different chromosome numbers and ploidy levels. All three plants were polyploids: G10 and G15 exhibited 2n = 6x = 54 chromosomes (arranged in 27 bivalents), while G16 exhibited 2n = 4x = 36 chromosomes (18 bivalents). Meiotic behavior was mainly normal in the hexaploid G15 and the tetraploid G16 (5.3 and 6.2% of the cells were abnormal, respective-ly), revealing only a few meiotic abnormalities that are common to polyploids, i.e., those related to irregular chromosome segregation. G10 exhibited other meiotic abnormalities during meiosis II, such as chromosome stickiness, irregular spindle orientation, and irregular cytokinesis, which led to the formation of a few triads, resulting in 16.9% of the cells being abnormal. The origin of these abnormalities is discussed, and we suggest that the genes that control meiotic steps may be present in the Urochloa gene pool.

  17. B Chromosomes - A Matter of Chromosome Drive.

    PubMed

    Houben, Andreas

    2017-01-01

    B chromosomes are supernumerary chromosomes which are often preferentially inherited, deviating from usual Mendelian segregation. The balance between the so-called chromosome drive and the negative effects that the presence of Bs applies on the fitness of their host determines the frequency of Bs in a particular population. Drive is the key for understanding most B chromosomes. Drive occurs in many ways at pre-meiotic, meiotic or post-meiotic divisions, but the molecular mechanism remains unclear. The cellular mechanism of drive is reviewed based on the findings obtained for the B chromosomes of rye, maize and other species. How novel analytical tools will expand our ability to uncover the biology of B chromosome drive is discussed.

  18. A prenatally ascertained, maternally inherited 14.8 Mb duplication of chromosomal bands Xq13.2-q21.31 associated with multiple congenital abnormalities in a male fetus.

    PubMed

    Sismani, C; Donoghue, J; Alexandrou, A; Karkaletsi, M; Christopoulou, S; Konstantinidou, A E; Livanos, P; Patsalis, P C; Velissariou, V

    2013-11-01

    Duplications of the X chromosome are rare cytogenetic findings, and have been associated with an abnormal phenotype in the male offspring of apparently normal or near normal female carriers. We report on the prenatal diagnosis of a duplication on the long arm of chromosome X from chromosomal band Xq13.2 to q21.31 in a male fetus with increased nuchal translucency in the first trimester and polyhydramnios at 22 weeks of gestation. Amniocentesis was undertaken and cytogenetic analysis revealed additional chromosomal material in the long arm of chromosome X at position Xq13. Analysis with high resolution array CGH revealed the additional material is in fact a duplication of the region Xq13.2-q21.13. The duplication is 14.8 Mb in size and includes fourteen genes: SLC16A2, KIAA2022, ABCB7, ZDHHC15, ATRX, MAGT1, ATP7A, PGK1, TBX22, BRWD3, POU3F4, ZNF711, POF1B and CHM. Analysis of the parents revealed the mother to be a carrier of the same duplication. After elected termination of the pregnancy at 28 weeks a detailed autopsy of the fetus allowed for genotype-phenotype correlations.

  19. Childhood-onset schizophrenia case with 2.2 Mb deletion at chromosome 3p12.2–p12.1 and two large chromosomal abnormalities at 16q22.3–q24.3 and Xq23–q28

    PubMed Central

    Rudd, Danielle; Axelsen, Michael; Epping, Eric A; Andreasen, Nancy; Wassink, Thomas

    2015-01-01

    Key Clinical Message Childhood-onset schizophrenia is rare, comprising 1% of known schizophrenia cases. Here, we report a patient with childhood-onset schizophrenia who has three large chromosomal abnormalities: an inherited 2.2 Mb deletion of chromosome 3p12.2–p12.1, a de novo 16.7 Mb duplication of 16q22.3–24.3, and a de novo 43 Mb deletion of Xq23–q28. PMID:25914809

  20. Paternal adjacent I segregation of an insertional translocation results in partial 4q monosomy and 4q trisomy in two siblings

    SciTech Connect

    Hegman, K.; Spikes, A.S.; Orr-Urteger, A.

    1994-09-01

    A genetic evaluation was requested for a 6 week old infant with multiple congenital malformations including mild craniofacial anomalies, truncal hypotonia, hypospadias and a VSD. Blood obtained for chromosome analysis revealed an abnormal chromosome 4. Paternal chromosome analysis showed a 46,XY,inv ins(3;4)(p21.32;q25q21.2),inv(4)(p15.3q21.3) karyotype. Therefore, the proband`s chromosome 4 was the unbalanced product of this insertional translocation from the father resulting in partial monosomy 4q. Additionally, the derivative 4 had a pericentric inversion which was also seen in the father`s chromosome 4. During genetic counseling, the proband`s 2 year-old brother was evaluated. Although he was not felt to be dysmorphic, he was described as having impulsive behavior. Chromosome analysis on this child revealed 46,XY,der(3)inv ins(3;4)(p21.32;q25q21.2)pat. This karyotype results in partial trisomy 4q. FISH using two-color {open_quotes}painting{close_quotes} probes for chromosomes 3 and 4 confirmed the G-banded interpretation in this family. The segregation seen in this family was due to adjacent I segregation with both reciprocal products observed in the two children. Few patients with partial 4q trisomy or partial 4q monosomy have been described in the literature. This family revealed both possible unbalanced products from adjacent I segregation with partial 4q monosomy showing multiple congenital anomalies and partial 4q trisomy showing very few phenotypic abnormalities.

  1. Micromechanics of human mitotic chromosomes

    NASA Astrophysics Data System (ADS)

    Sun, Mingxuan; Kawamura, Ryo; Marko, John F.

    2011-02-01

    Eukaryote cells dramatically reorganize their long chromosomal DNAs to facilitate their physical segregation during mitosis. The internal organization of folded mitotic chromosomes remains a basic mystery of cell biology; its understanding would likely shed light on how chromosomes are separated from one another as well as into chromosome structure between cell divisions. We report biophysical experiments on single mitotic chromosomes from human cells, where we combine micromanipulation, nano-Newton-scale force measurement and biochemical treatments to study chromosome connectivity and topology. Results are in accord with previous experiments on amphibian chromosomes and support the 'chromatin network' model of mitotic chromosome structure. Prospects for studies of chromosome-organizing proteins using siRNA expression knockdowns, as well as for differential studies of chromosomes with and without mutations associated with genetic diseases, are also discussed.

  2. Fluorescent in situ hybridization (FISH) assessment of chromosome copy number in sperm

    SciTech Connect

    Sheu, M.; Sigman, M.; Mark, H.F.L.

    1994-09-01

    Approximately 15% of all recognized pregnancies end in spontaneous abortions. The overall frequency of chromosome abnormalities in spontaneous abortions is approximately 50%. Thus aneuploidy is a significant cause of fetal wastage. In addition, structural and numerical abnormalities of chromosomes can also lead to birth defects, developmental delay, mental retardation and infertility. Conventional cytogenetic analysis via GTG- and other banding techniques is a powerful tool in the elucidation of the nature of chromosomal abnormalities. Fluorescent in situ hybridization (FISH) enables detection of numerical chromosomal abnormalities, especially trisomies, in intact cells. Using FISH and commercially available biotin-labeled probes, we have initiated a prospective study to assess specific chromosome copy number of preparations of unstained smears from men referred for a male infertility evaluation as well as smears from normal control males chosen randomly from the sample of sperm donors. A total of approximately 19,000 sperm nuclei have been examined thus far. Of those suitable for analysis, 7382 (38.75%) were normal possessing one copy of chromosome 8, 155 (0.81%) were disomic, and 15 (0.079%) had more than two copies of chromosome 8. Comparisons with data available in the literature will be discussed. Work is ongoing to increase the efficiency of hybridization using both reported and previously untried pretreatment and fixation protocols. We have also initiated studies using multicolor FISH with various chromosome enumeration probes. The assay described here is a potentially powerful tool for detecting rare events such as spontaneous germ cell aneuploidy, aneuploidy detected in semen from men with carcinoma in situ of the testis and aneuploidy induced by potential environmental genotoxicants. It can also be utilized for segregation analysis and for correlating chromosome copy number with germ cell morphology.

  3. Biased DNA segregation in Drosophila male germline stem cells.

    PubMed

    Yamashita, Yukiko M

    2013-01-01

    The immortal strand hypothesis, which emerged four decades ago, proposes that certain cells retain a template copy of chromosomal DNA to protect against replication-induced mutations. As the interest in stem cells rose in recent years, researchers speculated that stem cells, which must maintain proliferative capacity throughout the life of the organism, may be the population that most needs the strong protection afforded by immortal strand segregation. Alternative hypotheses have also been proposed to explain observed non-random sister chromatid segregation. We recently found that Drosophila male germline stem cells segregate sister chromatids non-randomly, but such bias was limited to the sex chromosomes. Interestingly, the biased segregation does not lead to immortal strand segregation. We will discuss the implications of this observation and molecular mechanisms, which might be applicable to non-random sister chromatid segregation in other systems as well.

  4. Overcoming Triple Segregation

    ERIC Educational Resources Information Center

    Gandara, Patricia

    2010-01-01

    Latinos are, after whites, the most segregated student group in the United States, and their segregation is closely tied to poor academic outcomes. Latinos experience a triple segregation: by race/ethnicity, poverty, and language. Racial segregation perpetuates negative stereotypes, reduces the likelihood of a strong teaching staff, and is often…

  5. Double partial trisomy of 6p23-pter and 9pter-q21.2 in a neonate resulting from 4:2 meiotic segregation of a maternal complex t(6;7;9)(p23;p15;q21.2) translocation.

    PubMed

    Cetin, Z; Mihci, E; Keser, I; Karaali, K; Berker, S; Luleci, G

    2012-01-01

    We report, a newborn presenting multiple congenital abnormalities with karyotype; 47,XY,der(7)t(6;7)(pter-p23::p15-->qter),+der(9)t(7;9)(pter-->p15::q21.2--> pter)t(6;7;9)(p23;p15;q21.2)mat[20]. The mother and her phenotypically normal daughter were carriers of a complex chromosomal rearrangement with karyotypes; 46,XX,t(6;7;9)(p23;p15;q21.2)[20]. Paternal chromosomes were normal. In our case the extra derivative chromosome was the result of a 4:2 segregation of the chromosomes involved in translocation during oogenesis. Double partial trisomy in newborns resulting from 4:2 segregation is a rare event, and double partial trisomies of the 6p23-pter and trisomy 9pter-q22 regions have not reported to date.

  6. Chromosome segregation: Samurai separation of Siamese sisters.

    PubMed

    Glotzer, M

    1999-07-15

    How do cells ensure that sister chromatids are precisely partitioned in mitosis? New studies on budding yeast have revealed that sister chromatid separation at anaphase requires endoproteolytic cleavage of a protein that maintains the association between sister chromatids.

  7. Structural rearrangements of chromosome 15 satellites resulting in Prader-Willi syndrome suggest a complex mechanism for uniparental disomy

    SciTech Connect

    Toth-Fijel, S.; Gunter, K.; Olson, S.

    1994-09-01

    We report two cases of PWS in which there was abnormal meiosis I segregation of chromosome 15 following a rare translocation event between the heteromorphic satellite regions of chromosomes 14 and 15 and an apparent meiotic recombination in the unstable region of 15q11.2. PWS and normal appearing chromosomes in case one prompted a chromosome 15 origin analysis. PCR analysis indicated maternal isodisomy for the long arm of chromosome. However, only one chromosome 15 had short arm heteromorphisms consistent with either paternal or maternal inheritance. VNTR DNA analysis and heteromorphism data suggest that a maternal de novo translocation between chromosome 14 and 15 occurred prior to meiosis I. This was followed by recombination between D15Z1 and D15S11 and subsequent meiosis I nondisjunction. Proband and maternal karyotype display a distamycin A-DAPI positive region on the chromosome 14 homolog involved in the translocation. Fluorescent in situ hybridization (FISH) analyses of ONCOR probes D15S11, SNRPN, D15S11 and GABRB 3 were normal, consistent with the molecular data. Case two received a Robertsonian translocation t(14;15)(p13;p13) of maternal origin. Chromosome analysis revealed a meiosis I error producing UPD. FISH analysis of the proband and parents showed normal hybridization of ONCOR probes D15Z1, D15S11, SNRPN, D15S10 and GABRB3. In both cases the PWS probands received a structurally altered chromosome 15 that had rearranged with chromosome 14 prior to meiosis. If proper meiotic segregation is dependent on the resolution of chiasmata and/or the binding to chromosome-specific spindle fibers, then it may be possible that rearrangements of pericentric or unstable regions of the genome disrupt normal disjunction and lead to uniparental disomy.

  8. An interstitial deletion of 7.1Mb in chromosome band 6p22.3 associated with developmental delay and dysmorphic features including heart defects, short neck, and eye abnormalities.

    PubMed

    Bremer, Anna; Schoumans, Jacqueline; Nordenskjöld, Magnus; Anderlid, Britt-Marie; Giacobini, Maibritt

    2009-01-01

    Seven cases with an interstitial deletion of the short arm of chromosome 6 involving the 6p22 region have previously been reported. The clinical phenotype of these cases includes developmental delay, brain-, heart-, and kidney defects, eye abnormalities, short neck, craniofacial malformations, hypotonia, as well as clinodactyly or syndactyly. Here, we report a patient with a 7.1Mb interstitial deletion of chromosome band 6p22.3, detected by genome-wide screening array CGH. The patient is a 4-year-old girl with developmental delay and dysmorphic features including eye abnormalities, short neck, and a ventricular septum defect. The deleted region at 6p22.3 in our patient overlaps with six out of the seven previously reported cases with a 6p22-24 interstitial deletion. This enabled us to further narrow down the critical region for the 6p22 deletion phenotype to 2.2Mb. Twelve genes are mapped to the overlapping deleted region, among them the gene encoding the ataxin-1 protein, the ATXN1 gene. Mice with homozygous deletions in ATXN1 are phenotypically normal but show cognitive delay. Haploinsufficiency of ATXN1 may therefore contribute to the learning difficulties observed in the patients harboring a 6p22 deletion.

  9. Cytogenetic Analysis of Segregation Distortion in Drosophila Melanogaster: The Cytological Organization of the Responder (Rsp) Locus

    PubMed Central

    Pimpinelli, S.; Dimitri, P.

    1989-01-01

    The segregation distortion phenomenon occurs in Drosophila melanogaster males carrying an SD second chromosome and an SD(+) homolog. In such males the SD chromosome is transmitted to the progeny more frequently than the expected 50% because of an abnormal differentiation of the SD(+)-bearing sperms. Three major loci are involved in this phenomenon: SD and Rsp, associated with the SD and SD(+) chromosome, respectively, and E(SD). In the present work we performed a cytogenetic analysis of the Rsp locus which was known to map to the centromeric heterochromatin of the second chromosome. Hoechst- and N-banding techniques were used to characterize chromosomes carrying Responder insensitive (Rsp(i)), Responder sensitive (Rsp(s)) and Responder supersensitive (Rsp(ss)) alleles. Our results locate the Rsp locus to the h39 region of 2R heterochromatin. This region is a Hoechstbright, N-banding negative heterochromatic block adjacent to the centromere. Quantitative variations of the h39 region were observed. The degree of sensitivity to Sd was found to be directly correlated with the physical size of that region, demonstrating that the Rsp locus is composed of repeated DNA. PMID:2470640

  10. Depletion of topoisomerase IIalpha leads to shortening of the metaphase interkinetochore distance and abnormal persistence of PICH-coated anaphase threads.

    PubMed

    Spence, Jennifer M; Phua, Hui Hui; Mills, Walter; Carpenter, Adam J; Porter, Andrew C G; Farr, Christine J

    2007-11-15

    Topoisomerase II (topo II) is a major component of mitotic chromosomes, and its unique decatenating activity has been implicated in many aspects of chromosome dynamics, of which chromosome segregation is the most seriously affected by loss of topo II activity in living cells. There is considerable evidence that topo II plays a role at the centromere including: the centromere-specific accumulation of topo II protein; cytogenetic/molecular mapping of the catalytic activity of topo II to active centromeres; the influence of sumoylated topo II on sister centromere cohesion; and its involvement in the activation of a Mad2-dependent spindle checkpoint. By using a human cell line with a conditional-lethal mutation in the gene encoding DNA topoisomerase IIalpha, we find that depletion of topo IIalpha, while leading to a disorganised metaphase plate, does not have any overt effect on general assembly of kinetochores. Fluorescence in situ hybridisation suggested that centromeres segregate normally, most segregation errors being chromatin bridges involving longer chromosome arms. Strikingly, a linear human X centromere-based minichromosome also displayed a significantly increased rate of missegregation. This sensitivity to depletion of topo IIalpha might be linked to structural alterations within the centromere domain, as indicated by a significant shortening of the distance across metaphase sister centromeres and the abnormal persistence of PICH-coated connections between segregating chromatids.

  11. The analysis of mutant alleles of different strength reveals multiple functions of topoisomerase 2 in regulation of Drosophila chromosome structure.

    PubMed

    Mengoli, Valentina; Bucciarelli, Elisabetta; Lattao, Ramona; Piergentili, Roberto; Gatti, Maurizio; Bonaccorsi, Silvia

    2014-10-01

    Topoisomerase II is a major component of mitotic chromosomes but its role in the assembly and structural maintenance of chromosomes is rather controversial, as different chromosomal phenotypes have been observed in various organisms and in different studies on the same organism. In contrast to vertebrates that harbor two partially redundant Topo II isoforms, Drosophila and yeasts have a single Topo II enzyme. In addition, fly chromosomes, unlike those of yeast, are morphologically comparable to vertebrate chromosomes. Thus, Drosophila is a highly suitable system to address the role of Topo II in the assembly and structural maintenance of chromosomes. Here we show that modulation of Top2 function in living flies by means of mutant alleles of different strength and in vivo RNAi results in multiple cytological phenotypes. In weak Top2 mutants, meiotic chromosomes of males exhibit strong morphological abnormalities and dramatic segregation defects, while mitotic chromosomes of larval brain cells are not affected. In mutants of moderate strength, mitotic chromosome organization is normal, but anaphases display frequent chromatin bridges that result in chromosome breaks and rearrangements involving specific regions of the Y chromosome and 3L heterochromatin. Severe Top2 depletion resulted in many aneuploid and polyploid mitotic metaphases with poorly condensed heterochromatin and broken chromosomes. Finally, in the almost complete absence of Top2, mitosis in larval brains was virtually suppressed and in the rare mitotic figures observed chromosome morphology was disrupted. These results indicate that different residual levels of Top2 in mutant cells can result in different chromosomal phenotypes, and that the effect of a strong Top2 depletion can mask the effects of milder Top2 reductions. Thus, our results suggest that the previously observed discrepancies in the chromosomal phenotypes elicited by Topo II downregulation in vertebrates might depend on slight differences

  12. A prenatally ascertained de novo terminal deletion of chromosomal bands 1q43q44 associated with multiple congenital abnormalities in a female fetus.

    PubMed

    Sismani, Carolina; Christopoulou, Georgia; Alexandrou, Angelos; Evangelidou, Paola; Donoghue, Jacqueline; Konstantinidou, Anastasia E; Velissariou, Voula

    2015-01-01

    Terminal deletions in the long arm of chromosome 1 result in a postnatally recognizable disorder described as 1q43q44 deletion syndrome. The size of the deletions and the resulting phenotype varies among patients. However, some features are common among patients as the chromosomal regions included in the deletions. In the present case, ultrasonography at 22 weeks of gestation revealed choroid plexus cysts (CPCs) and a single umbilical artery (SUA) and therefore amniocentesis was performed. Chromosomal analysis revealed a possible terminal deletion in 1q and high resolution array CGH confirmed the terminal 1q43q44 deletion and estimated the size to be approximately 8 Mb. Following termination of pregnancy, performance of fetopsy allowed further clinical characterization. We report here a prenatal case with the smallest pure terminal 1q43q44 deletion, that has been molecularly and phenotypically characterized. In addition, to our knowledge this is the first prenatal case reported with 1q13q44 terminal deletion and Pierre-Robin sequence (PRS). Our findings combined with review data from the literature show the complexity of the genetic basis of the associated syndrome.

  13. Incidence, characterization and prognostic significance of chromosomal abnormalities in 640 patients with primary myelodysplastic syndromes. Grupo Cooperativo Español de Citogenética Hematológica.

    PubMed

    Solé, F; Espinet, B; Sanz, G F; Cervera, J; Calasanz, M J; Luño, E; Prieto, F; Granada, I; Hernández, J M; Cigudosa, J C; Diez, J L; Bureo, E; Marqués, M L; Arranz, E; Ríos, R; Martínez Climent, J A; Vallespí, T; Florensa, L; Woessner, S

    2000-02-01

    Recently, a consensus International Prognostic Scoring System (IPSS) for predicting outcome and planning therapy in the myelodysplastic syndromes (MDS) has been developed. However, the intermediate-risk cytogenetic subgroup defined by the IPSS includes a miscellaneous number of different single abnormalities for which real prognosis at present is uncertain. The main aims of this study were to evaluate in an independent series the prognostic value of the IPSS and to identify chromosomal abnormalities with a previously unrecognized good or poor prognosis in 640 patients. In univariate analyses, cases with single 1q abnormalities experienced poor survival, whereas those with trisomy 8 had a higher risk of acute leukaemic transformation than the remaining patients (P = 0.004 and P = 0.009 respectively). Patients with single del(12p) had a similar survival to patients with a normal karyotype and showed some trend for a better survival than other cases belonging to the IPSS intermediate-risk cytogenetic subgroup (P = 0.045). Multivariate analyses demonstrated that IPSS cytogenetic prognostic subgroup, proportion of bone marrow blasts and haemoglobin level were the main prognostic factors for survival, and the first two characteristics and platelet count were the best predictors of acute leukaemic transformation risk. A large international co-operative study should be carried out to clarify these findings.

  14. Extensive enteric nervous system abnormalities in mice transgenic for artificial chromosomes containing Parkinson disease-associated α-synuclein gene mutations precede central nervous system changes

    PubMed Central

    Kuo, Yien-Ming; Li, Zhishan; Jiao, Yun; Gaborit, Nathalie; Pani, Amar K.; Orrison, Bonnie M.; Bruneau, Benoit G.; Giasson, Benoit I.; Smeyne, Richard J.; Gershon, Michael D.; Nussbaum, Robert L.

    2010-01-01

    Parkinson disease (PD) is a neurodegenerative disease with motor as well as non-motor signs in the gastrointestinal tract that include dysphagia, gastroparesis, prolonged gastrointestinal transit time, constipation and difficulty with defecation. The gastrointestinal dysfunction commonly precedes the motor symptoms by decades. Most PD is sporadic and of unknown etiology, but a fraction is familial. Among familial forms of PD, a small fraction is caused by missense (A53T, A30P and E46K) and copy number mutations in SNCA which encodes α-synuclein, a primary protein constituent of Lewy bodies, the pathognomonic protein aggregates found in neurons in PD. We set out to develop transgenic mice expressing mutant α-synuclein (either A53T or A30P) from insertions of an entire human SNCA gene as models for the familial disease. Both the A53T and A30P lines show robust abnormalities in enteric nervous system (ENS) function and synuclein-immunoreactive aggregates in ENS ganglia by 3 months of age. The A53T line also has abnormal motor behavior but neither demonstrates cardiac autonomic abnormalities, olfactory dysfunction, dopaminergic neurotransmitter deficits, Lewy body inclusions or neurodegeneration. These animals recapitulate the early gastrointestinal abnormalities seen in human PD. The animals also serve as an in vivo system in which to investigate therapies for reversing the neurological dysfunction that target α-synuclein toxicity at its earliest stages. PMID:20106867

  15. Bacterial partition complexes segregate within the volume of the nucleoid

    PubMed Central

    Le Gall, Antoine; Cattoni, Diego I.; Guilhas, Baptiste; Mathieu-Demazière, Céline; Oudjedi, Laura; Fiche, Jean-Bernard; Rech, Jérôme; Abrahamsson, Sara; Murray, Heath; Bouet, Jean-Yves; Nollmann, Marcelo

    2016-01-01

    Precise and rapid DNA segregation is required for proper inheritance of genetic material. In most bacteria and archaea, this process is assured by a broadly conserved mitotic-like apparatus in which a NTPase (ParA) displaces the partition complex. Competing observations and models imply starkly different 3D localization patterns of the components of the partition machinery during segregation. Here we use super-resolution microscopies to localize in 3D each component of the segregation apparatus with respect to the bacterial chromosome. We show that Par proteins locate within the nucleoid volume and reveal that proper volumetric localization and segregation of partition complexes requires ATPase and DNA-binding activities of ParA. Finally, we find that the localization patterns of the different components of the partition system highly correlate with dense chromosomal regions. We propose a new mechanism in which the nucleoid provides a scaffold to guide the proper segregation of partition complexes. PMID:27377966

  16. Chromosome choreography: the meiotic ballet.

    PubMed

    Page, Scott L; Hawley, R Scott

    2003-08-08

    The separation of homologous chromosomes during meiosis in eukaryotes is the physical basis of Mendelian inheritance. The core of the meiotic process is a specialized nuclear division (meiosis I) in which homologs pair with each other, recombine, and then segregate from each other. The processes of chromosome alignment and pairing allow for homolog recognition. Reciprocal meiotic recombination ensures meiotic chromosome segregation by converting sister chromatid cohesion into mechanisms that hold homologous chromosomes together. Finally, the ability of sister kinetochores to orient to a single pole at metaphase I allows the separation of homologs to two different daughter cells. Failures to properly accomplish this elegant chromosome dance result in aneuploidy, a major cause of miscarriage and birth defects in human beings.

  17. Replication termination at eukaryotic chromosomes is mediated by Top2 and occurs at genomic loci containing pausing elements.

    PubMed

    Fachinetti, Daniele; Bermejo, Rodrigo; Cocito, Andrea; Minardi, Simone; Katou, Yuki; Kanoh, Yutaka; Shirahige, Katsuhiko; Azvolinsky, Anna; Zakian, Virginia A; Foiani, Marco

    2010-08-27

    Chromosome replication initiates at multiple replicons and terminates when forks converge. In E. coli, the Tus-TER complex mediates polar fork converging at the terminator region, and aberrant termination events challenge chromosome integrity and segregation. Since in eukaryotes, termination is less characterized, we used budding yeast to identify the factors assisting fork fusion at replicating chromosomes. Using genomic and mechanistic studies, we have identified and characterized 71 chromosomal termination regions (TERs). TERs contain fork pausing elements that influence fork progression and merging. The Rrm3 DNA helicase assists fork progression across TERs, counteracting the accumulation of X-shaped structures. The Top2 DNA topoisomerase associates at TERs in S phase, and G2/M facilitates fork fusion and prevents DNA breaks and genome rearrangements at TERs. We propose that in eukaryotes, replication fork barriers, Rrm3, and Top2 coordinate replication fork progression and fusion at TERs, thus counteracting abnormal genomic transitions.

  18. 8.6Mb interstitial deletion of chromosome 4q13.3q21.23 in a boy with cognitive impairment, short stature, hearing loss, skeletal abnormalities and facial dysmorphism.

    PubMed

    Lipska, B S; Brzeskwiniewicz, M; Wierzba, J; Morzuchi, L; Piotrowski, A; Limon, J

    2011-01-01

    We describe a 16-year-old boy with an 8.6Mb interstitial deletion of chromosome 4q 13.3q21.23 identified by oligo array-CGH. The patient presents psychomotor developmental delay, absent speech, marked progressive growth restriction, hearing loss, skeletal defects and minor facial anomalies. The patient required surgical treatment for cleft lip and palate, bilateral cryptorchidism and a neurofibroma. The analysis of the presented patient against previously published cases allowed us to expand further on the phenotype and to reevaluate previously proposed critical overlapping region at 4q21. As an addition to PRKG2 and RASGEFIB genes, we propose to include BMP3 gene as the principal determinant of the observed common phenotype. BMP3 haploinsufficiency appears to be causative of hearing loss and peculiar skeletal abnormalities including hemivertebrae and brachydactyly.

  19. Negative Regulation of p21Waf1/Cip1 by Human INO80 Chromatin Remodeling Complex Is Implicated in Cell Cycle Phase G2/M Arrest and Abnormal Chromosome Stability

    PubMed Central

    Cao, Lingling; Ding, Jian; Dong, Liguo; Zhao, Jiayao; Su, Jiaming; Wang, Lingyao; Sui, Yi; Zhao, Tong; Wang, Fei; Jin, Jingji; Cai, Yong

    2015-01-01

    We previously identified an ATP-dependent human Ino80 (INO80) chromatin remodeling complex which shares a set of core subunits with yeast Ino80 complex. Although research evidence has suggested that INO80 complex functions in gene transcription and genome stability, the precise mechanism remains unclear. Herein, based on gene expression profiles from the INO80 complex-knockdown in HeLa cells, we first demonstrate that INO80 complex negatively regulates the p21Waf1/Cip1 (p21) expression in a p53-mediated mechanism. In chromatin immunoprecipitation (ChIP) and a sequential ChIP (Re-ChIP) assays, we determined that the INO80 complex and p53 can bind to the same promoter region of p21 gene (-2.2kb and -1.0kb upstream of the p21 promoter region), and p53 is required for the recruitment of the INO80 complex to the p21 promoter. RNAi knockdown strategies of INO80 not only led to prolonged progression of cell cycle phase G2/M to G1, but it also resulted in abnormal chromosome stability. Interestingly, high expression of p21 was observed in most morphologically-changed cells, suggesting that negative regulation of p21 by INO80 complex might be implicated in maintaining the cell cycle process and chromosome stability. Together, our findings will provide a theoretical basis to further elucidate the cellular mechanisms of the INO80 complex. PMID:26340092

  20. Negative Regulation of p21Waf1/Cip1 by Human INO80 Chromatin Remodeling Complex Is Implicated in Cell Cycle Phase G2/M Arrest and Abnormal Chromosome Stability.

    PubMed

    Cao, Lingling; Ding, Jian; Dong, Liguo; Zhao, Jiayao; Su, Jiaming; Wang, Lingyao; Sui, Yi; Zhao, Tong; Wang, Fei; Jin, Jingji; Cai, Yong

    2015-01-01

    We previously identified an ATP-dependent human Ino80 (INO80) chromatin remodeling complex which shares a set of core subunits with yeast Ino80 complex. Although research evidence has suggested that INO80 complex functions in gene transcription and genome stability, the precise mechanism remains unclear. Herein, based on gene expression profiles from the INO80 complex-knockdown in HeLa cells, we first demonstrate that INO80 complex negatively regulates the p21Waf1/Cip1 (p21) expression in a p53-mediated mechanism. In chromatin immunoprecipitation (ChIP) and a sequential ChIP (Re-ChIP) assays, we determined that the INO80 complex and p53 can bind to the same promoter region of p21 gene (-2.2 kb and -1.0 kb upstream of the p21 promoter region), and p53 is required for the recruitment of the INO80 complex to the p21 promoter. RNAi knockdown strategies of INO80 not only led to prolonged progression of cell cycle phase G2/M to G1, but it also resulted in abnormal chromosome stability. Interestingly, high expression of p21 was observed in most morphologically-changed cells, suggesting that negative regulation of p21 by INO80 complex might be implicated in maintaining the cell cycle process and chromosome stability. Together, our findings will provide a theoretical basis to further elucidate the cellular mechanisms of the INO80 complex.

  1. Detection of amplified or deleted chromosomal regions

    DOEpatents

    Stokke, T.; Pinkel, D.; Gray, J.W.

    1995-12-05

    The present invention relates to in situ hybridization methods for the identification of new chromosomal abnormalities associated with various diseases. In particular, it provides probes which are specific to a region of amplification in chromosome 20. 3 figs.

  2. Detection of amplified or deleted chromosomal regions

    SciTech Connect

    Stokke, Trond; Pinkel, Daniel; Gray, Joe W.

    1995-01-01

    The present invention relates to in situ hybridization methods for the identification of new chromosomal abnormalities associated with various diseases. In particular, it provides probes which are specific to a region of amplification in chromosome 20.

  3. Detection Of Amplified Or Deleted Chromosomal Regions

    SciTech Connect

    Stokke, Trond , Pinkel, Daniel , Gray, Joe W.

    1997-05-27

    The present invention relates to in situ hybridization methods for the identification of new chromosomal abnormalities associated with various diseases. In particular, it provides probes which are specific to a region of amplification in chromosome 20.

  4. Single nucleotide polymorphism array-based karyotyping in acute myeloid leukemia or myelodysplastic syndrome with trisomy 8 as the sole chromosomal abnormality.

    PubMed

    Hahm, Chorong; Mun, Yeung Chul; Seong, Chu Myong; Han, Sung-Hee; Chung, Wha Soon; Huh, Jungwon

    2013-01-01

    The clinical heterogeneity of patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) with trisomy 8 as the sole abnormality may result from cytogenetically undetectable genetic changes. The purpose of this study was to identify hidden genomic aberrations not detected by metaphase cytogenetics (MC) using high-resolution single nucleotide polymorphism array (SNP-A)-based karyotyping in AML/MDS patients with a sole trisomy 8. The study group included 8 patients (3 AML and 5 MDS) and array-based karyotyping was done using whole-genome SNP-A (SNP 6.0 and SNP 2.7M). By SNP-A, additional genomic aberrations not detected by MC were identified in 2 patients: 1 AML patient exhibited a copy-neutral loss of heterozygosity (CN-LOH) of 3q21.1-q29 and 11q13.1-q25 and the other patient with MDS (refractory cytopenia with unilineage dysplasia) had CN-LOH of 2p25.3-p15. In particular, the latter patient progressed to AML 18 months after the diagnosis. In 3 patients, aberrations in addition to trisomy 8 were not identified by SNP-A. In the remaining 3 patients, SNP-A could not detect trisomy 8, while trisomy 8 was found in 25-67% of metaphase cells by MC. This study suggests that additional genomic aberrations may in fact be present even in cases of trisomy 8 as sole abnormality by MC, and SNP-A could be a useful karyotyping tool to identify hidden aberrations such as CN-LOH.

  5. Explaining gender segregation.

    PubMed

    Blackburn, Robert M; Browne, Jude; Brooks, Bradley; Jarman, Jennifer

    2002-12-01

    Occupational gender segregation--the tendency for women and men to work in different occupations--is an important feature of all societies, and particularly the wealthy industrialized ones. To understand this segregation, and to explain its significance, we need to distinguish between vertical segregation entailing inequality and horizontal segregation representing difference without inequality, with overall segregation being the resultant of these components. Three major theoretical approaches to understanding occupational gender segregation are examined: human capital/rational choice, patriarchy, and preference theories. All are found to be inadequate; they tend to confuse overall segregation with its vertical component, and each entails a number of other faults. It is generally assumed or implied that greater empowerment of women would reduce gender segregation. This is the reverse of what actually happens; in countries where the degree of women's empowerment is greater, the level of gender segregation is also greater. An alternative theoretical approach based on processes of social reproduction is shown to be more useful.

  6. AML with gain of chromosome 8 as the sole chromosomal abnormality (+8sole) is associated with a specific molecular mutation pattern including ASXL1 mutations in 46.8% of the patients.

    PubMed

    Alpermann, Tamara; Haferlach, Claudia; Eder, Christiane; Nadarajah, Niroshan; Meggendorfer, Manja; Kern, Wolfgang; Haferlach, Torsten; Schnittger, Susanne

    2015-03-01

    Trisomy 8 is the most frequent cytogenetically gained aberration in AML. We compared 79 adult de novo AML with trisomy 8 as the sole cytogenetic abnormality (+8sole) to 511 normal karyotype AML patients (NK). +8sole patients were older (p=0.013), presented lower WBC counts (p=0.010), harbored more often ASXL1 mutations (p<0.001) and RUNX1 mutations (p=0.009), but less frequent FLT3-ITD (p=0.038), NPM1 mutations (p<0.001) and double-mutated CEBPA (p=0.038) than NK patients. No prognostic difference was found between +8sole and NK. With respect to genetic stability we found +8sole was instable, and molecular markers were either stable or gained in number and diversity.

  7. Autosomal dominant postaxial polydactyly, nail dystrophy, and dental abnormalities map to chromosome 4p16, in the region containing the Ellis-van Creveld syndrome locus.

    PubMed Central

    Howard, T D; Guttmacher, A E; McKinnon, W; Sharma, M; McKusick, V A; Jabs, E W

    1997-01-01

    We have studied a four-generation family with features of Weyers acrofacial dysostosis, in which the proband has a more severe phenotype, resembling Ellis-van Creveld syndrome. Weyers acrofacial dysostosis is an autosomal dominant condition with dental anomalies, nail dystrophy, postaxial polydactyly, and mild short stature. Ellis-van Creveld syndrome is a similar condition, with autosomal recessive inheritance and the additional features of disproportionate dwarfism, thoracic dysplasia, and congenital heart disease. Linkage and haplotype analysis determined that the disease locus in this pedigree resides on chromosome 4p16, distal to the genetic marker D4S3007 and within a 17-cM region flanking the genetic locus D4S2366. This region includes the Ellis-van Creveld syndrome locus, which previously was reported to map within a 3-cM region between genetic markers D4S2957 and D4S827. Either the genes for the condition in our family and for Ellis-van Creveld syndrome are near one another or these two conditions are allelic with mutations in the same gene. These data also raise the possibility that Weyers acrofacial dysostosis is the heterozygous expression of a mutation that, in homozygous form, causes the autosomal recessive disorder Ellis-van Creveld syndrome. Images Figure 1 PMID:9399901

  8. Maternal characteristics of a cohort of preterm infants with a birth weight ≤750 g without major structural anomalies and chromosomal abnormalities.

    PubMed

    Claas, Marieke J; de Vries, Linda S; Bruinse, Hein W

    2011-05-01

    Our objectives were to describe the obstetric complications of women who delivered an extremely low-birth-weight infant by comparing two consecutive 5-year periods and infants appropriate for gestational age (AGA) versus infants small for gestational age (SGA). This descriptive study included women ( N = 261) who delivered an infant ≤750 g (major structural and chromosomal anomalies excluded) between 1996 and 2000 (cohort I, N = 145) and 2001 to 2005 (cohort II, N = 116) in the University Hospital Utrecht, the Netherlands. Of these, 84.3% of the multigravidas ( N = 121) had a complicated obstetric history: 46.3% miscarriage(s), 22.3% preterm deliveries, and 16.5% hypertensive disorders. In the index pregnancies ( N = 261), the most prevalent complications were hypertensive disorders (52.1%, P = 0.002; more in cohort II) and SGA ( P = 0.007), fetal distress (39.5%), and intrauterine growth restriction (32.6%) resulting in a caesarean section in 47.9% and a spontaneous vaginal delivery in 19.2%. Intrauterine deaths occurred in 35.2%, merely due to placental insufficiency (59.8%) and termination of pregnancy because of deteriorating hypertensive disorders (23.9%). A high percentage of parous mothers had a seriously complicated obstetric history. The index pregnancy was largely complicated by hypertensive disorders. The majority of infants with a birth weight ≤750 g were growth-restricted due to placental insufficiency. Follow-up is extremely important to evaluate neonatal morbidity and neurodevelopmental outcome.

  9. Polymer segregation under confinement: Influences of macromolecular crowding and the interaction between the polymer and crowders

    NASA Astrophysics Data System (ADS)

    Chen, Yuhao; Yu, Wancheng; Wang, Jiajun; Luo, Kaifu

    2015-10-01

    Entropy driven polymer segregation in confinements as a model for chromosome separation in bacteria has attracted wide attention; however, the effects of macromolecular crowding and the interaction between the binding protein and the newly replicated DNA on the segregation dynamics are not clear. Using Langevin dynamics simulations, we investigate the influences of crowders and the attractive interaction between the polymer and a small number of crowders on segregation of two overlapping polymers under a cylindrical confinement. We find that the segregation time increases with increasing the volume fraction of crowders due to the slower chain diffusion in crowded environments. For a fixed volume fraction of crowders, the segregation time decreases with increasing the size of crowders. Moreover, the attractive interaction between the polymer and a small number of crowders can significantly facilitate the chain segregation. These results are important for understanding the chromosome segregation in living cells.

  10. B Chromosomes – A Matter of Chromosome Drive

    PubMed Central

    Houben, Andreas

    2017-01-01

    B chromosomes are supernumerary chromosomes which are often preferentially inherited, deviating from usual Mendelian segregation. The balance between the so-called chromosome drive and the negative effects that the presence of Bs applies on the fitness of their host determines the frequency of Bs in a particular population. Drive is the key for understanding most B chromosomes. Drive occurs in many ways at pre-meiotic, meiotic or post-meiotic divisions, but the molecular mechanism remains unclear. The cellular mechanism of drive is reviewed based on the findings obtained for the B chromosomes of rye, maize and other species. How novel analytical tools will expand our ability to uncover the biology of B chromosome drive is discussed. PMID:28261259

  11. Segregation and Civic Virtue

    ERIC Educational Resources Information Center

    Merry, Michael S.

    2012-01-01

    In this essay Michael Merry defends the following prima facie argument: that civic virtue is not dependent on integration and in fact may be best fostered under conditions of segregation. He demonstrates that civic virtue can and does take place under conditions of involuntary segregation, but that voluntary separation--as a response to…

  12. Heteromorphic sex chromosomes: navigating meiosis without a homologous partner.

    PubMed

    Checchi, Paula M; Engebrecht, Joanne

    2011-09-01

    Accurate chromosome segregation during meiosis relies on homology between the maternal and paternal chromosomes. Yet by definition, sex chromosomes of the heterogametic sex lack a homologous partner. Recent studies in a number of systems have shed light on the unique meiotic behavior of heteromorphic sex chromosomes, and highlight both the commonalities and differences in divergent species. During meiotic prophase, the homology-dependent processes of pairing, synapsis, and recombination have been modified in many different ways to ensure segregation of heteromorphic sex chromosomes at the first meiotic division. Additionally, an almost universal feature of heteromorphic sex chromosomes during meiosis is transcriptional silencing, or meiotic sex chromosome inactivation, an essential process proposed to prevent expression of genes deleterious to meiosis in the heterogametic sex as well as to shield unpaired sex chromosomes from recognition by meiotic checkpoints. Comparative analyses of the meiotic behavior of sex chromosomes in nematodes, mammals, and birds reveal important conserved features as well as provide insight into sex chromosome evolution.

  13. Chromosomes and clinical anatomy.

    PubMed

    Gardner, Robert James McKinlay

    2016-07-01

    Chromosome abnormalities may cast light on the nature of mechanisms whereby normal anatomy evolves, and abnormal anatomy arises. Correlating genotype to phenotype is an exercise in which the geneticist and the anatomist can collaborate. The increasing power of the new genetic methodologies is enabling an increasing precision in the delineation of chromosome imbalances, even to the nucleotide level; but the classical skills of careful observation and recording remain as crucial as they always have been. Clin. Anat. 29:540-546, 2016. © 2016 Wiley Periodicals, Inc.

  14. Bayesian linkage and segregation analysis: factoring the problem.

    PubMed

    Matthysse, S

    2000-01-01

    Complex segregation analysis and linkage methods are mathematical techniques for the genetic dissection of complex diseases. They are used to delineate complex modes of familial transmission and to localize putative disease susceptibility loci to specific chromosomal locations. The computational problem of Bayesian linkage and segregation analysis is one of integration in high-dimensional spaces. In this paper, three available techniques for Bayesian linkage and segregation analysis are discussed: Markov Chain Monte Carlo (MCMC), importance sampling, and exact calculation. The contribution of each to the overall integration will be explicitly discussed.

  15. Alveolar abnormalities

    MedlinePlus

    ... page: //medlineplus.gov/ency/article/001093.htm Alveolar abnormalities To use the sharing features on this page, please enable JavaScript. Alveolar abnormalities are changes in the tiny air sacs in ...

  16. Nail abnormalities

    MedlinePlus

    Beau's lines; Fingernail abnormalities; Spoon nails; Onycholysis; Leukonychia; Koilonychia; Brittle nails ... 2012:chap 71. Zaiac MN, Walker A. Nail abnormalities associated with systemic pathologies. Clin Dermatol . 2013;31: ...

  17. Behavior of Aberrant Chromosome Configurations in Drosophila melanogaster Female Meiosis I

    PubMed Central

    Gilliland, William D.; Colwell, Eileen M.; Lane, Fiona M.; Snouffer, Ashley A.

    2014-01-01

    One essential role of the first meiotic division is to reduce chromosome number by half. Although this is normally accomplished by segregating homologous chromosomes from each other, it is possible for a genome to have one or more chromosomes that lack a homolog (such as compound chromosomes), or have chromosomes with multiple potential homologs (such as in XXY females). These configurations complete meiosis but engage in unusual segregation patterns. In Drosophila melanogaster females carrying two compound chromosomes, the compounds can accurately segregate from each other, a process known as heterologous segregation. Similarly, in XXY females, when the X chromosomes fail to cross over, they often undergo secondary nondisjunction, where both Xs segregate away from the Y. Although both of these processes have been known for decades, the orientation mechanisms involved are poorly understood. Taking advantage of the recent discovery of chromosome congression in female meiosis I, we have examined a number of different aberrant chromosome configurations. We show that these genotypes complete congression normally, with their chromosomes bioriented at metaphase I arrest at the same rates that they segregate, indicating that orientation must be established during prometaphase I before congression. We also show that monovalent chromosomes can move out on the prometaphase I spindle, but the dot 4 chromosomes appear required for this movement. Finally, we show that, similar to achiasmate chromosomes, heterologous chromosomes can be connected by chromatin threads, suggesting a mechanism for how heterochromatic homology establishes these unusual biorientation patterns. PMID:25491942

  18. Genetic dosage and position effect of small supernumerary marker chromosome (sSMC) in human sperm nuclei in infertile male patient

    PubMed Central

    Olszewska, Marta; Wanowska, Elzbieta; Kishore, Archana; Huleyuk, Nataliya; Georgiadis, Andrew P.; Yatsenko, Alexander N.; Mikula, Mariya; Zastavna, Danuta; Wiland, Ewa; Kurpisz, Maciej

    2015-01-01

    Chromosomes occupy specific distinct areas in the nucleus of the sperm cell that may be altered in males with disrupted spermatogenesis. Here, we present alterations in the positioning of the human chromosomes 15, 18, X and Y between spermatozoa with the small supernumerary marker chromosome (sSMC; sSMC+) and spermatozoa with normal chromosome complement (sSMC−), for the first time described in the same ejaculate of an infertile, phenotypically normal male patient. Using classical and confocal fluorescent microscopy, the nuclear colocalization of chromosomes 15 and sSMC was analyzed. The molecular cytogenetic characteristics of sSMC delineated the karyotype as 47,XY,+der(15)(pter->p11.2::q11.1->q11.2::p11.2->pter)mat. Analysis of meiotic segregation showed a 1:1 ratio of sSMC+ to sSMC− spermatozoa, while evaluation of sperm aneuploidy status indicated an increased level of chromosome 13, 18, 21 and 22 disomy, up to 7 × (2.7 − 15.1). Sperm chromatin integrity assessment did not reveal any increase in deprotamination in the patient’s sperm chromatin. Importantly, we found significant repositioning of chromosomes X and Y towards the nuclear periphery, where both chromosomes were localized in close proximity to the sSMC. This suggests the possible influence of sSMC/XY colocalization on meiotic chromosome division, resulting in abnormal chromosome segregation, and leading to male infertility in the patient. PMID:26616419

  19. Sex Chromosome Drive

    PubMed Central

    Helleu, Quentin; Gérard, Pierre R.; Montchamp-Moreau, Catherine

    2015-01-01

    Sex chromosome drivers are selfish elements that subvert Mendel's first law of segregation and therefore are overrepresented among the products of meiosis. The sex-biased progeny produced then fuels an extended genetic conflict between the driver and the rest of the genome. Many examples of sex chromosome drive are known, but the occurrence of this phenomenon is probably largely underestimated because of the difficulty to detect it. Remarkably, nearly all sex chromosome drivers are found in two clades, Rodentia and Diptera. Although very little is known about the molecular and cellular mechanisms of drive, epigenetic processes such as chromatin regulation could be involved in many instances. Yet, its evolutionary consequences are far-reaching, from the evolution of mating systems and sex determination to the emergence of new species. PMID:25524548

  20. Chromosome dynamics: new light on Aurora B kinase function.

    PubMed

    Shannon, Katie B; Salmon, E D

    2002-07-09

    Aurora B family kinases play an essential role in chromosome segregation and cytokinesis. Recent work suggests that the kinase activity is required for bipolar chromosome orientation, kinetochore assembly, spindle checkpoint and microtubule dynamics. Aurora B also has additional functions in chromosome condensation and cohesion.

  1. Alternative meiotic chromatid segregation in the holocentric plant Luzula elegans

    PubMed Central

    Heckmann, Stefan; Jankowska, Maja; Schubert, Veit; Kumke, Katrin; Ma, Wei; Houben, Andreas

    2014-01-01

    Holocentric chromosomes occur in a number of independent eukaryotic lineages. They form holokinetic kinetochores along the entire poleward chromatid surfaces, and owing to this alternative chromosome structure, species with holocentric chromosomes cannot use the two-step loss of cohesion during meiosis typical for monocentric chromosomes. Here we show that the plant Luzula elegans maintains a holocentric chromosome architecture and behaviour throughout meiosis, and in contrast to monopolar sister centromere orientation, the unfused holokinetic sister centromeres behave as two distinct functional units during meiosis I, resulting in sister chromatid separation. Homologous non-sister chromatids remain terminally linked after metaphase I, by satellite DNA-enriched chromatin threads, until metaphase II. They then separate at anaphase II. Thus, an inverted sequence of meiotic sister chromatid segregation occurs. This alternative meiotic process is most likely one possible adaptation to handle a holocentric chromosome architecture and behaviour during meiosis. PMID:25296379

  2. Chromosomal Conditions

    MedlinePlus

    ... 150 babies is born with a chromosomal condition. Down syndrome is an example of a chromosomal condition. Because ... all pregnant women be offered prenatal tests for Down syndrome and other chromosomal conditions. A screening test is ...

  3. SEGREGATION IN SMALL STEEL CASTINGS

    DTIC Science & Technology

    Carbon segregation in small castings often occurs near riser necks. Systematic studies were continued to determine effect on segregation of such...intensity of carbon segregation under ’neck-down’ risers varies directly as the neck length and inversely as the neck diameter. The degree of segregation

  4. Commentary: Genger Segregation in Childhood.

    ERIC Educational Resources Information Center

    Maccoby, Eleanor E.

    1994-01-01

    Provides an overview of the preceding articles in this journal issue. Considers the timing of gender segregation, compatibility between play styles and gender segregation, possible physiological processes underlying gender segregation in play, children's cognitive knowledge about gender, and the consequences of gender segregation. (BAC)

  5. [Chromosome analysis and genetic testing].

    PubMed

    Isobe, Yasushi; Miura, Ikuo

    2014-03-01

    Chromosomal and genetic tests are essential to establish correct diagnoses of the lymphoma. When the tissue examination is planned, these should be done simultaneously with the morphological and immunophenotypic evaluations. Chromosome analyses can identify the genomic alterations of tumor cells. Some chromosome abnormalities define disease subtypes. For example, recurrent 14q32 translocations involving the immunoglobulin heavy chain locus support the diagnosis of B-cell lymphoma, and their translocation partners identify the types. In contrast, genetic testings are performed to confirm the presence of certain abnormalities including gene rearrangements, mutations, amplifications and deletions in each case. These results provide us detailed information for diagnosis, prognosis, and choice of therapy.

  6. Novel homozygous mutations in the EVC and EVC2 genes in two consanguineous families segregating autosomal recessive Ellis-van Creveld syndrome.

    PubMed

    Aziz, Abdul; Raza, Syed I; Ali, Salman; Ahmad, Wasim

    2016-01-01

    Ellis-van Creveld syndrome (EVC) is a rare developmental disorder characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails, teeth, oral and cardiac abnormalities. It is caused by biallelic mutations in the EVC or EVC2 gene, separated by 2.6 kb of genomic sequence on chromosome 4p16. In the present study, we have investigated two consanguineous families of Pakistani origin, segregating EVC in autosomal recessive manner. Linkage in the families was established to chromosome 4p16. Subsequently, sequence analysis identified a novel nonsense mutation (p.Trp234*) in exon 8 of the EVC2 gene and 15 bp duplication in exon 14 of the EVC gene in the two families. This further expands the mutations in the EVC or EVC2 genes resulting in the EVC syndrome.

  7. Comparative Analysis of Regions with Distorted Segregation in Three Diploid Populations of Potato

    PubMed Central

    Manrique-Carpintero, Norma C.; Coombs, Joseph J.; Veilleux, Richard E.; Buell, C. Robin; Douches, David S.

    2016-01-01

    Genes associated with gametic and zygotic selection could underlie segregation distortion, observed as alterations of expected Mendelian genotypic frequencies in mapping populations. We studied highly dense genetic maps based on single nucleotide polymorphisms to elucidate the genetic nature of distorted segregation in potato. Three intra- and interspecific diploid segregating populations were used. DRH and D84 are crosses between the sequenced doubled monoploid DM 1-3 516 R44 Solanum tuberosum Group Phureja and either RH89-039-16 S. tuberosum or 84SD22, a S. tuberosum × S. chacoense hybrid. MSX902 is an interspecific cross between 84SD22 and Ber83 S. berthaultii × 2 × species mosaic. At the 0.05 significance level, 21%, 57%, and 51% of the total markers mapped in DRH, D84, and MSX902 exhibited distorted segregation, respectively. Segregation distortion regions for DRH were located on chromosomes 9 and 12; for D84 on chromosomes 2, 3, 4, 6, 7, and 8; and on chromosomes 1, 2, 7, 9, and 12 for MSX902. In general, each population had unique segregation distortion regions and directions of distortion. Interspecific crosses showed greater levels of distorted segregation and lower recombination rates as determined from the male parents. The different genomic regions where the segregation distortion regions occurred in the three populations likely reflect unique genetic combinations producing distorted segregation. PMID:27342736

  8. Tracking of Chromosome and Replisome Dynamics in Myxococcus xanthus Reveals a Novel Chromosome Arrangement

    PubMed Central

    Schumacher, Dominik; Søgaard-Andersen, Lotte

    2013-01-01

    Cells closely coordinate cell division with chromosome replication and segregation; however, the mechanisms responsible for this coordination still remain largely unknown. Here, we analyzed the spatial arrangement and temporal dynamics of the 9.1 Mb circular chromosome in the rod-shaped cells of Myxococcus xanthus. For chromosome segregation, M. xanthus uses a parABS system, which is essential, and lack of ParB results in chromosome segregation defects as well as cell divisions over nucleoids and the formation of anucleate cells. From the determination of the dynamic subcellular location of six genetic loci, we conclude that in newborn cells ori, as monitored following the ParB/parS complex, and ter regions are localized in the subpolar regions of the old and new cell pole, respectively and each separated from the nearest pole by approximately 1 µm. The bulk of the chromosome is arranged between the two subpolar regions, thus leaving the two large subpolar regions devoid of DNA. Upon replication, one ori region remains in the original subpolar region while the second copy segregates unidirectionally to the opposite subpolar region followed by the rest of the chromosome. In parallel, the ter region of the mother chromosome relocates, most likely passively, to midcell, where it is replicated. Consequently, after completion of replication and segregation, the two chromosomes show an ori-ter-ter-ori arrangement with mirror symmetry about a transverse axis at midcell. Upon completion of segregation of the ParB/parS complex, ParA localizes in large patches in the DNA-free subpolar regions. Using an Ssb-YFP fusion as a proxy for replisome localization, we observed that the two replisomes track independently of each other from a subpolar region towards ter. We conclude that M. xanthus chromosome arrangement and dynamics combine features from previously described systems with new features leading to a novel spatiotemporal arrangement pattern. PMID:24068967

  9. Down syndrome consequent to a cryptic maternal 12p;21q chromosome translocation

    SciTech Connect

    Scott, J.A.; Wenger, S.L.; Chakravarti, A.

    1995-03-13

    A 9-year-old, mildly mentally retarded girl presented with phenotypic manifestations of Down syndrome. G-banded chromosomal analyses of peripheral blood lymphocytes from the patient and her parents, and skin fibroblasts from the patient, did not detect any abnormality. Molecular analysis of 15 highly polymorphic chromosome 21 dinucleotide repeat markers demonstrated a partial duplication of the Down syndrome critical region (D21S55, subband 21q22.2) of maternal origin in the patient. The segmental trisomy was confirmed by FISH analysis using the cosmid probe D21S55. Further analysis demonstrated that the trisomy was due to segregation of an apparently balanced cryptic translocation from the mother. The patient`s karyotype is 46,XX,-12,tder(12)t(12;21)(p13.1;q22.2)mat. 21 refs., 3 figs., 1 tab.

  10. Wolfram syndrome maps to distal human chromosome 4p

    SciTech Connect

    Polymeropoulos, M.H.; Swift, R.; Swift, M.

    1994-09-01

    Wolfram syndrome (MIM 222300) is an autosomal recessive disorder defined by the occurrence of diabetes mellitus and progressive bilateral optic atrophy. Wolfram syndrome homozygotes develop widespread nervous system abnormalities; in particular, they exhibit severe behavioral difficulties that often lead to suicide attempts or psychiatric hospitalizations. The Wolfram syndrome gene also predisposes heterozygous carriers to psychiatric disorders. Since these heterozygotes are common in the general population, the Wolfram syndrome gene may contribute significantly to the overall burden of psychiatric illness. Based on a linkage analysis of 11 families segregating for this syndrome, using microsatellite repeat polymorphisms throughout the human genome, we found the Wolfram syndrome gene to be linked to markers on the short arm of human chromosome 4, with Zmax=6.46 at {theta}=0.02 for marker D4S431.

  11. Understanding Segregation Processes

    NASA Astrophysics Data System (ADS)

    Bruch, Elizabeth

    There is growing consensus that living in neighborhoods of concentrated poverty increases the likelihood of social problems such as teenage parenthood, drug and alcohol use, crime victimization, and chronic unemployment. Neighborhood inequality is also implicated in studies of enduring race/ethnic health disparities, and there are recent moves to broaden the definition of health care policy to policies targeting social inequality (Mechanic 2007). Residential segregation affects health outcomes in several different ways. First, income, education, and occupation are all strongly related to health (Adler and Newman 2002). Segregation is a key mechanism through which socioeconomic inequality is perpetuated and reinforced, as it hinders the upward mobility of disadvantaged groups by limiting their educational and employment opportunities. Second, segregation increases minority exposure to unhealthy neighborhood environments. Residential segregation creates areas with concentrated poverty and unemployment, both of which are key factors that predict violence and create racial differences in homicide (Samson and Wilson 1995). Neighborhood characteristics, such as exposure to environmental hazards, fear of violence, and access to grocery stores, affect health risks and health behaviors (Cheadle et al. 1991). Tobacco and alcohol industries also advertise their products disproportionately in poor, minority areas (Moore, Williams, and Qualls 1996). Finally, residential segregation leads to inequalitie in health care resources, which contributes to disparities in quality of treatment (Smedley, Stith, and Nelson 2002).

  12. Autism Spectrum Disorders Associated with Chromosomal Abnormalities

    ERIC Educational Resources Information Center

    Lo-Castro, Adriana; Benvenuto, Arianna; Galasso, Cinzia; Porfirio, Cristina; Curatolo, Paolo

    2010-01-01

    Autism spectrum disorders (ASDs) constitute a class of severe neurodevelopmental conditions with complex multifactorial and heterogeneous etiology. Despite high estimates of heritability, genetic causes of ASDs remain elusive, due to a high degree of genetic and phenotypic heterogeneity. So far, several "monogenic" forms of autism have been…

  13. Gyramides prevent bacterial growth by inhibiting DNA gyrase and altering chromosome topology.

    PubMed

    Rajendram, Manohary; Hurley, Katherine A; Foss, Marie H; Thornton, Kelsey M; Moore, Jared T; Shaw, Jared T; Weibel, Douglas B

    2014-06-20

    Antibiotics targeting DNA gyrase have been a clinical success story for the past half-century, and the emergence of bacterial resistance has fueled the search for new gyrase inhibitors. In this paper we demonstrate that a new class of gyrase inhibitors, the gyramides, are bacteriostatic agents that competitively inhibit the ATPase activity of Escherichia coli gyrase and produce supercoiled DNA in vivo. E. coli cells treated with gyramide A have abnormally localized, condensed chromosomes that blocks DNA replication and interrupts chromosome segregation. The resulting alterations in DNA topology inhibit cell division through a mechanism that involves the SOS pathway. Importantly, gyramide A is a specific inhibitor of gyrase and does not inhibit the closely related E. coli enzyme topoisomerase IV. E. coli mutants with reduced susceptibility to gyramide A do not display cross-resistance to ciprofloxacin and novobiocin. The results demonstrate that the gyramides prevent bacterial growth by a mechanism in which the topological state of chromosomes is altered and halts DNA replication and segregation. The specificity and activity of the gyramides for inhibiting gyrase makes these compounds important chemical tools for studying the mechanism of gyrase and the connection between DNA topology and bacterial cell division.

  14. Evolutionary dynamics of adult stem cells: Comparison of random and immortal-strand segregation mechanisms

    NASA Astrophysics Data System (ADS)

    Tannenbaum, Emmanuel; Sherley, James L.; Shakhnovich, Eugene I.

    2005-04-01

    This paper develops a point-mutation model describing the evolutionary dynamics of a population of adult stem cells. Such a model may prove useful for quantitative studies of tissue aging and the emergence of cancer. We consider two modes of chromosome segregation: (1) random segregation, where the daughter chromosomes of a given parent chromosome segregate randomly into the stem cell and its differentiating sister cell and (2) “immortal DNA strand” co-segregation, for which the stem cell retains the daughter chromosomes with the oldest parent strands. Immortal strand co-segregation is a mechanism, originally proposed by [Cairns Nature (London) 255, 197 (1975)], by which stem cells preserve the integrity of their genomes. For random segregation, we develop an ordered strand pair formulation of the dynamics, analogous to the ordered strand pair formalism developed for quasispecies dynamics involving semiconservative replication with imperfect lesion repair (in this context, lesion repair is taken to mean repair of postreplication base-pair mismatches). Interestingly, a similar formulation is possible with immortal strand co-segregation, despite the fact that this segregation mechanism is age dependent. From our model we are able to mathematically show that, when lesion repair is imperfect, then immortal strand co-segregation leads to better preservation of the stem cell lineage than random chromosome segregation. Furthermore, our model allows us to estimate the optimal lesion repair efficiency for preserving an adult stem cell population for a given period of time. For human stem cells, we obtain that mispaired bases still present after replication and cell division should be left untouched, to avoid potentially fixing a mutation in both DNA strands.

  15. Characterization of the breakpoint regions of a pericentric inversion on chromosome 6

    SciTech Connect

    Gastier, J.M.; Brody, T.; Charfat, O.

    1994-09-01

    We are attempting to clone the breakpoints of a pericentric inversion [inv(6)(p23q23.1)] which segregates in a three generation family. Phenotypic abnormalities associated with this chromosome anomaly include senori-neural hearing loss, eye (anterior segment) abnormalities, dental anomalies, and mild mental retardation. The breakpoints have been microdissected and a small insert library was created. More than 100 sequence tagged sites (STSs) have been developed from these clones for screening of the CEPH mega-YAC library. This work will yield a high density physical map of the breakpoint regions for further characterization of the loci. YACs from the region are being screened by fluorescence in situ hybridization (FISH) to obtain a YAC which crosses the breakpoint as an initial step in defining the molecular basis of the disease phenotype. Progress towards cloning of the breakpoints will be described.

  16. Centromeric heterochromatin: the primordial segregation machine.

    PubMed

    Bloom, Kerry S

    2014-01-01

    Centromeres are specialized domains of heterochromatin that provide the foundation for the kinetochore. Centromeric heterochromatin is characterized by specific histone modifications, a centromere-specific histone H3 variant (CENP-A), and the enrichment of cohesin, condensin, and topoisomerase II. Centromere DNA varies orders of magnitude in size from 125 bp (budding yeast) to several megabases (human). In metaphase, sister kinetochores on the surface of replicated chromosomes face away from each other, where they establish microtubule attachment and bi-orientation. Despite the disparity in centromere size, the distance between separated sister kinetochores is remarkably conserved (approximately 1 μm) throughout phylogeny. The centromere functions as a molecular spring that resists microtubule-based extensional forces in mitosis. This review explores the physical properties of DNA in order to understand how the molecular spring is built and how it contributes to the fidelity of chromosome segregation.

  17. Centromeric Heterochromatin: The Primordial Segregation Machine

    PubMed Central

    Bloom, Kerry S.

    2014-01-01

    Centromeres are specialized domains of heterochromatin that provide the foundation for the kinetochore. Centromeric heterochromatin is characterized by specific histone modifications, a centromere-specific histone H3 variant (CENP-A), and the enrichment of cohesin, condensin, and topo-isomerase II. Centromere DNA varies orders of magnitude in size from 125 bp (budding yeast) to several megabases (human). In metaphase, sister kinetochores on the surface of replicated chromosomes face away from each other, where they establish microtubule attachment and bi-orientation. Despite the disparity in centromere size, the distance between separated sister kinetochores is remarkably conserved (approximately 1 μm) throughout phylogeny. The centromere functions as a molecular spring that resists microtubule-based extensional forces in mitosis. This review explores the physical properties of DNA in order to understand how the molecular spring is built and how it contributes to the fidelity of chromosome segregation. PMID:25251850

  18. Asplenia syndrome in a child with a reciprocal translocation of chromosomes 11 and 20 [46,XX,t(11;20)(q13.1;q13.13)

    SciTech Connect

    Freeman, S.B.; Muraldharan, K.; Pettay, D.

    1994-09-01

    Failure to establish the left-right embryonic axis results in abnormalities of laterality; situs solitus is replaced by situs inversus totalis or various degrees of heterotaxy involving the heart, great vessels, lungs, liver, spleen, and/or bowel. Laterality syndromes are likely to be genetically heterogeneous although specific human genes have not been identified. Families with dominant, recessive, and X-linked laterality syndromes have been reported as well as individuals with situs abnormalities and chromosome rearrangements. The latter offer the possibility of narrowing the gene search to specific chromosome regions. A recent report described an infant with polysplenia syndrome and a paracentric inversion of chromosome 11 [46,XX,inv(11)(q13q25)pat]. We report the second case of a child with laterality abnormalities and a chromosome rearrangement involving a similar breakpoint on chromosome 11. The proband is a 6 y/o female with mental retardation, dysmorphic features, pulmonic stenosis, asplenia, Hirschsprung disease, and a balanced, reciprocal translocation involving chromosomes 11 and 20 [46,XX,t(11;20)(q13,1;q13.13)pat]. Using DNA probes we have excluded uniparental disomy for chromosomes 11 and 20. If a gene for determination of laterality lies in the 11q13 region, the proband`s abnormalities could be the result of her receiving an allele disrupted by the paternal translocation as well as a mutant allele from her mother. To investigate this possibility, we are studying the segregation of maternal chromosome 11 markers in the proband and her balanced carrier and non-carrier siblings.

  19. The Role of Residential Segregation in Contemporary School Segregation

    ERIC Educational Resources Information Center

    Frankenberg, Erica

    2013-01-01

    Inaction to address housing segregation in metropolitan areas has resulted in persistently high levels of residential segregation. As the Supreme Court has recently limited school districts' voluntary integration efforts, this article considers the role of residential segregation in maintaining racially isolated schools, namely what is known about…

  20. Mechanisms of chromosome behaviour during mitosis

    PubMed Central

    Walczak, Claire E.; Cai, Shang; Khodjakov, Alexey

    2010-01-01

    For over a century, scientists have strived to understand the mechanisms that govern the accurate segregation of chromosomes during mitosis. The most intriguing feature of this process, which is particularly prominent in higher eukaryotes, is the complex behaviour exhibited by the chromosomes. This behaviour is based on specific and highly regulated interactions between the chromosomes and spindle microtubules. Recent discoveries, enabled by high-resolution imaging combined with the various genetic, molecular, cell biological and chemical tools, support the idea that establishing and controlling the dynamic interaction between chromosomes and microtubules is a major factor in genomic fidelity. PMID:20068571

  1. Molecular structure of the number 21 chromosome and Down syndrome

    SciTech Connect

    Smith, G.F.

    1985-01-01

    This book contains 19 papers. Some of the titles are: The Biology of Down Syndrome, Human Chromosome Analysis, Expression of Genes on Human Chromosome 21, Comparative Gene Mapping of Human Chromosome 21 and Mouse Chromosome 16, and Relating Molecular Specificity to Normal and Abnormal Brain Development.

  2. Microtubule detyrosination guides chromosomes during mitosis

    PubMed Central

    Barisic, Marin; Silva e Sousa, Ricardo; Tripathy, Suvranta K.; Magiera, Maria M.; Zaytsev, Anatoly V.; Pereira, Ana L.; Janke, Carsten; Grishchuk, Ekaterina L.; Maiato, Helder

    2015-01-01

    Before chromosomes segregate into daughter cells they align at the mitotic spindle equator, a process known as chromosome congression. CENP-E/Kinesin-7 is a microtubule plus-end-directed kinetochore motor required for congression of pole-proximal chromosomes. Because the plus-ends of many astral microtubules in the spindle point to the cell cortex, it remains unknown how CENP-E guides pole-proximal chromosomes specifically towards the equator. Here we found that congression of pole-proximal chromosomes depended on specific post-translational detyrosination of spindle microtubules that point to the equator. In vitro reconstitution experiments demonstrated that CENP-E-dependent transport was strongly enhanced on detyrosinated microtubules. Blocking tubulin tyrosination in cells caused ubiquitous detyrosination of spindle microtubules and CENP-E transported chromosomes away from spindle poles in random directions. Thus, CENP-E-driven chromosome congression is guided by microtubule detyrosination. PMID:25908662

  3. Abnormalities of gonadal differentiation.

    PubMed

    Berkovitz, G D; Seeherunvong, T

    1998-04-01

    Gonadal differentiation involves a complex interplay of developmental pathways. The sex determining region Y (SRY) gene plays a key role in testis determination, but its interaction with other genes is less well understood. Abnormalities of gonadal differentiation result in a range of clinical problems. 46,XY complete gonadal dysgenesis is defined by an absence of testis determination. Subjects have female external genitalia and come to clinical attention because of delayed puberty. Individuals with 46,XY partial gonadal dysgenesis usually present in the newborn period for the valuation of ambiguous genitalia. Gonadal histology always shows an abnormality of seminiferous tubule formation. A diagnosis of 46,XY true hermaphroditism is made if the gonads contain well-formed testicular and ovarian elements. Despite the pivotal role of the SRY gene in testis development, mutations of SRY are unusual in subjects with a 46,XY karyotype and abnormal gonadal development. 46,XX maleness is defined by testis determination in an individual with a 46,XX karyotype. Most affected individuals have a phenotype similar to that of Klinefelter syndrome. In contrast, subjects with 46,XX true hermaphroditism usually present with ambiguous genitalia. The majority of subjects with 46,XX maleness have Y sequences including SRY in genomic DNA. However, only rare subjects with 46,XX true hermaphroditism have translocated sequences encoding SRY. Mosaicism and chimaerism involving the Y chromosome can also be associated with abnormal gonadal development. However, the vast majority of subjects with 45,X/46,XY mosaicism have normal testes and normal male external genitalia.

  4. Learning Disabilities in Children with Sex Chromosome Anomalies.

    ERIC Educational Resources Information Center

    Pennington, Bruce F.; And Others

    1982-01-01

    Results obtained from 44 children (ages 7 through 16) with sex chromosome abnormalities and from 17 chromosomally normal siblings demonstrated that children in the former group have an increased risk of encountering learning problems. (MP)

  5. Identification and molecular confirmation of a small chromosome 10q duplication [dir dup(10)(q24.2 {r_arrow}q24.3)] inherited from a mother mosiac for the abnormality

    SciTech Connect

    Tonk, V.; Schneider, N.R.; Schultz, R.A.; Delgado, M.R.; Mao, Jen-i

    1996-01-02

    We describe a family in which two siblings exhibited developmental delay, reduced muscle tone and mild muscle weakness. Cytogenetic evaluation demonstrated that both children had a tandem duplication of a small portion of the long arm of chromosome 10 [46,XX or XY, dir dup(10)(q24.2{r_arrow}q24.3)], inherited from their clinically normal mother, who was found to be mosaic for the duplicated chromosome 10. Fluorescence in situ hybridization approaches, including total chromosome painting and the use of regional specific cosmid probes, were used to confirm the chromosome 10q origin of the duplicated material. This is the smallest confirmed duplication of this portion of chromosome 10 reported to date. 28 refs., 4 figs.

  6. Focus on granular segregation

    NASA Astrophysics Data System (ADS)

    Daniels, Karen E.; Schröter, Matthias

    2013-03-01

    Ordinary fluids mix themselves through thermal motions, or can be even more efficiently mixed by stirring. In contrast, granular materials such as sand often unmix when they are stirred, shaken or sheared. This granular segregation is both a practical means to separate materials in industry, and a persistent challenge to uniformly mixing them. While segregation phenomena are ubiquitous, a large number of different mechanisms have been identified and the underlying physics remains the subject of much inquiry. Particle size, shape, density and even surface roughness can play significant roles. The aim of this focus issue is to provide a snapshot of the current state of the science, covering a wide range of packing densities and driving mechanisms, from thermal-like dilute systems to dense flows.

  7. Monaural speech segregation

    NASA Astrophysics Data System (ADS)

    Wang, Deliang; Hu, Guoning

    2003-04-01

    Speech segregation from a monaural recording is a primary task of auditory scene analysis, and has proven to be very challenging. We present a multistage model for the task. The model starts with simulated auditory periphery. A subsequent stage computes midlevel auditory representations, including correlograms and cross-channel correlations. The core of the system performs segmentation and grouping in a two-dimensional time-frequency representation that encodes proximity in frequency and time, periodicity, and amplitude modulation (AM). Motivated by psychoacoustic observations, our system employs different mechanisms for handling resolved and unresolved harmonics. For resolved harmonics, our system generates segments-basic components of an auditory scene-based on temporal continuity and cross-channel correlation, and groups them according to periodicity. For unresolved harmonics, the system generates segments based on AM in addition to temporal continuity and groups them according to AM repetition rates. We derive AM repetition rates using sinusoidal modeling and gradient descent. Underlying the segregation process is a pitch contour that is first estimated from speech segregated according to global pitch and then adjusted according to psychoacoustic constraints. The model has been systematically evaluated, and it yields substantially better performance than previous systems.

  8. A 1.6-Mb microdeletion in chromosome 17q22 leads to NOG-related symphalangism spectrum disorder without intellectual disability.

    PubMed

    Pang, Xiuhong; Luo, Huajie; Chai, Yongchuan; Wang, Xiaowen; Sun, Lianhua; He, Longxia; Chen, Penghui; Wu, Hao; Yang, Tao

    2015-01-01

    Microdeletions in chromosome 17q22, where the NOG gene resides, have been reported leading to the NOG-related symphalangism spectrum disorder (NOG-SSD), intellectual disability and other developmental abnormalities. In this study we reported a dominant Chinese Han family segregating with typical NOG-SSD symptoms including proximal symphalangism, conductive hearing loss, amblyopia and strabismus, but not intellectual disability. Sanger sequencing identified no pathogenic mutation in the coding regions of candidate genes NOG, GDF5 and FGF9. SNP genotyping in the genomic region surrounding NOG identified loss of heterozygosity in the affected family members. By array comparative genomic hybridization and quantitative real-time polymerase chain reaction, we identified and mapped the breakpoints of a novel 1.6-Mb microdeletion in chromosome 17q22 that included NOG and twelve other genes. It is the first microdeletion reported in chromosome 17q22 that is associated with NOG-SSD only but not with intellectual disability. Our results may help identifying the dosage sensitive genes for intellectual disability and other developmental abnormalities in chromosome 17q22. Our study also suggested that genomic deletions in chromosome 17q22 should be screened in the NOG-SSD patients in which no pathogenic mutation is identified by conventional sequencing methods.

  9. Meiosis I: when chr