scholarly journals Complex biology of constitutional ring chromosomes structure and (in)stability revealed by somatic cell reprogramming

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
T. V. Nikitina ◽  
A. A. Kashevarova ◽  
M. M. Gridina ◽  
M. E. Lopatkina ◽  
A. A. Khabarova ◽  
...  
Keyword(s):  
Ring Chromosome ◽  
Chromosome Loss ◽  
Genotype Distribution ◽  
Distribution Analysis ◽  
Mitotic Stability ◽  
Somatic Cell Reprogramming ◽  
Ring Chromosomes ◽  
Spontaneous Correction ◽  
Wide Range ◽  
Induced Pluripotent

AbstractHuman ring chromosomes are often unstable during mitosis, and daughter cells can be partially or completely aneuploid. We studied the mitotic stability of four ring chromosomes, 8, 13, 18, and 22, in long-term cultures of skin fibroblasts and induced pluripotent stem cells (iPSCs) by GTG karyotyping and aCGH. Ring chromosome loss and secondary aberrations were observed in all fibroblast cultures except for r(18). We found monosomy, fragmentation, and translocation of indexed chromosomes. In iPSCs, aCGH revealed striking differences in mitotic stability both between iPSC lines with different rings and, in some cases, between cell lines with the same ring chromosome. We registered the spontaneous rescue of karyotype 46,XY,r(8) to 46,XY in all six iPSC lines through ring chromosome loss and intact homologue duplication with isoUPD(8)pat occurrence, as proven by SNP genotype distribution analysis. In iPSCs with other ring chromosomes, karyotype correction was not observed. Our results suggest that spontaneous correction of the karyotype with ring chromosomes in iPSCs is not universal and that pluripotency is compatible with a wide range of derivative karyotypes. We conclude that marked variability in the frequency of secondary rearrangements exists in both fibroblast and iPSC cultures, expanding the clinical significance of the constitutional ring chromosome.

scholarly journals Mutant alleles of the meiotic locus, mei-9, differ in degree of effects on rod chromosome magnification and ring chromosome transmission in Drosophila

1989 ◽  
Vol 53 (3) ◽  
pp. 155-161 ◽  
Author(s):  
Donald J. Komma ◽  
Heath Graves ◽  
Sharyn A. Endow
Keyword(s):  
Excision Repair ◽  
Ring Chromosome ◽  
Inhibitory Effect ◽  
Ribosomal Gene ◽  
Chromosome Loss ◽  
Repair Pathway ◽  
Chromosome Transmission ◽  
Ring Chromosomes ◽  
Allele Specific

SummaryTwo mutant alleles of the meiotic locus, mei-9, have been examined for their effect on magnification of a rod Xbb chromosome and transmission of a ring Xbb chromosome under magnifying conditions. Our results indicate that the effects of these two mutations are allele-specific: mei-9a strongly inhibits both rod chromosome magnification and ring chromosome loss under magnifying conditions, while mei-9b has a smaller inhibitory effect on rod chromosome magnification and on the transmission of ring chromosomes under magnifying conditions. These observations can be explained by a difference in leakiness between the two alleles. Our results demonstrate that mutants defective in excision repair and repair replication inhibit ribosomal gene magnification. This suggests that a component of the excision repair pathway is involved in the process of magnification.

Spontaneous duplication loss and breakage in Caenorhabditis elegans

Genome ◽  
1994 ◽  
Vol 37 (4) ◽  
pp. 595-606
Author(s):  
Kim S. McKim ◽  
Ann M. Rose
Keyword(s):  
Caenorhabditis Elegans ◽  
X Chromosome ◽  
Fragile Site ◽  
Ring Chromosome ◽  
Chromosome Breakage ◽  
Chromosome Loss ◽  
Spontaneous Breakage ◽  
Ring Chromosomes ◽  
Ring Structures ◽  
Chromosome I

Duplications in Caenorhabditis elegans spontaneously delete at frequencies ranging from 10−4 to 10−5. We have analyzed the structure and mitotic stability of 33 deleted duplications resulting from spontaneous breakage events. (i) Breakage usually occurred at a variety of sites; that is, there were no hot spots for breakage. An exception was the spontaneous breakage of the X chromosome into which hDp14 was inserted. These breaks were close to or at the site of the chromosome I insertion; therefore, the insertion created a type of fragile site. (ii) Spontaneous duplications often had complex structures. In some cases, their structures were most simply resolved by proposing that the progenitor duplication was a ring chromosome with a superimposed inversion. Most of the proposed ring chromosomes were mitotically unstable, suggesting that ring structures increase the frequency of chromosome loss, (iii) Clusters of spontaneous deletion events were rarely observed, suggesting that the majority of spontaneous breakage events probably occurred during meiosis. (iv) A minority of the spontaneous breakage events were associated with linkage to an autosome. Like free duplications of chromosome I, these linked duplications tended to segregate from the X chromosome in males. (v) Three meiotic mutants, him-3, him-6, and him-8, had no effect on somatic loss of the duplications but did reduce the frequency of breakage events. Given the conclusion that chromosome breakage is a meiotic event, these data are consistent with the function of the three meiotic genes being restricted to meiosis.Key words: chromosome structure, duplication, mitosis, meiosis, Caenorhabditis species.

scholarly journals RING CHROMOSOMES AND rDNA MAGNIFICATION IN DROSOPHILA

Genetics ◽  
1984 ◽  
Vol 108 (4) ◽  
pp. 969-983
Author(s):  
Sharyn A Endow ◽  
Donald J Komma ◽  
K C Atwood
Keyword(s):  
Sister Chromatid ◽  
Sister Chromatid Exchange ◽  
Ring Chromosome ◽  
Ribosomal Gene ◽  
Lower Number ◽  
Chromosome Loss ◽  
Primary Event ◽  
Ring Chromosomes ◽  
Ring Structures

ABSTRACT Tartof showed that ribosomal gene magnification in Drosophila was inhibited in a ring Χ chromosome. The present studies extend this observation by showing that ring Χ chromosomes are lost meiotically in male Drosophila undergoing ribosomal gene magnification as evidenced by the recovery of a lower number of ring-bearing progeny under magnifying conditions compared with nonmagnifying conditions. Associated with ring chromosome loss is a highly significant increase in the number of double-sized dicentric ring chromosomes in meiotic cells from magnifying males. These observations explain the failure of ring Χ chromosomes to magnify and imply that magnification in rod chromosomes occurs via a mechanism of unequal sister chromatid exchange. Our results support the hypothesis that the primary event of magnification is a sister chromatid exchange in the rDNA, that the frequency of sister strand exchanges is increased in magnifying flies, that a significant number of exchanges in magnifying flies occurs meiotically and that some of the exchanges are nonreciprocal. We have also found that autosomal mutations can affect both the frequency of abnormal ring structures and the ability of ring Χ chromosomes to magnify.

Modeling of dynamic mosaicism on ring chromosomes in human fibroblasts and IPSCS

2020 ◽  
pp. 12-13
Author(s):  
Т.В. Никитина ◽  
А.А. Кашеварова ◽  
М.М. Гридина ◽  
А.А. Хабарова ◽  
А.Г. Мензоров ◽  
...  
Keyword(s):  
Genetic Structure ◽  
Human Fibroblasts ◽  
Cellular Heterogeneity ◽  
Mitotic Stability ◽  
Factors Affecting ◽  
Ring Chromosomes ◽  
Cell Clones ◽  
Mitotic Instability ◽  
Mitotic Behavior

Митотическая нестабильность кольцевых хромосом может приводить к появлению клеточных клонов с различной генетической структурой. В качестве модели нестабильности кольцевых хромосом в митозе мы использовали фибробласты от пациентов с r(8), r(13), r(18) и r(22) и полученные из них индуцированные плюрипотентные стволовые клетки (ИПСК). Линии ИПСК с r(22) имели относительно стабильный кариотип на протяжении десятков (до 60) пассажей и сохраняли неизменную структуру кольцевой хромосомы. Кариотип линий ИПСК с r(8) и r(18) на ранних пассажах стабильный, планируется его изучение на поздних пассажах. Наибольшее разнообразие кариотипа выявлено в линиях ИПСК с r(13), в которых наблюдали различные перестройки и выраженную клеточную гетерогенность. Определение факторов, влияющих на митотическую стабильность кольцевых хромосом, может иметь значение для консультирования пациентов. Mitotic instability of ring chromosomes can lead to the appearance of cell clones with different genetic structure. IPSCs from fibroblasts of patients with r(8), r(13), r(18), and r(22) were used as a model of ring chromosomes mitotic behavior. Karyotypes of iPSC lines with r(8) and r(18) have so far been evaluated only in the early passages, lines with r(22) have maintained a relatively stable karyotype up to 60 passages. The occurrence of rearrangements and cellular heterogeneity was found characteristic for r(13) iPSCs. The determination of factors affecting the ring chromosomes mitotic stability would be beneficial for the patient’s prognosis.

Strong Association between Serotonin Transporter 5-HTTVNTR Variant and Psychoactive Substance (Nicotine) Use in the Turkish Cypriot Population

2020 ◽  
Vol 21 (6) ◽  
pp. 466-470
Author(s):  
Emine Kandemis ◽  
Gulten Tuncel ◽  
Ozen Asut ◽  
Sehime G. Temel ◽  
Mahmut C. Ergoren
Keyword(s):  
Serotonin Transporter ◽  
Association Studies ◽  
Strong Association ◽  
Smoking Behavior ◽  
Population Based ◽  
Genome Wide Association Studies ◽  
Genotype Distribution ◽  
Psychological Traits ◽  
Wide Range ◽  
Turkish Cypriot

Background: The use of psychoactive substances is one of the most dangerous social problems worldwide. Nicotine dependence results from the interaction between neurobiological, environmental and genetic factors. Serotonin is a neurotransmitter that has a wide range of central nervous system activities. The serotonin transporter gene has been previously linked to psychological traits. Objective: A variable number of tandem repeats within the serotonin transporter-linked polymorphic gene region are believed to alter the transcriptional efficiency of the 5-HTT gene. Therefore, we aimed to investigate the association between this polymorphic site and smoking behavior in the Turkish Cypriot population. Methods: A total of 259 (100 smokers, 100 non-smokers and 59 ex-smokers) Turkish Cypriots were included in this population-based cross-sectional study. Genomic DNA was extracted from peripheral blood samples and the 5-HTTVNTR2 polymorphisms were determined by the PCR-RFLP. Results: The allelic frequency and genotype distribution results of this study showed a strong association (P<0.0001) between smokers and non-smokers. No statistical significance was found between non-smokers and ex-smokers. Conclusion: This is the first genetic epidemiology study to investigate the allelic frequencies of 5-HTTVNTR2 polymorphisms associated with smoking behavior in the Turkish Cypriot population. Based on the results of this study, genome-wide association studies should be designed for preventive medicine in this population.

scholarly journals Positive feedback between retinoic acid and 2-phospho-L-ascorbic acid trisodium salt during somatic cell reprogramming

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Mengdan Zhang ◽  
Qian Li ◽  
Tingting Yang ◽  
Fei Meng ◽  
Xiaowei Lai ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Retinoic Acid ◽  
Positive Feedback ◽  
Dehydroascorbic Acid ◽  
Rna Seq ◽  
Somatic Cell Reprogramming ◽  
Trisodium Salt ◽  
Induced Pluripotent ◽  
High Level ◽  
Mesenchymal Epithelial Transition

AbstractRetinoic acid (RA) and 2-phospho-L-ascorbic acid trisodium salt (AscPNa) promote the reprogramming of mouse embryonic fibroblasts to induced pluripotent stem cells. In the current studies, the lower abilities of RA and AscPNa to promote reprogramming in the presence of each other suggested that they may share downstream pathways at least partially. The hypothesis was further supported by the RNA-seq analysis which demonstrated a high-level overlap between RA-activated and AscPNa activated genes during reprogramming. In addition, RA upregulated Glut1/3, facilitated the membrane transportation of dehydroascorbic acid, the oxidized form of L-ascorbic acid, and subsequently maintained intracellular L-ascorbic acid at higher level and for longer time. On the other hand, AscPNa facilitated the mesenchymal-epithelial transition during reprogramming, downregulated key mesenchymal transcriptional factors like Zeb1 and Twist1, subsequently suppressed the expression of Cyp26a1/b1 which mediates the metabolism of RA, and sustained the intracellular level of RA. Furthermore, the different abilities of RA and AscPNa to induce mesenchymal-epithelial transition, pluripotency, and neuronal differentiation explain their complex contribution to reprogramming when used individually or in combination. Therefore, the current studies identified a positive feedback between RA and AscPNa, or possibility between vitamin A and C, and further explored their contributions to reprogramming.

scholarly journals A Comprehensive In Silico Perspective For Discovery of Novel Inhibitory Candidates Targeting Versatile Transcriptional Repressor MBD2

2021 ◽  
Author(s):  
Zihni Onur Çalışkaner
Keyword(s):  
Dna Methylation ◽  
Cancer Progression ◽  
Md Simulation ◽  
Dna Interaction ◽  
Binding Energies ◽  
Epigenetic Mechanism ◽  
Energy Decomposition ◽  
Computational Docking ◽  
Somatic Cell Reprogramming ◽  
Wide Range

Abstract Genome methylation is a key epigenetic mechanism in various biological events such as development, cellular differentiation, cancer progression, aging, and iPSC reprogramming. Crosstalk between DNA methylation and regulation in gene expression is employed through MBD2, known as reader of DNA methylation and suggested as a drug target. Despite its magnitude of significance and rationale of nomination, a scarcely limited number of druggable ligands has been detected so far. Hence, we screened a comprehensive compound library, and then certain of them were subjected to computational docking analysis by targeting the methylated DNA-binding domain of human MBD2. We could detect reasonable binding energies and docking residues presumably located in druggable pockets. Docking results were also validated via MD simulation and per-residue energy decomposition calculation. Drug-likeness of tested ligands was assessed through ADMET prediction in order to foresee off-target side effects for future studies. Herein, on the basis of collaborating approaches such as molecular docking, MD simulation, energy decomposition, and ADMET prediction, notably two compounds named CID3100583 and 8,8-Ethylenebistheophylline, have become prominent as novel candidates, possibly disrupting MBD2MBD–DNA interaction. Hereby, these compounds exhibit a promising usage potential in a wide range of implementations from cancer treatment to somatic cell reprogramming protocols.

scholarly journals Association Between Polymorphisms of the Complement 3 Gene and Schizophrenia in a Han Chinese Population

2018 ◽  
Vol 46 (6) ◽  
pp. 2480-2486 ◽  
Author(s):  
Shangchao Zhang ◽  
Na Zhou ◽  
Rui Liu ◽  
Wenwang Rao ◽  
Mingjia Yang ◽  
...  
Keyword(s):  
Chinese Population ◽  
Significant Risk ◽  
Protective Role ◽  
Han Chinese ◽  
Genotype Distribution ◽  
Distribution Analysis ◽  
Nucleotide Polymorphisms ◽  
Han Chinese Population ◽  
Complement 3 ◽  
Risk Effect

Background/Aims: Schizophrenia is a severe psychiatric disorder, and complement 3 (C3) is closely related to schizophrenia. We investigated the association between C3 polymorphisms and schizophrenia in a Northeast Han Chinese population. Methods: A total of 2240 Chinese people, consisting of 1086 patients with schizophrenia and 1154 healthy controls, were recruited for this study. Ten single nucleotide polymorphisms (SNPs; rs11569562, rs344555, rs2241393, rs2241392, rs11569514, rs445750, rs451760, rs11672613, rs2230205, and rs2250656) in C3 were selected and genotyped. Results: Genotype distribution analysis indicated that rs11569514 was significantly associated with schizophrenia. In the dominant model (AA vs. GG+GA genotypes), we found a significant protective effect for rs344555 against schizophrenia (odds ratio [OR]: 0.72, 95% confidence interval [CI]: 0.53–0.99, P = 0.04). In the codominant model (TT vs. AA), we found a significant risk effect for rs11569514 on schizophrenia (OR: 4.39, 95% CI: 2.06–9.37, P < 0.001). Haplotypes, including TG (rs11569562 and rs344555), TGG (rs11569562-rs344555-rs2241393), AG (rs344555-rs2241393), CGGGT (rs11569562-rs344555-rs2241393-rs2241392-rs11569514), and ACGTG (rs11569514-rs445750-rs451760-rs11672613-rs2230205), showed either a risk or protective role for schizophrenia. Conclusions: SNP rs11569514 in C3 and haplotypes of C3 variants were associated with schizophrenia in a Han Chinese population.

scholarly journals Human Ring Chromosomes – New Insights for their Clinical Significance

2013 ◽  
Vol 16 (1) ◽  
pp. 13-19 ◽  
Author(s):  
R.S. Guilherme ◽  
E Klein ◽  
A.B. Hamid ◽  
S Bhatt ◽  
M Volleth ◽  
...  
Keyword(s):  
In Situ Hybridization ◽  
Clinical Signs ◽  
Ring Chromosome ◽  
Signs And Symptoms ◽  
Molecular Techniques ◽  
Ring Chromosomes ◽  
Multicolor Banding ◽  
Clinical Signs And Symptoms ◽  
Clinical Problems

Abstract Twenty-nine as yet unreported ring chromosomes were characterized in detail by cytogenetic and molecular techniques. For FISH (fluorescence in situ hybridization) previously published high resolution approaches such as multicolor banding (MCB), subcentromere-specific multi-color-FISH (cenM-FISH) and two to three-color-FISH applying locus-specific probes were used. Overall, ring chromosome derived from chromosomes 4 (one case), 10 (one case), 13 (five cases), 14, (three cases), 18 (two cases), 21 (eight cases), 22 (three cases), X (five cases) and Y (one case) were studied. Eight cases were detected prenatally, eight due developmental delay and dysmorphic signs, and nine in connection with infertility and/or Turner syndrome. In general, this report together with data from the literature, supports the idea that ring chromosome patients fall into two groups: group one with (severe) clinical signs and symptoms due to the ring chromosome and group two with no obvious clinical problems apart from infertility.

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