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Results for “chromosome modeling”

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At least 19 recordsLinked to original sources
PubMed1999

Clustering of radiation-produced breaks along chromosomes: modelling the effects on chromosome aberrations.

PURPOSE: For high-LET radiations, and perhaps even for hard X-rays, DNA double-strand breaks (dsb) are clustered nonrandomly along chromosomes; disproportionately, many inter-dsb segments are less than a few Mbp (10(6) base pairs). The implications of such dsb clustering for chromosome aberrations are analysed. METHODS: Chromosome segments between different dsb within one dsb cluster are assumed too small to detect in the aberration assay. Enumeration or Monte-Carlo computer simulations are used to compute the relative frequencies of many observable aberration patterns: apparently simple or visibly complex. The theoretical predictions are compared with X-ray data for human fibroblasts, involving painted chromosomes 1, 2, 4, 5, 7 or 13. RESULTS AND CONCLUSIONS: Surprisingly, cryptic dsb multiplicity does not affect the frequency ratios predicted for aberration patterns by a random breakage-and-rejoining model. The model is generally consistent with current data on many different types of aberrations, whether or not dsb usually occur in cryptic clusters. For a Revell-type exchange model, however, the predictions do depend on clustering configurations; they gradually approach the predictions of the breakage-and-rejoining model as average cluster multiplicity increases. The model is consistent with the data, for example with the ratio of visibly complex to apparently simple aberrations, only if there is considerable dsb clustering even at low-LET, with approximately 1.5 or more reactive dsb per cluster on average.

Chromosome Aberrations↗
PubMed1996

Effects of homology, size and exchange of the meiotic segregation of model chromosomes in Saccharomyces cerevisiae.

In most eukaryotic organisms, chiasmata, the connections formed between homologous chromosomes as a consequence of crossing over, are important for ensuring that the homologues move away from each other at meiosis I. Some organisms have the capacity to partition the rare homologues that have failed to experience reciprocal recombination. The yeast Saccharomyces cerevisiae is able to correctly partition achiasmate homologues with low fidelity by a mechanism that is largely unknown. It is possible to test which parameters affect the ability of achiasmate chromosomes to segregate by constructing strains that will have three achiasmate chromosomes at the time of meiosis. The meiotic partitioning of these chromosomes can be monitored to determine which ones segregate away from each other at meiosis I. This approach was used to test the influence of homologous yeast DNA sequences, recombination intiation sites, chromosome size and crossing over on the meiotic segregation of the model chromosomes. Chromosome size had no effect on achiasmate segregation. The influence of homologous yeast sequences on the segregation of noncrossover model chromosomes was negligible. In meioses in which two of the three model chromosomes experienced a crossover, they nearly always disjoined at meiosis I.

Chromosome Mapping↗
PubMed1983

Curves for modelling chromosome shapes.

Representation of chromosome shapes by a single smooth curve forms an important step in a chromosome analysis system. During development of an interactive system for use in plant chromosome studies, the behavior of certain types of curves commonly used in human chromosome analysis systems was found to be unsuitable for modelling plant chromosomes. These chromosomes require modelling by a flexible smooth curve, such as the cubic spline. Preliminary investigation of human chromosomes indicates that some of these must also be modelled by the cubic spline curve. The results of modelling chromosome shapes by several different types of curves are illustrated.

Chromosomes↗
PubMed2001

Modeling chromosomal instability and epithelial carcinogenesis in the telomerase-deficient mouse.

Human carcinomas are intimately linked to advancing age. These cancers have complex cytogenetic profiles, including aneuploidy and chromosomal structural aberrations. While aged humans sustain a high rate of carcinomas, mice bearing common tumor suppressor gene mutations typically develop soft tissue sarcomas and lymphomas. One marked species distinction between human and mouse that bears on the predisposition to carcinogenesis lies in the radical differences in length and regulation of the telomere, nucleoprotein complexes that cap the ends of eukaryotic chromosomes. Recent cancer modeling studies in the telomerase knockout p53 mutant mice revealed that telomere dynamics might be relevant to carcinogenesis. In these mice, there is a shift in the tumor spectrum towards epithelial carcinomas, and these cancers emerge with complex cytogenetic profiles classical for human carcinomas. In this review, we suggest that the mechanism of fusion-bridge-breakage-translocation, triggered by critically short telomeres, may be one of the generators of genomic instability commonly seen in human carcinomas.

Animals↗
PubMed1992

Male common shrews (Sorex araneus) with long meiotic chain configurations can be fertile: implications for chromosomal models of speciation.

Two chromosomal races of common shrews (Sorex araneus) were crossed in captivity to generate chain VII-forming complex Robertsonian heterozygotes. Meiosis and gametogenesis were studied in three male hybrids. Regular chain VII configurations were observed at both pachytene and diakinesis/metaphase I, although in many pachytene spreads the chain configuration was incomplete (the basis of this peculiarity is unknown). From metaphase II counts, the frequency of anaphase I nondisjunction in the complex heterozygotes was estimated to be 13%. Germ-cell death in the chain VII-forming complex heterozygotes was 22% greater than it was in controls, but this difference is unlikely to have greatly influenced the capacity of the heterozygotes to sire offspring. Thus, the fecundity of these complex heterozygous common shrews would probably have been only slightly reduced relative to homozygous or simple heterozygous shrews. These results call into question the generality of speciation models based on the presumed sterility of complex heterozygotes.

Animals↗
PubMed1979

Reconstruction of a chromosome model from its projections.

As a pilot experiment towards the reconstruction of human chromosomes from their electron microscopic projections, a chromosome model was photographed and several cross-sectional planes successfully reconstructed. Some practical constraints and conditions for this type of work are defined.

Chromatin↗
PubMed2002

Genome compartimentation by a hybrid chromosome model (HXM). Application to Saccharomyces cerevisae subtelomeres.

The aim of this paper is to present a new approach, called 'Hybrid Chromosome Model' (HXM), which allows both the extraction of regions of similarity between two sequences, and the compartimentation of a set of DNA sequences. The principle of the method consists in compacting a set of sequences (split into fragments of fixed length) into a 'hybrid chromosome', which results from the stacking of the whole sequence fragments. We have illustrated our approach on the 32 subtelomeres of Saccharomyces cerevisae. The compartimentation of these chromosome extremities into common regions of similarity has been carried out. The approach HXM is a fast and efficient tool for mapping entire genomes and for extracting ancient duplications within or between genomes.

Base Sequence↗
PubMed1975

[Stretched polytene chromosomes--model for studying the functional organization of eukaryotic chromosomes].

To localize functional loci on cytological maps of polytene chromosomes we propose to use 10-100 times stretched chromosomes. Three different ways of stretchening are briefly considered: the squash tissue preparation, when chromosomes are stretched by hydrodynamical forces; the treatment of isolated polytene chromosomes in 10-minus 4M EDTA OR 0.8M NaCL with subsequent change of these solution for saline when abrupt structural changes occur in chromosomes and they become morphologically homogeneous threads (Gruzdev and Belaya, 1973); and, finally, the use of microneedles of the micromanipulator. After an intense (ca. 100 times) stretchening, the autoradiography is sufficient to localize the loci within one micron length of double helical DNA molecule.

Chromosome Mapping↗
PubMed2002

Intrachromosomal exchange aberrations predicted on the basis of the globular interphase chromosome model.

One of the key questions in understanding mechanisms of chromosome aberration production is how does interphase chromosome structure affect aberration formation. To explore this a modelling approach is presented which combines Monte Carlo simulation of both alpha particle track and interphase chromosome structure. The structural state of interphase chromosome influences a dose-effect relationship for intrachromosomal exchange aberrations (intrachanges). It is shown that intrachanges are induced frequently by both X rays and alpha particles if the chromosome is in the condensed globular but not in the decondensed coiled state. Truly simple intra-arm intrachanges induced by X rays are dose squared in coiled chromosomes, but exhibit linear dose dependence in globular chromosomes. Experimental data on interarm intrachanges obtained by dual arm chromosome painting are analysed by means of the technique presented. Results of analysis support the conclusion about the arms proximity of chromosome 1 in human lymphocytes.

Chromatids↗
PubMed2000

A new chromosome model.

We present a new model of the three-dimensional structure of chromosomes. With DNA and protein staining it could be shown by high-resolution scanning electron microscopy that metaphase chromosomes are mainly composed of DNA packed in "chromomeres" (coiled solenoides) and a dynamic matrix formed of parallel protein fibers. In the centromeric region, the chromomeres are less densely packed, giving insight into the matrix fibers. We postulate that chromosome condensation is achieved by the binding of solenoids to matrix fibers which have contact sites to one another and move antiparallel to each other. As condensation progresses, loops of solenoids accumulate to form additional chromomeres, causing chromosomes to become successively shorter and thicker as more chromomeres are formed. For sterical reasons, a tension vertical to the axial direction forces the chromatids apart. The model can simply explain the enormous variety of chromosome morphology in plant and animal systems by varying only a few cytological parameters. Primary and secondary constrictions and deletions are defined as regions devoid of chromomeres. Even in the highly condensed metaphase, all genes would be easily accessible.

Chromatin↗
PubMed2001

Modelling chromosomal aberration induction by ionising radiation: the influence of interphase chromosome architecture.

Several advances have been achieved in the knowledge of nuclear architecture and functions during the last decade, thus allowing the identification of interphase chromosome territories and sub-chromosomal domains (e.g. arm and band domains). This is an important step in the study of radiation-induced chromosome aberrations; indeed, the coupling between track-structure simulations and reliable descriptions of the geometrical properties of the target is one of the main tasks in modelling aberration induction by radiation, since it allows one to clarify the role of the initial positioning of two DNA lesions in determining their interaction probability. In the present paper, the main recent findings on nuclear and chromosomal architecture are summarised. A few examples of models based on different descriptions of interphase chromosome organisation (random-walk models, domain models and static models) are presented, focussing on how the approach adopted in modelling the target nuclei and chromosomes can influence the simulation of chromosomal aberration yields. Each model is discussed by taking into account available experimental data on chromosome aberration induction and/or interphase chromatin organisation. Preliminary results from a mechanistic model based on a coupling between radiation track-structure features and explicitly-modelled, non-overlapping chromosome territories are presented.

Animals↗
PubMed2006

Modeling chromosomes in mouse to explore the function of genes, genomic disorders, and chromosomal organization.

One of the challenges of genomic research after the completion of the human genome project is to assign a function to all the genes and to understand their interactions and organizations. Among the various techniques, the emergence of chromosome engineering tools with the aim to manipulate large genomic regions in the mouse model offers a powerful way to accelerate the discovery of gene functions and provides more mouse models to study normal and pathological developmental processes associated with aneuploidy. The combination of gene targeting in ES cells, recombinase technology, and other techniques makes it possible to generate new chromosomes carrying specific and defined deletions, duplications, inversions, and translocations that are accelerating functional analysis. This review presents the current status of chromosome engineering techniques and discusses the different applications as well as the implication of these new techniques in future research to better understand the function of chromosomal organization and structures.

Aneuploidy↗
PubMed1997

Centric rings, acentric rings and excess acentric fragments based on a random-walk interphase chromosome model.

Excess acentric fragments, consisting of acentric rings and acentric linear fragments, are among the most frequent kinds of chromosome-type aberrations produced by radiation. The frequency of acentric rings cannot be obtained directly by experiment but is estimated here from the ratio of acentric to centric rings, evaluated using a random-walk model for the organization of chromatin during interphase and an assumption that the probability of an exchange formation is proportional to the rate of collision between two DSB. This ratio is calculated to be 2.5 in low-LET irradiated human fibroblasts, significantly greater than the ratio if proximity effects are not considered. The calculated frequency of acentric rings is insufficient to account for all the observed excess acentric fragments. Assuming that the rest of the excess acentric fragments are due to incomplete exchanges, all possible recombinations between two DSB that result in acentric rings and acentric linear fragments have been identified. From the chromosome aberration data, the incompleteness parameter has been estimated. Intra-arm chromosome exchanges, either complete or incomplete, were estimated to account for more than 50% of the excess acentric fragments in human fibroblasts.

Chromosome Aberrations↗
PubMed1999

Polymer chromosome models and Monte Carlo simulations of radiation breaking DNA.

MOTIVATION: Chromatin breakage by ionizing radiation is relevant to studies of carcinogenesis, tumor radiotherapy, biodosimetry and molecular biology. This article focuses on computer analysis of chromosome irradiation in mammlian cells. METHODS: Polymer physics and Monte Carlo numerical methods are used to develop a coarse-grained computational approach. Chromatin is modeled as a random walk on a cubic lattice, and the radiation tracks hitting the chromatin are modeled as straight lines hitting lattice sites. Each track can make a cluster of DSBs on a chromosome. RESULTS: The results obtained replace conjectured DNA fragment-size distribution functions in the recently developed RLC formalism by more mechanistically motivated distributions. The discrete lattice algorithm reproduces features of current radiation experiments relevant to chromatin on large scales. It approximates the continuous formalism and experimental data with adequate precision. It was also found that assuming either fixed chromatin with correlations among different clusters of DSBs or moving chromatin with no such correlations gives virtually identical numerical predictions.

Algorithms↗
PubMed2002

Using graph theory to describe and model chromosome aberrations.

A comprehensive description of chromosome aberrations is introduced that is suitable for all cytogenetic protocols (e.g. solid staining, banding, FISH, mFISH, SKY, bar coding) and for mathematical analyses. "Aberration multigraphs" systematically characterize and interrelate three basic aberration elements: (1) the initial configuration of chromosome breaks; (2) the exchange process, whose cycle structure helps to describe aberration complexity; and (3) the final configuration of rearranged chromosomes, which determines the observed pattern but may contain cryptic misrejoinings in addition. New aberration classification methods and a far-reaching generalization of mPAINT descriptors, applicable to any protocol, emerge. The difficult problem of trying to infer actual exchange processes from cytogenetically observed final patterns is analyzed using computer algorithms, adaptations of known theorems on cubic graphs, and some new graph-theoretical constructs. Results include the following: (1) For a painting protocol, unambiguously inferring the occurrence of a high-order cycle requires a corresponding number of different colors; (2) cycle structure can be computed by a simple trick directly from mPAINT descriptors if the initial configuration has no more than one break per homologue pair; and (3) higher-order cycles are more frequent than the obligate cycle structure specifies. Aberration multigraphs are a powerful new way to describe, classify and quantitatively analyze radiation-induced chromosome aberrations. They pinpoint (but do not eliminate) the problem that, with present cytogenetic techniques, one observed pattern corresponds to many possible initial configurations and exchange processes.

Algorithms↗
PubMed2000

A phenotype map of the mouse X chromosome: models for human X-linked disease.

The identification of many of the transcribed genes in man and mouse is being achieved by large scale sequencing of expressed sequence tags (ESTs). Attention is now being turned to elucidating gene function and many laboratories are looking to the mouse as a model system for this phase of the genome project. Mouse mutants have long been used as a means of investigating gene function and disease pathogenesis, and recently, several large mutagenesis programs have been initiated to fulfill the burgeoning demand of functional genomics research. Nevertheless, there is a substantial existing mouse mutant resource that can be used immediately. This review summarizes the available information about the loci encoding X-linked phenotypic mutants and variants, including 40 classical mutants and 40 that have arisen from gene targeting.

Animals↗
PubMed1986

Satellite DNA in the three C-bands of an unusual mouse marker chromosome. A model of chromosomal evolution.

A marker chromosome in the stemline of a new murine cell line is described on the basis of different stainings and in situ hybridization. The marker was characterized originally by three C-bands, one from each centromeric region of the three chromosomes constituting the marker. In the course of stemline evolution, two of the C-bands have been lost and the marker has developed into a monocentric chromosome, phenotypically and functionally normal.

Animals↗