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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.
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.
Mitotic chromosome organization and assembly remain fundamental questions in genetics. Since the chromosome scaffold model proposed in 1977 highlighted the role of nonhistone proteins in determining chromosome shape and size, key nonhistone proteins, including condensins and topoisomerase IIα (topoIIα), have been shown to play critical roles in organizing chromosome axes and chromatin loops. Emerging evidence from biochemistry, imaging, and genomics suggests that mitotic chromosome assembly is a dynamic process driven by the interplay of condensin-mediated looping, topoIIα-dependent entanglement/disentanglement, and multiple physical forces, including electrostatic nucleosome interactions, linker histone H1, free Mg2+, and depletion attraction. In this review, we discuss how these mechanisms contribute to chromosome assembly and propose that interphase chromatin domains function as dynamic building blocks of mitotic chromosomes.
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In many organisms, most notably Drosophila, homologous chromosomes associate in somatic cells, a phenomenon known as somatic pairing, which takes place without double strand breaks or strand invasion, thus requiring some other mechanism for homologs to recognize each other. Several studies have suggested a "specific button" model, in which a series of distinct regions in the genome, known as buttons, can associate with each other, mediated by different proteins that bind to these different regions. Here, we use computational modeling to evaluate an alternative "button barcode" model, in which there is only one type of recognition site or adhesion button, present in many copies in the genome, each of which can associate with any of the others with equal affinity. In this model, buttons are nonuniformly distributed, such that alignment of a chromosome with its correct homolog, compared with a nonhomolog, is energetically favored; since to achieve nonhomologous alignment, chromosomes would be required to mechanically deform in order to bring their buttons into mutual register. By simulating randomly generated nonuniform button distributions, many highly effective button barcodes can be easily found, some of which achieve virtually perfect pairing fidelity. This model is consistent with existing literature on the effect of translocations of different sizes on homolog pairing. We conclude that a button barcode model can attain highly specific homolog recognition, comparable to that seen in actual cells undergoing somatic homolog pairing, without the need for specific interactions. This model may have implications for how meiotic pairing is achieved.
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A theoretical model to explain the occurrence of chromosome rearrangements at the DNA molecular level is proposed. It involves: (10) breakage of one strand of each DNA molecule; (20) enzymatic digestion by an exonuclease of a short sequence of bases adjacent to the lesion, hence the presence of a short monocatenar segment on the complementary strand; (30) association of two monocatenar sequences if they are sufficiently complementary hence the formation of an X-shaped heteroduplex; (40) repair synthesis of DNA and, during this repair, an exhange of strands identical to that occuring in sister-chromatid exchanges, hence the rearrangement. This model has the advantage of necessitating one single breakpoint per DNA molecule, and explains the efficiency of radiations with low linear transfer of energy, such as X- and gamma-rays. It also explains how rearrangements such as translocations can be totally balanced since they would occur base to base within identical sequences.
A multivariate Gaussian model for mammalian development is presented with the associated biological and mathematical assumptions. Many biological investigations use the female mammal X chromosome to test hypotheses and to estimate parameters of the developmental system. In particular, Lyon's (1961) hypotheses are used as a basis of the mathematical model. Experimental mouse data and three sets of human experimental data are analyzed using the hypothesized Gaussian model. The estimated biological parameters are consistent with some current biological theories.
Karyotype analyses were conducted on spontaneous mammary tumors of 11 GR, 2 C3H, and 2 noninbred Swiss mice with the use of trypsin-Giemsa banding procedures. All tumors manifested trisomy of chromosome No 13 in most cells, and all except 1 tumor had cells with a model chromosome number of 40.
The karyotype of the human cell line, J-111, has been studied employing R-banding by fluorescence using acridine orange technique (RFA). The model chromosome number of this line was 112. All human chromosomes except the Y were present in each metaphase. Twenty-one marker chromosomes were distinguished and their possible origins were investigated. Of these, twelve were consistently present in all cells. Nine markers were highly variable. Four typical marker chromosomes of HeLa cells were found and their origins were identified, indicating that the line is a HeLa contaminant. The reverse banding patterns of all marker chromosomes are presented and the value of the RFA technique is discussed.
Several cell lines, originally thought to be derived from a human placenta at term but possibly HeLa-contaminated, have been studied. These cells secrete a protein indistinguishable immunochemically from the alpha subunit of chorionic gonadotropin but not the beta subunit of chorionic gonadotropin or placental lactogen. Complete chorionic gonadotropin was detected but amounted to less than 1% of the level of the alpha subunit. The cells also produce an alkaline phosphatase similar to placental alkaline phosphatase in immunochemical, gel-electrophoretic, and heat-denaturation properties. They induce tumor growth when inoculated into nude mice. These cells are aneuploid and have a model chromosome number of 66. The common HeLa karyologic markers, designated 1, 2, and 3, and A-type glucose-6-phosphate dehydrogenase are present in these cells. HeLa cells have not previously been shown to secrete the alpha subunit of hCG.
1. Successive sampling of ovarian cancers during cytostatic treatment showed several cases of notable changes in their ploidy distribution and one change in model chromosome number, indicating selection of a resistant tumour-cell population. 2. Studies of cell suspensions from human tumour specimens incubated with [3H]-TdR after exposure in vitro to various cytostatic agents have shown variation in labelling between different parts of the same tumour, as well as between the primary tumour and its metastases or ascitic tumour-cell population, which may be accounted for by variation in sensitivity of the tumour-cell population. 3. Studies of nuclear morphology in 20 endometrial cancers before and after progesterone therapy demonstrate considerable variation in the proportion of cells undergoing secretory conversion within the same tumour, indicating primary heterogeneity of the tumour-cell population in response to progesterone.
MOTIVATION: Chromosome Conformation Capture methods, including Hi-C, micro-C or Capture-C, are used to map chromatin interactions genome-wide. Most of the existing computational methods do not account for sources of bias (such as DNA accessibility, GC content or TE content) in the data. RESULTS: We previously developed ZipHiC, a Bayesian method based on the hidden Markov random field (HMRF) model and the Approximate Bayesian Computation (ABC), that uses zero-inflated Poisson distribution to model the noise, signal and false signal of the data and showed that this approach was able to detect bias from DNA accessibility, GC content and TE content in both Hi-C and micro-C data. Here, we present HiCPotts, another Bayesian method based on the HMRF model and the ABC that uses a zero-inflated Negative Binomial distribution instead to model the noise and signal of the data. We systematically show that HiCPotts reduces false positives and increases recovery of true interactions compared to ZipHiC, but also compared to other methods such as FastHiC, Juicer and HiCExplorer. Most importantly, we provide an R/Bioconductor package that allows modelling the noise, signal and false signal using various distributions such as the zero-inflated Negative Binomial (ZINB) and the zero-inflated Poisson distribution (ZIP). AVAILABILITY AND IMPLEMENTATION: https://bioconductor.org/packages/HiCPotts/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
A general method is presented for stable transfer of genetic information to eukaryotic cells, utilizing metaphase chromosomes as the vehicle. Recent progress, current problems and large areas of uncertainty in this field are reviewed; particular consideration is given to frequency of transfer, size of the transgenome, evidence of cotransfer of linked genes and serial chromosome transfer. A reasonable model for chromosome transfer is considered with respect to the available information, and various descrepancies are noted. The utility of this method for fine structural mapping, cloning small regions of the eukaryotic genome and other potential applications are discussed.
Some difficulties with the classical model for the evolution of a genetically invert Y chromosome are discussed. An alternative model is proposed, which is based on the principle of Mullers ratchet; this involves the accumulation of chromosomes bearing deleterious mutant genes in a finite population in the absence of crossing-over. This process would result in the gradual increase, with time, in the number of mutant loci carried in an average Y chromosome, although the frequency of individual deleterious alleles at most loci remains low. It is shown that this creates a selection pressure for differentially increasing the activity of the X chromosome in heterogametic individuals at the expense of that of the Y, leading eventually to a genetically inert Y chromosome and to the evolution of dosage compensation.
Cancer development is characterized by chromosomal instability, manifesting in frequent occurrences of different genomic alteration mechanisms ranging in extent and impact. Mathematical modeling can help evaluate the role of each mutational process during tumor progression, however existing frameworks can only capture certain aspects of chromosomal instability (CIN). We present CINner, a mathematical framework for modeling genomic diversity and selection during tumor evolution. The main advantage of CINner is its flexibility to incorporate many genomic events that directly impact cellular fitness, from driver gene mutations to copy number alterations (CNAs), including focal amplifications and deletions, missegregations and whole-genome duplication (WGD). We apply CINner to find chromosome-arm selection parameters that drive tumorigenesis in the absence of WGD in chromosomally stable cancer types from the Pan-Cancer Analysis of Whole Genomes (PCAWG, [Formula: see text]). We found that the selection parameters predict WGD prevalence among different chromosomally unstable tumors, hinting that the selective advantage of WGD cells hinges on their tolerance for aneuploidy and escape from nullisomy. Analysis of inference results using CINner across cancer types in The Cancer Genome Atlas ([Formula: see text]) further reveals that the inferred selection parameters reflect the bias between tumor suppressor genes and oncogenes on specific genomic regions. Direct application of CINner to model the WGD proportion and fraction of genome altered (FGA) in PCAWG uncovers the increase in CNA probabilities associated with WGD in each cancer type. CINner can also be utilized to study chromosomally stable cancer types, by applying a selection model based on driver gene mutations and focal amplifications or deletions (chronic lymphocytic leukemia in PCAWG, [Formula: see text]). Finally, we used CINner to analyze the impact of CNA probabilities, chromosome selection parameters, tumor growth dynamics and population size on cancer fitness and heterogeneity. We expect that CINner will provide a powerful modeling tool for the oncology community to quantify the impact of newly uncovered genomic alteration mechanisms on shaping tumor progression and adaptation.
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The basic technical facts of human cytogenetics and the laboratory methods employed in chromosome research are explained in simple terms. The main variables used to describe chromosome images are defined and discussed. Three discriminant analysis models for chromosome classification are developed: one in which each chromosome is classified in isolation, a modification in which the cell, if normal, contains 2 chromosomes of each of the 23 kinds, and a final one in which the cell is the unit of analysis instead of the chromosome. Suggestions are made to reduce the calculations involved and to take into account missing chromosomes. The problem of detection and classification of aberrative chromosomes is studied, also in relation to multiple cell analysis. Finally four relevant problems are briefly discussed: selection of metaphase spreads, selection of variables, uncertain reference classification and measurement of performance.