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PubMed1994

HPV DNA in autopsy-derived material from multiple metastases of a cervical carcinoma.

Fresh tissue from primary tumor and a metastasis of a cervical carcinoma and 13 autopsy-derived tissue specimens of the same patient were analyzed for HPV DNA by Southern blot hybridization and PCR. Primary tumor and 7 of 10 histologically proven distant metastases contained HPV 16 DNA by Southern blot. PCR detected HPV 16 in all 10 metastases and in 2 of 3 additional tumor-free autopsy-derived tissues. The restriction pattern was identical in all HPV-positive lesions and only slight variations in copy number occurred. Two-dimensional gel electrophoresis showed the viral DNA fully integrated in the cellular genome without any difference between primary tumor and metastasis. The relevance of HPV also for the metastatic spread of the malignant disease is indicated by its conserved presence in multiple distant metastases of cervical carcinoma.

Adult↗
PubMed2001

Quantitative analysis of herpesvirus sequences from normal tissue and fibropapillomas of marine turtles with real-time PCR.

Quantitative real-time PCR has been used to measure fibropapilloma-associated turtle herpesvirus (FPTHV) pol DNA loads in fibropapillomas, fibromas, and uninvolved tissues of green, loggerhead, and olive ridley turtles from Hawaii, Florida, Costa Rica, Australia, Mexico, and the West Indies. The viral DNA loads from tumors obtained from terminal animals were relatively homogeneous (range 2-20 copies/cell), whereas DNA copy numbers from biopsied tumors and skin of otherwise healthy turtles displayed a wide variation (range 0.001-170 copies/cell) and may reflect the stage of tumor development. FPTHV DNA loads in tumors were 2.5-4.5 logs higher than in uninvolved skin from the same animal regardless of geographic location, further implying a role for FPTHV in the etiology of fibropapillomatosis. Although FPTHV pol sequences amplified from tumors are highly related to each other, single signature amino acid substitutions distinguish the Australia/Hawaii, Mexico/Costa Rica, and Florida/Caribbean groups.

Amino Acid Sequence↗
PubMedDate not supplied

[Chromosomal anomalies in children with undifferentiated forms of metal retardation based on molecular cytogenetic research data].

The results of cytogenetic diagnosis of 1333 children with mental retardation and congenital malformations are presented. Chromosomal aberrations and chromosomal variants (1qh+, 9qh+, 16qh+) have been detected in 181 (13.9%) cases analyzed and in 158 (11.85%) cases, respectively. Molecular cytogenetic methods have been used for diagnosis or detalization of diagnosis in 42 cases from 181 (23.2%). Independent variation (or polymorphism) of copies number of "classical" and alpha-satellite DNA sequences, forming pericentromeric regions (1qh+, 9qh+, 16qh+) has been detected in patients with chromosomal variants.

Child↗
PubMed2006

Comparative genomic hybridization and prenatal diagnosis.

PURPOSE OF REVIEW: Microarray-based comparative genomic hybridization (array-CGH) which detects aneuploidies and submicroscopic deletions and duplications in one assay is now offered for genetic diagnosis in children and adults. Its application to prenatal diagnosis is still limited, but very promising. We predict that array-CGH on fetal DNA obtained through amniocentesis or chorionic villus sampling and in the future possibly through noninvasive collection from the maternal cervix or blood, will transform the practice of prenatal diagnosis. RECENT FINDINGS: The power of array-CGH for genetic diagnosis and gene discovery is supported by recent studies. Most arrays for clinical use carry large DNA fragments, but alternative designs containing oligonucleotides will move into the clinic. Some oligonucleotide arrays can simultaneously analyze DNA copy number and single nucleotide polymorphisms, thereby adding potential assessment of uniparental disomy and paternity. Recent array-CGH studies have revealed extensive interindividual copy number variation of genomic segments, unanticipated complexity of apparently balanced translocations, and new phenotypes associated with DNA deletions and duplications. These observations affect counseling for prenatal diagnosis by array-CGH. SUMMARY: We believe that array-CGH will be embraced as a tool for prenatal diagnosis of chromosomal defects, but its introduction into clinical practice should proceed with caution by experienced laboratories.

Aneuploidy↗
PubMed1983

Differences in the organization and methylation patterns of integrated avian sarcoma proviral DNA sequences in nonpermissive and permissive mammalian cells.

Four types of avian sarcoma virus (ASV)-transformed mammalian cells were analyzed for the presence of ASV-specific sequences in their genome DNA. A great variability in the number of proviral copies and their structure within the DNA of these lines was observed. In all cells tested gag and src sequences were present in a flexible arrangement. The greatest variation was detected within proviral sequences corresponding to pol and env regions. The number of integrated ASV proviral copies do not correlate with the capability of these cells to produce viral particles. Virus-producing (K2S and K12) and virogenic (XC) cells contain in their chromosomal DNA at least one complete proviral genome, whereas proviral sequences in helper-dependent nonvirogenic cells are substantially changed. Provirus expression level does not correlate with the number of integrated virus copies. In the non-virus-producing cells the proviral sequences are hypermethylated.

Animals↗
PubMed2006

Copy number variation in regions flanked (or unflanked) by duplicons among patients with developmental delay and/or congenital malformations; detection of reciprocal and partial Williams-Beuren duplications.

Duplicons, that is, DNA sequences with minimum length 10 kb and a high sequence similarity, are known to cause unequal homologous recombination, leading to deletions and the reciprocal duplications. In this study, we designed a Multiplex Amplifiable Probe Hybridisation (MAPH) assay containing 63 exon-specific single-copy sequences from within a selection of the 169 regions flanked by duplicons that were identified, at a first pass, in 2001. Subsequently, we determined the frequency of chromosomal rearrangements among patients with developmental delay (DD) and/or congenital malformations (CM). In addition, we tried to identify new regions involved in DD/CM using the same assay. In 105 patients, six imbalances (5.8%) were detected and verified. Three of these were located in microdeletion-related regions, two alterations were polymorphic duplications and the effect of the last alteration is currently unknown. The same study population was tested for rearrangements in regions with no known duplicons nearby, using a set of probes derived from 58 function-selected genes. The latter screening revealed two alterations. As expected, the alteration frequency per unit of DNA is much higher in regions flanked by duplicons (fraction of the genome tested: 5.2%) compared to regions without known duplicons nearby (fraction of the genome tested: 24.5-90.2%). We were able to detect three novel rearrangements, including the previously undescribed reciprocal duplication of the Williams Beuren critical region, a subduplicon alteration within this region and a duplication on chromosome band 16p13.11. Our results support the hypothesis that regions flanked by duplicons are enriched for copy number variations.

Child↗
PubMed1995

PCR amplification of intergenic spacers in the ribosomal DNA of Drosophila melanogaster reveals high levels of turnover in length and copy-number of spacers in geographically separated populations.

A recently described PCR-based method for the analysis of intergenic spacer (IGS) length variation in the ribosomal (r) DNA of Drosophila melanogaster was used to analyse the distribution of IGS length variants in the rDNA of a number of recently collected D. melanogaster populations. One group of populations, from Europe and North Africa, was shown to have low intrapopulation IGS length variation following maintenance of massed populations in the laboratory for an extended period. However, a greater degree of IGS profile variability was detected at a number of levels in the majority of laboratory-maintained isofemale lines from two of these populations plus a second group of populations which were collected more recently from the eastern coast of Australia; all of which were immediately divided into isofemale lines following collection. Interestingly, PCR analysis of pooled DNA extracts from 30 individuals of either sex showed almost identical PCR profiles from each of the Australian populations. These preliminary results are discussed with regard to the possible combinations of forces (natural selection, neutral drift and genomic molecular drive) on the patterns of IGS length variation.

Animals↗
PubMed1995

Mitochondrial DNA rearrangements: intracellular information system.

The extent of mtDNA rearrangements has been analyzed in nDNA preparations of rat and human with a statistically representative group of oligonucleotides directed to two regions of mtDNA: genes for cytochrome oxidase subunits I and III. Human PCR preparations generated with oligonucleotides directed 'normally' showed the expected fragment for mtDNA and the presence of a plethora of fragments with rearrangements (deletions and insertions), in contrast to rat PCR preparations under the same reaction conditions in which these kinds of rearranged fragments were rarely observed. Both human and rat PCR preparations generated with oligonucleotides directed 'inversely' showed numerous fragments, some of which showed differences in copy number correlating with distinct phases during development/aging. Sequence analysis of some normal and rearranged fragments demonstrated in all cases DNA sequences 99% homologous with other mtDNA sequences at rearranged fragments. No evidence of nuclear DNA sequences was found. The following scheme is proposed for mtDNA rearrangements during the lifetime of an organism: variation in copy number of some fragments with inversions of mtDNA depends on the specific developmental/aging period; in old cells there is an increase in higher molecular weight mtDNA deletions. These findings strongly suggest that the mtDNA rearrangements play a role as an intracellular 'information system'.

Adult↗
PubMed1989

The Caenorhabditis elegans genome contains monomorphic minisatellites and simple sequences.

Many species have been shown to contain tandemly repeated short sequence DNA known as minisatellites and simple sequence motifs. Due to allelic variation in the copy number of the repeat unit these loci are usually highly polymorphic. Here we demonstrate the presence of sequences in the genome of the nematode Caenorhabditis elegans which are homologous to two sets of short sequence DNA. However, when two independent strains were compared no polymorphism for these sequences could be detected.

Animals↗
PubMed1984

Tandem repeated DNA in an intergenic region of herpes simplex virus type 1 (Patton).

When the entire US region of HSV-1 (Patton) was cloned as an EcoRI fragment in bacteriophage lambda gtWES, the BamHI B6B5 fragment was observed to vary in size among independent isolates [Umene and Enquist, Gene 13 (1981) 251-268]. This fragment polymorphism also occurred in DNA of HSV-1 single plaque isolates. We report here that this heterogeneity is due to variation in copy number of a 15-bp tandem repeat of sequence 5'-CCACTCCCCACCCAC-3', which apparently lies in an intergenic region of the HSV-1 DNA.

Base Sequence↗
PubMed1992

Nucleotide variation and molecular structure of the heterochromatic repetitive AluI DNA in the brine shrimp Artemia franciscana.

It has been suggested that DNA bending could play a role in the regulation of gene expression, chromosome segregation, specific recombination and/or DNA packaging. We have previously demonstrated that an AluI DNA family of repeats is the major component of constitutive heterochromatin in the brine shrimp A. franciscana. By the analysis of cloned oligomeric (monomer to hexamer) heterochromatic fragments we verified that the repetitive AluI DNA shows a stable curvature that determines a solenoidal geometry to the double helix. This particular structure could be of relevant importance in conferring the characteristic heterochromatic condensation. In this paper we evaluate how the point mutations that occurred during the evolution of the AluI sequence of A. franciscana could influence the sequence-dependent tridimensional conformation. The obtained data underline that, in spite of the high sequence mutation frequency (10%) of the repetitive DNA, the general structure of the heterochromatic DNA is not greatly influenced, but rather there is a substantial variation of the copy number of the repetitive AluI fragment. This variation could be responsible for the hypothetical function of the constitutive heterochromatin.

Animals↗
PubMed2004

[Detection of HPV16 E6 gene in cervical tissues by quantitative polymerase chain reaction].

OBJECTIVE: To establish a method for detection of Human Papillomavirus (HPV) type16 E6 gene in Cervical carcinomas Specimens. To study the relationship between the quantities of HPV16 E6 (Human papillomavirus type16 E6 gene) in cervical tissues and the course of cervical disease in Xinjiang. METHODS: HPV16E6 gene and beta-actin was detected in parallel by FQ-PCR (fluorescence quantitative PCR). The number of copies of HPV16 E6 gene and beta-actin was detected in parallel by FQ-PCR (fluorescence quantitative PCR) in tissues of 69 cervical cancer, 65 cervical intraepithelial neoplasia (CIN), 33chronic cervicitis and samples of 96 cervical smear samples of vaginitis and cervicitis. The variation in HPV copies per genomic DNA equivalent can be estimated by dividing the HPV copy number by the beta-actin copy number. RESULTS: The positive rate of HPV16 E6 gene was 83.0%, 75.7%, 93.3% and 3.3% in tissues of cervical cancer, cervical intraepithelial neoplasia (CIN), chronic cervicitis and samples of cervical smear respectively. The amount of HPV16 E6 gene was gradually higher by the developing of the course of cervical disease. They have positive rank correlation, r = 0.83, P < 0.01. CONCLUSION: The study underscores the importance of the relationship between the HPV16 E6 gene and the course of cervical disease in Xinjiang. It also suggests that the quantification of HPV16 E6 gene may be useful as a prognostic tool to identify women who are at increased risk of developing cervical cancer. This method may be applied to studies of a number of issues related to the natural history of cervical cancer, such as the amounts of HPV in high- and low-grade lesions.

Cervix Uteri↗
PubMed2026

Integrated Clinicopathologic and Multiomic Profiling Reveals MEIS1-Rearranged Sarcoma as a Distinct Entity With 2 Prognostic Subgroups.

Sarcomas with MEIS1 fusions represent a rare, recently recognized group of mesenchymal neoplasms with a predilection for genitourinary and gynecologic sites. A subset exhibits skeletal muscle differentiation resembling spindle cell rhabdomyosarcoma. Existing literature is limited to case reports and small series, with scant comprehensive clinicopathologic, molecular, and outcome data. In this study, we analyzed a multi-institutional cohort of 20 MEIS1-rearranged sarcomas using integrated clinicopathologic review, genomic profiling, and DNA methylation analysis. The tumors occurred in 17 females and 3 males (median age, 41 years; range, 6-58 years), arising mainly in the uterus/vagina (n = 12), vulva/perineum (n = 4), bone (n = 2), and kidney (n = 2), with a median size of 9 cm (range, 2.5-20 cm). Histology showed mostly bland spindle cells in fascicles/storiform patterns, alternating cellularity, fibromyxoid stroma, prominent vascularity, and adipose metaplasia (45%). A subset of cases featured high-grade morphology with epithelioid cells and increased mitotic activity. Skeletal muscle markers were variably positive in 9 cases. Fusions involved MEIS1 with NCOA2 (16/20), NCOA1 (3/20), or FOXO1 (1/20). Recurrent additional genomic alterations included CTNNB1 mutations (31.6%) and MDM2 amplification (15%). DNA methylation profiling showed that MEIS1-rearranged sarcomas formed a unifying cluster comprising 2 subgroups, regardless of rhabdomyosarcomatous phenotype, clearly separated from other mesenchymal neoplasms, including various rhabdomyosarcoma subtypes and uterine sarcomas. The 2 DNA methylation (Meth) subgroups correlated with differences in genome-wide copy number variation (CNV) status (Meth-CNV high vs Meth-CNV low), with Meth-CNV high tumors characterized by high mitotic rate, frequent tumor necrosis, recurrent co-occurring CTNNB1 and MDM2 alterations, and recurrent chromosomal arm-level changes. Most importantly, this subgroup exhibited significantly worse overall survival (P = .027) and disease-free survival (median, 5 vs 99 months; P = .017). This study establishes MEIS1-rearranged sarcoma as a distinct entity with generally indolent but potentially aggressive behavior. The 2 methylation/CNV subgroups provide potential utility for prognostic stratification and highlight actionable molecular targets in high-risk cases.

Humans↗
PubMed2000

Structure and organization of the rDNA intergenic spacer in lake trout (Salvelinus namaycush).

A total-genomic cosmid library was created to isolate complete copies of the rDNA cistron of lake trout (Salvelinus namaycush) in order to study the structure and organization of the intergenic spacer (IGS) in this species. A total of 60 rDNA-positive clones (average inserts > 25 kb) was recovered by screening the library with a rDNA-specific probe. Positive clones were assayed for the presence of the two internal rDNA spacers (ITS-1 and ITS-2) and the entire IGS fragment was successfully amplified from 42 clones by PCR. Length of the IGS fragments ranged from 9.4 to 17.8 kb. Comparative restriction mapping of the IGS-PCR products of several clones indicated two regions of extensive length variation surrounding a central region with sequence conservation. DNA sequence analysis was used to investigate the molecular basis of the IGS length variation and focused on identifying the region responsible for this variation. Over 9 kb of DNA sequence was obtained for one clone (A1) with a total IGS length of approximately 12.4 kb. Sequence of a conserved central region contained two open reading frames and a number of short direct repeats. Length variation in the IGS was determined by RFLP to result from differences in the number of copies of repetitive DNA sequences. These included an 89-bp tandem repeat (alpha repeats), an 82-bp element (beta repeats), a 168-177-bp element (chi repeats), and a 179-201-bp element (delta repeats). Overall nucleotide composition of the IGS was biased towards A and T (%GC = 47.4). Maintenance of discrete rDNA-length variants in lake trout suggests that the rate of gene conversion is insufficient to produce homogeneous copies across the genome.

Animals↗
PubMed2005

A graphical simulation model of the entire DNA process associated with the analysis of short tandem repeat loci.

The use of expert systems to interpret short tandem repeat DNA profiles in forensic, medical and ancient DNA applications is becoming increasingly prevalent as high-throughput analytical systems generate large amounts of data that are time-consuming to process. With special reference to low copy number (LCN) applications, we use a graphical model to simulate stochastic variation associated with the entire DNA process starting with extraction of sample, followed by the processing associated with the preparation of a PCR reaction mixture and PCR itself. Each part of the process is modelled with input efficiency parameters. Then, the key output parameters that define the characteristics of a DNA profile are derived, namely heterozygote balance (Hb) and the probability of allelic drop-out p(D). The model can be used to estimate the unknown efficiency parameters, such as pi(extraction). 'What-if' scenarios can be used to improve and optimize the entire process, e.g. by increasing the aliquot forwarded to PCR, the improvement expected to a given DNA profile can be reliably predicted. We demonstrate that Hb and drop-out are mainly a function of stochastic effect of pre-PCR molecular selection. Whole genome amplification is unlikely to give any benefit over conventional PCR for LCN.

Computer Graphics↗
PubMed2006

Structural variants: changing the landscape of chromosomes and design of disease studies.

The near completeness of human chromosome sequences is facilitating accurate characterization and assessment of all classes of genomic variation. Particularly, using the DNA reference sequence as a guide, genome scanning technologies, such as microarray-based comparative genomic hybridization (array CGH) and genome-wide single nucleotide polymorphism (SNP) platforms, have now enabled the detection of a previously unrecognized degree of larger-sized (non-SNP) variability in all genomes. This heterogeneity can include copy number variations (CNVs), inversions, insertions, deletions and other complex rearrangements, most of which are not detected by standard cytogenetics or DNA sequencing. Although these genomic alterations (collectively termed structural variants or polymorphisms) have been described previously, mainly through locus-specific studies, they are now known to be more global in occurrence. Moreover, as just one example, CNVs can contain entire genes and their number can correlate with the level of gene expression. It is also plausible that structural variants may commonly influence nearby genes through chromosomal positional or domain effects. Here, we discuss what is known of the prevalence of structural variants in the human genome and how they might influence phenotype, including the continuum of etiologic events underlying monogenic to complex diseases. Particularly, we highlight the newest studies and some classic examples of how structural variants might have adverse genetic consequences. We also discuss why analysis of structural variants should become a vital step in any genetic study going forward. All these progresses have set the stage for a golden era of combined microscopic and sub-microscopic (cytogenomic)-based research of chromosomes leading to a more complete understanding of the human genome.

Chromosomes↗
PubMed2005

Identification of genetic aberrations on chromosome 22 outside the NF2 locus in schwannomatosis and neurofibromatosis type 2.

Schwannomatosis is characterized by multiple peripheral and cranial nerve schwannomas that occur in the absence of bilateral 8th cranial nerve schwannomas. The latter is the main diagnostic criterion of neurofibromatosis type 2 (NF2), which is a related but distinct disorder. The genetic factors underlying the differences between schwannomatosis and NF2 are poorly understood, although available evidence implicates chromosome 22 as the primary location of the gene(s) of interest. To investigate this, we comprehensively profiled the DNA copy number in samples from sporadic and familial schwannomatosis, NF2, and a large cohort of normal controls. Using a tiling-path chromosome 22 genomic array, we identified two candidate regions of copy number variation, which were further characterized by a PCR-based array with higher resolution. The latter approach allows the detection of minute alterations in total genomic DNA, with as little as 1.5 kb per measurement point of nonredundant sequence on the array. In DNA derived from peripheral blood from a schwannomatosis patient and a sporadic schwannoma sample, we detected rearrangements of the immunoglobulin lambda (IGL) locus, which is unlikely to be due to a B-cell specific somatic recombination of IGL. Analysis of normal controls indicated that these IGL rearrangements were restricted to schwannomatosis/schwannoma samples. In the second candidate region spanning GSTT1 and CABIN1 genes, we observed a frequent copy number polymorphism at the GSTT1 locus. We further describe missense mutations in the CABIN1 gene that are specific to samples from schwannomatosis and NF2 and make this gene a plausible candidate for contributing to the pathogenesis of these disorders.

Adaptor Proteins, Signal Transducing↗
PubMed1992

Heterogeneity in state and expression of viral DNA in polyoma virus-induced tumors of the mouse.

We have examined the state and expression of polyoma viral DNA in representative epithelial and mesenchymal tumors, using a combination of biochemical and in situ methods. Results showed wide variations among tumor types and also in different regions within individual tumors, with respect to copy number of viral DNA, presence or absence of deletions, and expression of early and late viral proteins. Epithelial tumors showed the greatest heterogeneity. High copy free viral DNA, frequently with deletions, was found in all such tumors. A portion of free viral DNA was recoverable as transcriptionally active minichromosomes. Three distinct subpopulations of cells were distinguished by in situ analyses. Type 1 cells showed high copy free viral DNA and expressed the major viral capsid protein VP1; these cells appeared to be at various stages of productive (lytic) viral infection. Some productively infected cells were able to undergo mitosis; in a portion of these cells, VP1 was found in close association with the mitotic spindle. Type 2 cells contained high copy free DNA but did not express VP1; by some unknown mechanism, these cells manifest a post-replication block to late gene expression and lytic infection. Type 3 cells contained only low copy, presumably integrated, viral DNA and expressed no VP1; they thus resemble cells transformed in vitro by the virus. Epithelial tumors contained variable mixtures of these subpopulations, while mesenchymal tumors were composed of Type 3 cells only. Differences in virus-cell interactions are discussed in terms of their possible implications in tumor development.

Animals↗