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Results for “DNA Copy Number Variations”

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PubMed1988

Unequal partitioning of bovine mitochondrial genotypes among siblings.

Two polymorphic mitochondrial DNA genomes, differing by a single Hpa II restriction site, are present at significantly different levels in tissue of three sibling dairy cows. The relative ratio of the two heteroplasmic molecules varies 3-fold among these three animals and documents a rapid segregation of mitochondrial genotypes in mammals. DNA sequencing shows the difference is due to a single guanine at position 364 in bovine mitochondrial DNA. A model involving unequal partitioning of the two amplified mitochondrial DNA species during the early cell divisions of the embryo can explain the appearance of such variation in heteroplasmic sibling animals. The model provides a basis for understanding the rapid DNA sequence variation observed in vertebrate mitochondrial DNA despite its high copy number and strict maternal inheritance.

Animals↗

PubMed1984

Effects of promoter strengths and growth conditions on copy number of transcription-fusion vectors.

Promoters with widely different transcriptional activities have been fused to the galactokinase gene contained in a multicopy plasmid ( McKenny , K., Shimatake , H., Court, D., Schmeissner , U., Brady, C., and Rosenberg, M. (1982) in Gene Amplification and Analysis: Analysis of Nucleic Acids ( Chirkjian , J. G., and Papas , T., eds) pp. 383-415, Elsevier /North-Holland Biomedical Press, Netherlands). Assay methods which allow determination of galactokinase-specific activity (nanomoles of galactose 1-phosphate/min/mg of protein) and plasmid-specific number (femtomoles of plasmid/mg of protein) in the same sonicated cellular extract are described. These methods provide a way to accurately measure and compare the promoter activities (nanomoles of galactose 1-phosphate/min/fmol of plasmid) of different plasmid constructions which exhibit different in vivo plasmid copy numbers. It is demonstrated that in vivo, copy number fluctuations are correlated with such parameters as promoter strength and cellular growth conditions. The ability to account for these uncontrolled in vivo copy number variations when comparing the transcriptional activities of different DNA inserts in multicopy transcription-fusion plasmids greatly facilitates the utility of these systems.

Base Sequence↗

PubMed1989

Distribution of the P-associated-pilus (pap) region among Escherichia coli from natural sources: evidence for horizontal gene transfer.

Variation in chromosomal DNA in Escherichia coli was studied with probes specific for the P-associated-pilus (pap) region. The presence of DNA homologous to pap was determined by dot blots. Variation in the number of copies of pap and in the organization of internal and flanking sequences was determined by Southern blot hybridization. The 229 strains studied were also classified by O:K:H serotyping and multilocus enzyme electrophoresis. There was considerable heterogeneity in the presence of pap and distribution of pap-homologous DNA in these E. coli strains from natural sources. In general, there was less variation in pap among strains of the same specific O:K:H serotype and enzyme electrophoretic type than among random isolates. There were, however, E. coli strains identified as members of the same clone by O:K:H serotyping and enzyme electrophoresis that were pap positive and pap negative or had different Southern blot patterns for the pap probes (pap type). There were also isolates of the same pap type that differed in two of three O:K:H serotype antigens and the majority of enzymes that determined their enzyme electrophoretic type. These latter two observations were interpreted as evidence for the horizontal (infectious) transfer of the pap-homologous sequences among clones of E. coli.

Bacterial Adhesion↗

PubMed1986

The evolution of the alpha- and beta-globin gene clusters in human populations.

DNA analysis of the alpha- and beta-globin gene clusters has revealed substantial variability between individuals and populations. As well as restriction enzyme site and length polymorphisms, variation in gene copy number and type is observed. Because of this extensive polymorphism DNA analysis offers a highly informative method of studying genetic affinities between human populations. Haplotypes, consisting of a set of restriction enzyme polymorphisms distributed along the cluster, have been developed for both loci. Analysis of the molecular basis of numerous beta-thalassaemia alleles has revealed, in general, different sets of mutations in different populations, indicating that these postdate the racial divergence. Recent microepidemiological studies on the distribution of alpha-thalassaemia support the hypothesis that this condition, like the beta s-mutation, has been selected because it confers protection against malaria. Population-specific DNA polymorphisms at these and other loci promise to be of considerable value to genetic anthropology.

Genetics, Population↗

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↗

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↗

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↗

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↗

PubMed1988

Studies of a novel repetitive sequence family in the genome of mice.

A new middle repetitive sequence is described in the mouse genome. It has been revealed with a recombinant clone isolated from a Mus musculus BamHI gene library constructed in pBR322 and containing an insertion of 1.73 kb. When digests of genomic DNA were subjected to Southern blot hybridization, using the 1.73-kb insert as probe, we obtained a light smear and discrete bands, indicating a dispersion in the mouse genome of this sequence. This 1.73-kb sequence seems to be a part of a greater repetitive sequence at least 6 kb in length. The sizes of the bands hybridizing with the 1.73-kb insert are similar when compared between different laboratory strains but differ remarkably between the two species M. musculus and Mus caroli. We have shown also a great variation in the copy number of the sequence studied between these two species. When rat DNA is probed with the 1.73-kb insert, no hybridization is observed. Subcloning of the 1.73-kb sequence in three fragments has pointed out that the reiteration was not homogeneous along the 1.73-kb sequence. The 1.73-kb clone was sequenced and compared with other interspersed repetitive sequences, previously described in the rodent genome, and no homology was found.

Animals↗

PubMed1991

Possible repetitive DNA markers for Eusorghum and Parasorghum and their potential use in examining phylogenetic hypotheses on the origin of Sorghum species.

Genomic structures of two major species in section Eusorghum (Sorghum), Sorghum bicolor and Sorghum halepense, and their phylogenetic relationships with a species in section Parasorghum, Sorghum versicolor, were studied by using cloned repetitive DNA sequences from the three species. Of the five repetitive DNA clones isolated from S. bicolor and S. halepense, four produced qualitatively similar hybridization patterns with detectable variations in copy numbers of some of the restriction fragments on the Southern blots of the two genomic DNAs. One clone was shown to be diagnostic for S. halepense. Molecular analysis at the DNA level indicates that S. bicolor and S. halepense have similar but not identical genomes, consonant with differences in karyotypes, meiotic chromosome behaviors, morphology, and physiology of the species. In addition to five repetitive clones isolated from S. bicolor and S. halepense, eight more sequences were cloned from S. versicolor. Nine clones were found to be specific for either S. bicolor and S. halepense or S. versicolor. The remaining four had a moderate to strong homology with sequences present in all Sorghum species studied. We speculate that the genome in the common ancestor of Sorghum has differentiated to give rise to genomes of at least three major chromosome sizes; large, medium, and small, as seen at present. Amplifications, eliminations, rearrangements, and new syntheses of repetitive sequences may have been involved in genome differentiation of these species. The results also suggest that the S. versicolor genome has strongly diverged from the genomes of the two species in section Eusorghum.

Base Sequence↗

PubMed1987

Phylogenetic screening of the human genome: identification of differentially hybridizing repetitive sequence families.

The phi-screen, a method of phylogenetic screening, can be employed to detect repetitive sequence families that differentially hybridize between closely related species. Such differences may involve sequence divergence or variations in copy number, including total presence versus absence of a family of repeated DNA. We present the results of a phi-screen comparing the human genome to that of the prosimian, Galago crassicaudatus. Three human repetitive families that are divergent or not present in galago have been detected. One of these families is described in detail; it is similar among the anthropoids but is present in a lower copy number and/or divergent form in prosimians. The family is clearly related to the transposon-like human element (THE) described by Paulson et al. (1985). THEs have long terminal repeats reminiscent of retroviruses but are unique in that they have no sequence similarity to known mammalian retroviruses. The sequence of a solo long terminal repeat, found unassociated with THE internal sequence, is presented. This family member, THE p2, is bordered by a 5-bp target-site repeat and is interrupted by the insertion of an Alu element. A solo THE element sequenced by Wiginton et al. (1986) contains an insertion of Alu at precisely the same position as does THE p2.

Animals↗

PubMed1990

Molecular characterization of a repeat element causing large-scale size variation in the mitochondrial DNA of the sea scallop Placopecten magellanicus.

The scallop Placopecten magellanicus has the largest reported animal mitochondrial DNA (average 35 kb) and exhibits large inter- and intraindividual length variation owing to the varying copy number of a repeated element. We have characterized the repeat array by using restriction mapping and sequence analysis. The repeated element consists of 1,442 bp flanked on either side by the sequence ACTTTCC in a direct orientation. The array contains two to eight copies of the repeated element arranged in a direct orientation and in tandem. Only complete copies of the element are present in the array. The repeat element contains three regions with characteristic nucleotide sequences: a 10-bp inverted repeat shown to extrude into a cruciform in a supercoiled DNA plasmid, a 120-bp tract rich in G/C (70%) and adjacent to the inverted repeat, and periodically interspersed homopolymer runs of A and T occurring near the middle of the element which induce DNA curvature in dimeric constructs of the element. The element appears to be unique to P. magellanicus. The structural properties of the repeat element and its organization in an array of repeats may be important in explaining the generation and maintenance of large-scale mitochondrial DNA size variation observed in many animal species.

Animals↗

PubMed1987

A hypervariable repeated sequence on human chromosome 1p36.

When used to probe Southern blots of TaqI-digested DNAs from unrelated individuals, p1-79, a 900 bp subclone of a random human cosmid, revealed at least 50 fragments, many of which were polymorphic. Each of 27 unrelated individuals tested with p1-79 displayed a distinct band pattern. Similar variation was seen with several other enzymes, including HaeIII, MspI, PstI and PvuII, whereas other enzymes yielded primarily large fragments of greater than 40 kb. In situ hybridization of p1-79 showed that the loci of hybridization are clustered on human chromosome band 1p36; localization of all TaqI fragments to chromosome 1 was confirmed with a human-rodent somatic cell hybrid panel. DNA sequencing of p1-79 revealed several copies of a 39 bp repeat whose variation in copy number might be the basis of the observed length polymorphisms. Studies of 3-generation Utah families suggest that the numerous restriction fragments homologous to p1-79 are inherited as haplotypes, implying that recombination within this cluster of loci is rare and allowing the cluster to serve as a useful marker for human gene mapping.

Animals↗

PubMed1988

Intrinsic polymorphism of variable number tandem repeat loci in the human genome.

In the human genome, short tandem repetitive (STR) DNA sequences often show restriction fragment length polymorphisms (RFLPs) due to variation in the number of copies of the repeat unit. For a subset of these sequences known as minisatellites or variable number tandem repeat loci (VNTR), it has been proposed that a homologous "core" sequence of 10-12 nucleotides is involved in the mechanism(s) generating the polymorphism. In our present study we have prepared oligonucleotide probes complementary to one or two repeat units of several VNTR loci. Under stringent hybridization and wash conditions these probes hybridize locus specifically thus allowing the evaluation of the intrinsic polymorphism of individual loci. Our results indicate that not all of the loci having STR DNA sequences are polymorphic despite the fact that they share the "core" sequence. This suggests that more than the DNA sequence of the locus is involved in the mechanism(s) generating the polymorphism.

Alleles↗

PubMed1976

DNA reassociation kinetics in relation to genome size in four amphibian species.

DNA reassociation kinetics were studied, by means of the hydroxyapatite chromatography method, for four species of Amphibians with different nuclear DNA content: Xenopus laevis (3 pg DNA per haploid genome) and Bufo bufo (7 pg) of the Anura subclass and Triturus cristatus (23 pg) and Necturus maculosus (52 pg) of the Urodela subclass. Within each subclass the two species studied were found to have about the same absolute amount of unique DNA. The differences of total nuclear DNA can be accounted for by quantitative variations of the repetitive sequence classes, at least in part due to changes in the number of copies of the various sequences. On the contrary the great difference in nuclear DNA between the two subclasses, Anura and Urodela, involves all sequence classes in parallel; the slowly reassociating fraction appears to be unique in spite of a tenfold difference in absolute amount. The dependence of reassociation kinetics on DNA fragment length for the four species indicates for all of them an interspersed organization of the various sequence classes.

Amphibians↗

PubMedDate not supplied

Hypervariable 'minisatellite' regions in human DNA.

The human genome contains many dispersed tandem-repetitive 'minisatellite' regions detected via a shared 10-15-base pair 'core' sequence similar to the generalized recombination signal (chi) of Escherichia coli. Many minisatellites are highly polymorphic due to allelic variation in repeat copy number in the minisatellite. A probe based on a tandem-repeat of the core sequence can detect many highly variable loci simultaneously and can provide an individual-specific DNA 'fingerprint' of general use in human genetic analysis.

Alleles↗