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Results for “Copy Number Variations”

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PubMed1999

Transposable elements and genome evolution: the case of Drosophila simulans.

Drosophila simulans presents a large variation in copy number among various transposable elements (TEs) and among natural populations for a given element. Some elements such as HMS beagle, blood, flea, tirant, coral, prygun, jockey, F, nomade and mariner are absent in most populations, except in one or two which have copies on their chromosome arms. This suggests that some TEs are being awakened in D. simulans and are in the process of invading the species while it is colonizing the world. The elements 412 and roo/B104 present a wide insertion polymorphism among D. simulans populations, but only the 412 copy number follows a temperature cline. One population (Canberra from Australia) has a very high copy number for the 412 element and for many other TEs as well, indicating that some populations may have lost control of some of their TEs. While the 412 transposition rate is similar in all populations, its transcription level throughout developmental stages varies with populations, depending on copy number. Populations with 412 copy number higher than 10-12 exhibit co-suppression, while the expression in populations with lower numbers depends on the insertion location. All these results suggest genomic invasions by 412 and other TEs during the worldwide spread of the D. simulans species.

Animals↗

PubMed1990

Specific DNA probe for the sensitive detection of Trypanosoma evansi.

Trypanosoma evansi is the parasitic protozoon that causes "Surra", a wasting disease of domestic animals. Detection of T. evansi plays an important role in epidemiology and animal health. DNA probes were constructed from T. evansi genomic DNA and kinetoplast DNA for sensitive detection of the parasite in infected blood. A 6.5 kb DNA insert of pMUT ec6 plasmid derived from the genomic DNA of T. evansi Npl isolate, selected from 575 recombinant E. coli exhibited the strongest nucleic acid hybridization signal to the T. evansi DNA. Using as the DNA probe, pMUT ec6 could detect as little as 60 pg T. evansi DNA and it did not hybridize to the DNA of cattle, waterbuffalo and two related blood parasites. A simple detection procedure by spotting 10 microliters infected blood onto nylon membrane could sense as little as 1000 parasites. The kinetoplast DNA was cloned in E. coli and found to show a comparable sensitivity to that of the pMUT ec6. However, the kinetoplast DNA exhibited variation in copy number among parasite isolates thus pMUT ec6 should be the DNA probe of choice for sensitive detection of T. evansi.

Animals↗

PubMed2026

Prenatal diagnosis and genetic counseling of a de novo 10q11.22q11.23 duplication associated with a normal development at 12 months of age.

BACKGROUND: Copy number variants are an important source of genomic variations, ranging from pathogenic to benign. The 10q11.22q11.23 region contains complex low-copy repeats that predispose to recurrent deletions and duplications via nonallelic homologous recombination. While some reports associate duplications of this region with developmental delay, intellectual disability, and autism spectrum disorders, emerging evidence suggests that such duplications may also be observed in phenotypically normal individuals, indicating incomplete penetrance and variable expressivity. CASE PRESENTATION: A 35-year-old pregnant woman with an unremarkable obstetric history underwent amniocentesis at 20 weeks of gestation. Conventional karyotyping and copy number variation sequencing (CNV-seq) were performed. CNV-seq revealed a de novo 4.56 Mb duplication at 10q11.22q11.23. The duplication was classified as a variant of uncertain significance. After extensive genetic counseling, the parents elected to continue the pregnancy. At 40 weeks of gestation, a female infant was delivered by cesarean section with normal birth parameters. A comprehensive physical examination at birth revealed no abnormalities. At the 12-month follow-up, the infant demonstrated normal growth parameters and age-appropriate neurodevelopmental milestones, with no evidence of dysmorphic features, developmental delay, or other clinical concerns. CONCLUSION: This report describes a prenatal case of a de novo 10q11.22q11.23 duplication with a normal development at 12 months of age. Our findings contribute to the growing body of literature suggesting that duplications in this pericentromeric region may exhibit incomplete penetrance and variable expressivity, and in some cases, may represent benign familial or de novo variants without apparent clinical consequences.

10q11.22q11.23 duplication↗

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↗

PubMed1991

Population genetics of the Y chromosome of Drosophila melanogaster: rDNA variation and phenotypic correlates.

One means of examining the evolutionary significance of molecular variation on the Y chromosome is to identify phenotypes specifically affected by Y-linked genes, and to quantify the phenotypic variation and its correlation to the molecular variation. The functional importance of the Y-linked array of rRNA genes is demonstrated by the ability of Y chromosome to rescue X-linked bobbed lethal alleles, whose lethality is seen in homozygous females. Because low numbers of X-linked rDNA gene copies result in increased developmental time and shortened bristles, and because there is considerable natural variation in Y-linked copy number, a careful examination of Y-linked variation in these two traits may uncover a mode of selection acting on the multigene family. In this study, 36 Y-chromosome replacement lines were tested to detect subtle variation in bristle phenotypes and developmental rates. Correlations among these traits, rDNA gene copy number, and intergenic sequence length were quantified. The absence of significant correlations between phenotypic characters and rDNA copy number of intergenic sequence length suggests that the extant molecular variation in Y-linked rDNA can have at most very small selective effects.

Animals↗

PubMed1986

Amplification of oncogenes and integrated SV40 sequences in mammalian cells by the decay of incorporated iodine-125.

Iodine-125, in the form of 5-[125I]iododeoxyuridine (I-UdR), was incorporated into the DNA of SV40 transformed Chinese hamster embryo cells. Disintegration of the 125I led to increased cell killing with increasing dose as measured by the colony-forming ability of single cells. The D37 (the dose at which 37% of the cells survive) amounts to 95 decays per cell, corresponding to 0.66 Gy. Variations in the copy number of specific DNA sequences was measured by using dispersed cell blotting with sensitive DNA hybridizations. A 13-fold amplification of the viral DNA sequences (SV40) and a twofold amplification of two cellular oncogenes of the ras-family (Ki-ras and Ha-ras) were found. Other cellular genes, like the alpha-actin gene, were not amplified, and no variation in gene copy number was detected after incubation of cells with cold I-UdR. We suggest the observed gene amplifications are induced by the densely ionizing radiation emitted by the decay of the incorporated 125I atoms.

Animals↗

PubMed2026

The genetic control of rapid genome content divergence in Arabidopsis thaliana.

Genome evolution in eukaryotes is predominantly driven by the dynamics of repetitive sequences, which vary widely in both copy number and sequence composition. Rates of repeat evolution differ between and within species and are likely modulated by both genetics and environment. To uncover factors shaping the rate of genome content evolution, we analyzed 1043 resequenced Arabidopsis thaliana genomes using a novel K-mer-based approach to characterize genome content variation and identify hypervariable regions underlying differences in repeat abundance. We next treated repeat abundance as a quantitative trait and performed genome-wide association analyses across more than 400 repeat families to identify the genetic basis of copy number variation. Integrating these results through a meta-GWAS approach revealed both cis-acting variants and more than 50 candidate trans-acting loci associated with repeat abundance genome-wide. Cis-acting variation was predominantly localized to pericentromeric and centromeric regions, whereas trans-acting loci were enriched for candidate genes involved in DNA replication, DNA repair, and DNA methylation regulation. The results are consistent with purifying selection acting against mutations that accelerate genome content divergence, favoring alleles that constrain repeat expansion. Together, these findings provide new insights into the genetic architecture and evolutionary forces shaping genome evolution in A. thaliana and establish a framework for investigating these processes in other plant species.

Arabidopsis↗

PubMed1998

The tomato Cf-5 disease resistance gene and six homologs show pronounced allelic variation in leucine-rich repeat copy number.

The tomato Cf-2 and Cf-5 genes confer resistance to Cladosporium fulvum and map to a complex locus on chromosome 6. The Cf-5 gene has been isolated and is predicted to encode a largely extracytoplasmic protein containing 32 leucine-rich repeats (LRRs), resembling the previously isolated Cf-2 gene, which has 38 LRRs. Three haplotypes of this locus from Lycopersicon esculentum, L. pimpinellifolium, and L. esculentum var cerasiforme were compared, and five additional homologs of Cf-5 were sequenced. All share extensive sequence identity, particularly within the C-terminal portions of the predicted proteins. In striking contrast to the Cf-9 gene family, six of seven homologs in the Cf-2/Cf-5 gene family vary in LRR copy number, ranging from 25 to 38 LRRs. Cf-5 and one adjacent homolog differ by only two LRRs. Recombination events that vary the LRR copy number in this region could provide a mechanism for the generation of new specificities for recognition of different ligands. A recombination breakpoint between the Cf-2 and Cf-5 loci was fully characterized and shown to be intragenic.

Alleles↗

PubMed1978

Evidence for variation in the number of functional gene copies at the AmaR locus in Chinese hamster cell lines.

The hypothesis of functional hemizygosity has been examined for the alpha-amanitin resistant (AmaR, a codominant marker) locus in a series of Chinese hamster cell lines. AmaR mutants were obtained from different cell lines, e.g., CHO, DHW, M3- 1 and CHO-Kl, at similar frequencies. After fractionation of different RNA polymerase activities in the extracts by chromatographic procedures, the sensitivity of the mutant RNA polymerase II towards alpha-amanitin was determined. While all of the RNA polymerase II activity in mutant CHO and CHO-Kl lines became resistant to alpha-amanitin inhibition, only about 50% of the activity is highly resistant in AmaR mutants of CHW and M3- 1 cell lines. The remaining activity in the latter cell lines shows alpha-amanitin sensitivity similar to that seen with the wild-type enzyme. This behaviour is similar to that observed with a 1:1 mixture of resistant and sensitive enzymes from CHO cells. These results, therefore, strongly indicate that while only one functional copy of the gene affected by alpha-amanitin is present in CHO and CHO-Kl cells, two copies of this gene are functional in the CHW and M3-1 cell lines.

Amanitins↗

PubMed2000

Variable human minisatellite-like regions in the Mycobacterium tuberculosis genome.

Mycobacterial interspersed repetitive units (MIRUs) are 40-100 bp DNA elements often found as tandem repeats and dispersed in intergenic regions of the Mycobacterium tuberculosis complex genomes. The M. tuberculosis H37Rv chromosome contains 41 MIRU loci. After polymerase chain reaction (PCR) and sequence analyses of these loci in 31 M. tuberculosis complex strains, 12 of them were found to display variations in tandem repeat copy numbers and, in most cases, sequence variations between repeat units as well. These features are reminiscent of those of certain human variable minisatellites. Of the 12 variable loci, only one was found to vary among genealogically distant BCG substrains, suggesting that these interspersed bacterial minisatellite-like structures evolve slowly in mycobacterial populations.

Base Sequence↗

PubMed2026

Detecting and reconstructing breakage-fusion-bridge cycles from long-read sequencing using BFBArchitect.

MOTIVATION: Focal oncogene amplification is a key driver of tumor progression. Remarkably, the increased pathology depends on the context-whether the amplification is extrachromosomal (ecDNA) or intrachromosomal. EcDNA amplifications promote heterogeneity, therapy resistance, and poor prognosis. Focal intrachromosomal amplifications often arise through breakage-fusion-bridge (BFB) cycles, which produce highly rearranged but stable chromosomes. Distinguishing BFB from ecDNA remains challenging due to overlapping genomic signatures. To address this, we present BFBArchitect, a computational method leveraging long-read Oxford Nanopore data to identify BFB sequences consistent with both copy number and structural variations. RESULTS: We provide a novel combinatorial characterization of BFB, which naturally leads to an integer linear programming (ILP) optimization. The ILP optimization generates a BFB sequence that best explains experimentally observed copy numbers and foldback structural variants. We implement this idea in a tool called BFBArchitect, which achieves near-perfect accuracy in distinguishing BFB from non-BFB structures in extensive simulations as well as on 18 validated tumor samples. Moreover, it generates sequence-level BFB reconstructions that provide mechanistic insights into BFB formation, including repair mechanisms with template switching and other structural variants, and recapture of telomere for stabilization. AVAILABILITY AND IMPLEMENTATION: BFBArchitect is available at https://github.com/AmpliconSuite/BFBArchitect.

Sequence Analysis, DNA↗

PubMed2026

Optimizing GRIDSS for clinical use: A targeted NGS filtering strategy for germline structural variant detection.

Detecting intermediate-sized structural variants (SVs) remains challenging in diagnostics, as tools for single-nucleotide and copy-number variants, particularly read-depth-based methods, are often insufficient. GRIDSS addresses this gap by integrating paired-end mapping, split-read analysis, and assembly-based approaches. However, its use in targeted sequencing and diagnostic workflows remains complex. NGS panel data from 9726 patients with suspected hereditary cancer were analyzed using GRIDSS. A filtering strategy was developed to prioritize clinically relevant germline SVs. Multiple parameter settings were tested to optimize performance. The initial dataset of 1,307,592 variants was reduced to 89 candidates after applying the selected filtering strategy. Of these, 24 had been previously detected by routine callers and were not further analyzed. Among the remaining 65, 13 were considered likely true positives after visual inspection using IGV. Experimental validation was performed by Sanger/Nanopore long-read sequencing for these variants, all of which were confirmed. Eight were classified as (likely) pathogenic, including two frameshift duplications in MSH6, one splicing variant in BARD1, and five mobile element insertions in APC, BRCA2, and PALB2. Altogether, GRIDSS implementation increased diagnostic yield while maintaining feasibility for diagnostic workflows. Comprehensive workflow scheme for germline structural variant detection and results in our diagnostic setting.

Humans↗

PubMed2025

Transition of Staphylococcus aureus tetracycline resistance plasmid pT181 from independent multicopy replicon to predominantly integrated chromosomal element over 65 years.

Mobile genetic elements (MGEs), including plasmids, phages and genome islands, are major sources of bacterial genetic diversity. The small plasmid pT181 confers tetracycline resistance in bacterial pathogen Staphylococcus aureus via an efflux pump, TetK. pT181 was one of the earliest sequenced S. aureus plasmids, and has been isolated in both clinical and livestock-associated strains for decades, both as an independent replicon and integrated in the chromosome as part of staphylococcal cassette chromosome mec (SCCmec). Bacterial genome analysis tools and high-quality sequences with metadata are publicly available, but these resources remain underleveraged for examining historical data, especially when studying the spread of MGEs across a species and over time. Using publicly available reads and metadata, we explored the evolution of pT181 over almost seven decades of samples to identify temporal trends in sequence evolution, copy number changes, and spread across S. aureus and beyond. pT181 was prevalent across S. aureus (found in 9.5% of 83,366 genomes tested), with a conserved sequence outside of three hypervariable regions. The history of pT181 since 1954 is characterized by spread across strains, significant variation in plasmid copy number of the independent replicon, and increasing frequency of integration of the plasmid into the S. aureus chromosome. We have identified multiple chromosomal integration locations of the plasmid, including outside of the previously characterized SCCmec. We find that pT181 has been transferred across staphylococcaceae and into a Gram-negative species. The repeated integration of pT181 into the chromosome may indicate co-evolution of the plasmid and the host, potentially to facilitate increased antibiotic resistance.

Journal Article↗

PubMed1988

Regulation of Mu element copy number in maize lines with an active or inactive Mutator transposable element system.

In the progeny of an active Mutator plant, the number of Mu elements increases on self-pollination and maintains the average parental Mu content on outcrossing to a non-Mutator line; both patterns of transmission require an increase in the absolute number of Mu elements from one generation to the next. The same average copy number of Mu elements is transmitted through the male and female, but there is wide variation in the absolute copy number among the progeny. In inactive Mutator plants-defined both by the loss of somatic instability at a reporter gene (bronze2-mu1) and by modification of the HinfI sites in the terminal inverted repeat sequences of Mu elements - the absolute copy number of Mu elements is fixed in the parent. Thus, in outcrosses Mu element number is halved, and on self-pollination Mu copy number is constant. Reactivation of somatic mutability at cryptic bz2-mu1 alleles in inactive individuals by crossing to an active line seems not to involve an increase in Mu element copy number transmitted by the inactive individual. These and other results suggest that increases in Mu copy number occur late in plant development or in the gametophyte rather than after fertilization.

DNA Transposable Elements↗

PubMed2000

Copy number lability and evolutionary dynamics of the Adh gene family in diploid and tetraploid cotton (Gossypium).

Nuclear-encoded genes exist in families of various sizes. To further our understanding of the evolutionary dynamics of nuclear gene families we present a characterization of the structure and evolution of the alcohol dehydrogenase (Adh) gene family in diploid and tetraploid members of the cotton genus (Gossypium, Malvaceae). A PCR-based approach was employed to isolate and sequence multiple Adh gene family members, and Southern hybridization analyses were used to document variation in gene copy number. Adh gene copy number varies among Gossypium species, with diploids containing at least seven Adh loci in two primary gene lineages. Allotetraploid Gossypium species are inferred to contain at least 14 loci. Intron lengths vary markedly between loci, and one locus has lost two introns usually found in other plant Adh genes. Multiple examples of apparent gene duplication events were observed and at least one case of pseudogenization and one case of gene elimination were also found. Thus, Adh gene family structure is dynamic within this single plant genus. Evolutionary rate estimates differ between loci and in some cases between organismal lineages at the same locus. We suggest that dynamic fluctuation in copy number will prove common for nuclear genes, and we discuss the implications of this perspective for inferences of orthology and functional evolution.

Alcohol Dehydrogenase↗

PubMed1991

Quantitative genetic variation of esterase activity associated with a gene amplification in Culex quinquefasciatus.

Amplification of the esterase B1 gene is responsible for insecticide resistance in the mosquito Culex quinquefasciatus. We used a mating scheme to isolate chromosomes carrying amplified esterase genes from a long-selected laboratory strain (Tem-R) to determine whether observed variation in esterase activity had a genetic basis. The amplified esterase genes segregated as a block and a possible newly arisen esterase B1 copy-number variant was found among the progeny of females which carried amplified B1 genes on only one homologue. A quantitative genetic analysis found significant genetic variation of esterase activity among families which carried different amplification-bearing chromosomes from the Tem-R strain. Esterase B1 copy-number variation among these Tem-R chromosomes is the most likely basis for the observed genetic variation in esterase activity.

Analysis of Variance↗

PubMed2002

Variation in primary sequence and tandem repeat copy number among i-antigens of Ichthyophthirius multifiliis.

The immobilization antigens (i-antigens) of Ichthyophthirius multifiliis are potential vaccine candidates for the prevention of 'white spot' disease in freshwater fish. These antigens vary with respect to antigenicity and molecular mass, and at least five i-antigen serotypes have been identified among parasite isolates thus far. In previous studies, the gene and corresponding cDNA encoding a approximately 48 kDa i-antigen from parasite isolate G1 (serotype A), had been cloned and sequenced. We now report on the isolation of two new genes, designated IAG52A[G5] and IAG52B[G5], encoding approximately 52/55 kDa i-antigens from a parasite isolate representing a different serotype, namely, D. Based on their deduced sequences, the approximately 52/55 kDa gene products have the same structural features as the 48 kDa protein including hydrophobic N- and C-termini, periodic cysteine residues with the potential for metal binding, and tandemly repetitive amino acid sequence domains that span their length. Nevertheless, the products of these genes vary in their tandem repeat copy number, and share only approximately 50% homology overall. When expressed in heterologous systems, the products of the newly described genes react strongly with monospecific polyclonal antisera against the i-antigens of serotype D and are clearly i-antigens. It would nevertheless appear that mRNA transcripts from the two genes are present at widely different levels within parasites themselves. Analysis at the protein level using 2-D SDS-PAGE would further suggest that multiple i-antigens are expressed within the same serotype at any given time.

Amino Acid Sequence↗

PubMed1985

Gyrase activity and number of copies of the gyrase B subunit gene in Haemophilus influenzae.

Gyrase activities in extracts of various strains of Haemophilus influenzae can differ by more than an order of magnitude (J. K. Setlow, E. Cabrera-Juárez, W. L. Albritton, D. Spikes, and A. Mutschler, J. Bacteriol. 164:525-534, 1985). Measurements of in vitro activity and copy number indicated that most of these differences arose from variations in the number of copies of the gene for the gyrase B subunit, with some strains containing multicopy plasmids coding for that subunit. The quantitative relationship between gyrase and copy number depended on the mutations in the plasmids and in the host. The gyrase and copy number were considerably lower in plasmid-bearing strains carrying the prophage HP1c1. Two mutations affecting gyrase that are apparently regulatory caused an increase in gyrase without a concomitant increase in copy number. The possibility that the in vivo gyrase activity did not reflect the in vitro data was explored by measurement of alkaline phosphatase and ATPase activity in the extracts. Alkaline phosphatase activity increased with increasing gyrase activity measured in vitro, but ATPase activity did not. We conclude that extra supercoiling enhanced transcription of the alkaline phosphatase gene but not the ATPase gene and that it is unlikely that there is much discrepancy between gyrase activity assayed in vitro and the activity in the cell.

Adenosine Triphosphatases↗