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PubMed2006

Alteration of hTERT full-length variant expression level showed different gene expression profiles and genomic copy number changes in breast cancer.

We analyzed hTERT splicing patterns with respect to telomerase activity in breast cancer. Using a cDNA microarray in 22 cell lines, we observed the difference in expression profiling based on the different levels of full-length variant expression with 71 selected genes. Using 33 known genes that act with the telomerase complex, we performed unsupervised clustering with all cell lines, and found a clustering tendency related to the full-length variant expression level. Using array-based CGH, highly altered genomic copy number changes were found more often in MCF-7 (159 genes) than in MDA-MB-231 (109 genes) and MDA-MB-435 (49 genes), suggesting more genomic changes in MCF-7 cells. On comparing MCF-7 with MDA-MB231 and MDA-MB-435 cell lines, we identified 8 genes with different copy numbers, including dystroglycan, which is located in the p12-21.2 area of chromosome 3. In conclusion, alterations in the level of the full-length variant of hTERT showed different gene expression profiles and genomic copy number changes in breast cancer, which require further study into their cause-and-effect relationship.

Alternative Splicing↗

PubMed1987

Cell-specific ribosomal DNA spacer variability in human urothelial carcinoma cultures.

Length variation of a ribosomal DNA "spacer" region in four chromosomally characterized transitional cell carcinoma cultures was analyzed by restriction endonuclease cleavage and Southern blotting. Cell lines with relative karyotypic conservation, such as UM-UC-2 (modal chromosome number 48, four marker chromosomes) demonstrate little change in the genetically regulated pattern of rDNA spacer length polymorphisms (7.6, 6.7 and 6.0 kilobases) which may be found in normal cells. Cell lines with more aberrant karyotypes, such as UM-UC-3 (modal chromosome number 86, 12 marker chromosomes) and UM-UC-4 (modal number 51, ten marker chromosomes) show fewer ribosomal DNA length variants (7.6, 6.7 kilobases for the former, 7.6 kilobases for the latter), consistent with relaxed constraints on the drive for ribosomal gene homogeneity through inter and intrachromosomal exchange. Uncharacterized rDNA length variants of low copy number were observed in cell lines with many marker chromosomes. Analysis of repetitive DNA structure provides an additional criterion for tumor diagnosis and staging, and a characterized series of tumor cell lines may provide a useful system for understanding repetitive DNA evolution.

Carcinoma, Transitional Cell↗

PubMed2005

Tandem repeat copy-number variation in protein-coding regions of human genes.

BACKGROUND: Tandem repeat variation in protein-coding regions will alter protein length and may introduce frameshifts. Tandem repeat variants are associated with variation in pathogenicity in bacteria and with human disease. We characterized tandem repeat polymorphism in human proteins, using the UniGene database, and tested whether these were associated with host defense roles. RESULTS: Protein-coding tandem repeat copy-number polymorphisms were detected in 249 tandem repeats found in 218 UniGene clusters; observed length differences ranged from 2 to 144 nucleotides, with unit copy lengths ranging from 2 to 57. This corresponded to 1.59% (218/13,749) of proteins investigated carrying detectable polymorphisms in the copy-number of protein-coding tandem repeats. We found no evidence that tandem repeat copy-number polymorphism was significantly elevated in defense-response proteins (p = 0.882). An association with the Gene Ontology term 'protein-binding' remained significant after covariate adjustment and correction for multiple testing. Combining this analysis with previous experimental evaluations of tandem repeat polymorphism, we estimate the approximate mean frequency of tandem repeat polymorphisms in human proteins to be 6%. Because 13.9% of the polymorphisms were not a multiple of three nucleotides, up to 1% of proteins may contain frameshifting tandem repeat polymorphisms. CONCLUSION: Around 1 in 20 human proteins are likely to contain tandem repeat copy-number polymorphisms within coding regions. Such polymorphisms are not more frequent among defense-response proteins; their prevalence among protein-binding proteins may reflect lower selective constraints on their structural modification. The impact of frameshifting and longer copy-number variants on protein function and disease merits further investigation.

Frameshift Mutation↗

PubMed2007

Mitochondrial DNA and the mammalian oocyte.

In mammals, mitochondria and mitochondrial DNA (mtDNA) are transmitted through the female germ line. Mature oocytes contain at least 100,000 copies of mtDNA, organized at 1-2 copies per organelle. Despite the high genome copy number, mtDNA sequence variants are observed to segregate rapidly between generations, and this has led to the concept of a developmental bottleneck for the transmission of mtDNA. Ultrastructural investigations of primordial germ cells show that they contain approximately 10 mitochondria, suggesting that mitochondrial biogenesis is arrested during early embryogenesis, and that the mitochondria contributing to the germ cell precursors are simply apportioned from those present in the zygote. Thus, as few as 0.01% of the mitochondria in the oocyte actually contribute to the offspring of the next generation. Mitochondrial replication restarts in the migrating primordial germ cells, and mitochondrial numbers steadily increase to a few thousand in primordial oocytes. Genetic evidence from both heteroplasmic mice and human pedigrees suggests that segregation of mtDNA sequence variants is largely a stochastic process that occurs during the mitotic divisions of the germ cell precursors. This process is essentially complete by the time the primary oocyte population is differentiated in fetal life. Analysis of the distribution of pathogenic mtDNA mutations in the offspring of carrier mothers shows that risk of inheriting a pathogenic mutation increases with the proportion in the mother, but there is no bias toward transmitting more or less of the mutant mtDNAs. This implies that there is no strong selection against oocytes carrying pathogenic mutations and that atresia is not a filter for oocyte quality based on oxidative phosphorylation capacity. The large number of mitochondria and mtDNAs present in the oocyte may simply represent a genetic mechanism to ensure their distribution to the gametes and somatic cells of the next generation. If true, mtDNA copy number, and by inference mitochondrial number, may be the most important determinant of oocyte quality, not because of the effects on oocyte metabolism, but because too few would result in a maldistribution in the early embryo.

Animals↗

PubMed1991

Influence of myc overexpression on the phenotypic properties of Chinese hamster lung cells resistant to antitumor agents.

In the Chinese hamster lung fibroblast cell line DC-3F, the development of resistance to different drugs, through several mechanisms like MDR expression or alteration of the DNA topoisomerase II activity, has been shown to be associated with a decreased tumorigenicity. Multiple studies have shown that the myc oncogene, in cooperation with ras, plays a major role in the oncogenic transformation of fibroblasts. As an approach to a better understanding of the relationship between the different phenotypic traits, we analyzed the expression of myc and ras oncogenes in the drug-sensitive DC-3F cells and in variants resistant to 9-hydroxyellipticine (9-OH-E) (DNA topoisomerase II alteration) or to actinomycin D (AD) (multidrug (MDR) expression). Southern and Northern blot analyses revealed about a 10-fold amplification and a 20-fold overexpression of the c-myc gene in the DC-3F cells as compared to the normal lung fibroblasts. Both amplification and overexpression are markedly decreased in the two resistant variants, ras gene copy number and expression were found to be identical in all cell types. In order to analyze the contribution of the decreased myc expression on the different phenotypic traits, the DC-3F/9-OH-E cells were transfected with the plasmid pSV-c-myc, and six clones expressing high amounts of the transfected myc were isolated and characterized. Morphological and caryological alterations, as well as an increased cloning efficiency in soft agar, indicated that the myc gene product was made in these cells. However, the tumorigenicity of the sensitive parental cells was not restored, thus showing that the decreased myc expression alone does not account for the loss of tumorigenicity in the resistant cells. 9-OH-E resistance was not modified in the transfected cells, while the cross-resistance of these cells to MDR-sensitive drugs, such as vincristine, actinomycin D, and taxol, was reversed roughly in proportion of the expression of the transfected myc.

Animals↗

PubMed2026

Tumor genomic landscape of older patients with metastatic breast cancer☆.

BACKGROUND: Metastatic breast cancer (MBC) in older patients has distinct clinical and histologic characteristics. Elucidating the genomic basis of MBC helps identify potential therapeutic targets to improve outcomes for older patients with MBC. PATIENTS AND METHODS: Using a prospective database and targeted DNA sequencing (OncoPanel), we examined MBC's genomic landscape in older patients (age ≥70 years at MBC diagnosis) and compared findings with those in younger (aged <50 years) and middle-aged (aged 50-69 years) patients. After classifying single nucleotide variants (SNVs) and copy number variations (CNVs) as oncogenic (via OncoKB), the frequencies of SNVs and CNVs, tumor mutational burden (TMB), and oncogenic signaling pathways were compared by age group using Fisher's exact tests. We estimated the association between continuous age at MBC diagnosis and mutations via multivariate logistic regression analysis, adjusting for race, stage at initial diagnosis, subtype, histology, and sample tested (primary versus metastatic). RESULTS: Our study included 2379 patients [853 (35%) younger, 1311 (55%) middle-aged, and 215 (9%) older] who underwent OncoPanel testing between 2013 and 2020. The most frequent tumor alterations in older patients were SNVs in PIK3CA (44%), TP53 (33%), CDH1 (22%) and amplifications in CCND1 (18%). After adjustment, older age was associated with higher frequency of SNVs in CDH1 [odds ratio (OR) = 1.43, 95% confidence interval (CI) 1.21-1.68, q < 0.001], MAP3K1 [OR = 1.30, 95% CI 1.10-1.54, q = 0.008], and PIK3CA [OR = 1.21, 95% CI 1.11-1.31, q < 0.001] and fewer SNVs in TP53 [OR = 0.84, 95% CI 0.77-0.91, q < 0.001]. Patients in the older group were more likely to have tumors with ≥10 mutations/megabase than the youngest patients (26% versus 17%, P = 0.003). CONCLUSIONS: In this large cohort of patients with MBC, the tumor genomic landscape differed between older and younger patients even after accounting for tumor subtype. Older patients were more likely to have high-TMB and PIK3CA-mutated tumors, highlighting the importance of genomic testing for treatment applications in this population.

NGS↗

PubMed2025

Epstein-Barr Virus-Associated Gastric Cancer: A Histopathologic Study With Comprehensive Molecular Profiling.

A subset of gastric cancers (GCs) is linked to Epstein-Barr virus (EBV) infection. This study aims to characterize the histopathological and molecular features of EBV-associated GCs (EBVaGCs), focusing on predictive biomarkers and genomic and transcriptomic analysis. A total of 35 primary EBVaGCs were considered. The presence of EBV was confirmed with in situ hybridization. Immunohistochemical analyses for HER2, PD-L1, claudin 18.2, and mismatch repair proteins were performed. Genomic and transcriptomic profiles were assessed using AmoyDx Master Panel, which can identify single-nucleotide variants, InDels, and copy number variations on 571 hot genes, as well as microsatellite status, tumor molecular burden, and homologous recombination deficiency at the DNA level; however, at the RNA level, it identifies rearrangements/fusions in 45 genes and also quantifies the expression of 2396 cancer-related transcripts. The following histotypes were identified: carcinoma with lymphoid stroma (CLS; 69%), tubular (20%), and mixed (11%). Most cases were associated with atrophic gastritis (71%), and only 11% with dysplasia. The vast majority (94%) of EBVaGCs expressed EBV-encoded RNA in all tumor cells. Mismatch repair deficiency and HER2 overexpression were each observed in 6% of cases, whereas all tumors had a PD-L1-combined positive score ≥10. Sixty-six percent of cases showed moderate/strong claudin 18.2 expression in ≥75% of cancer cells. The most frequently altered genes were PIK3CA (41%) and ARID1A (17%). Transcriptomic analysis revealed substantial differential gene expression between EBVaGCs and EBV-negative controls, with upregulation of genes involved in antigen presentation, natural killer cell-mediated cytotoxicity, and cytokine-cytokine receptor interaction in EBVaGCs. Within EBVaGC, CLS showed higher expression of immune-related transcripts and higher PD-L1 expression than other histotypes. This study establishes EBVaGC as a distinct molecular class, with a distinctive profile of genomic alterations and expression of predictive biomarkers, and also with a unique immune microenvironment with enhanced cytotoxic activity. The findings highlight EBV's role in early tumor development and EBVaG-CLS as a distinct subgroup within EBVaGC, characterized by unique morphologic features and a pronounced immune activation profile.

Humans↗

PubMed2025

Pseudomonas aeruginosa biofilm-deficient mutants undergo parallel adaptation during chronic infection.

Pseudomonas aeruginosa readily adapts to infection by acquiring stable and heritable mutations. Previously, we discovered that the first adaptations in a porcine wound model were rugose small-colony variants (RSCVs) caused by mutations in the wsp operon. These mutants overproduce Pel and Psl biofilm exopolysaccharides that improve defense against host responses. To identify other mechanisms of host adaptation that lead to hyperbiofilm phenotypes, we created a mutant with an activated wsp pathway but unable to produce these exopolysaccharides (ΔwspFΔpelAΔpslBCD). Porcine wounds were infected with this mutant and biopsies were sampled at days 7, 14 and 35. Small colony variants were isolated from the wound, and whole genome sequencing revealed these variants had acquired mutations in genes in lipopolysaccharide and type IV pili biosynthesis, with wzy and pilU genes being most commonly targeted. pilU mutants were associated with a hyperbiofilm phenotype that outcompeted the parental strain, and wzy mutants were associated with a hyperbiofilm phenotype and increased tolerance to host antimicrobial products. We further identified that several variants had acquired large genome deletions that spanned up to 320 consecutive genes and other variants with high copy numbers of Pf6 filamentous phage. Together our results suggest that the hyperbiofilm phenotype is adaptive in chronic infections and that P. aeruginosa has redundant and diverse pathways to generate this phenotype.

adaptation↗

PubMed2004

Conserved genetic basis of a quantitative plumage trait involved in mate choice.

A key question in evolutionary genetics is whether shared genetic mechanisms underlie the independent evolution of similar phenotypes across phylogenetically divergent lineages. Here we show that in two classic examples of melanic plumage polymorphisms in birds, lesser snow geese (Anser c. caerulescens) and arctic skuas (Stercorarius parasiticus), melanism is perfectly associated with variation in the melanocortin-1 receptor (MC1R) gene. In both species, the degree of melanism correlates with the number of copies of variant MC1R alleles. Phylogenetic reconstructions of variant MC1R alleles in geese and skuas show that melanism is a derived trait that evolved in the Pleistocene.

Animals↗

PubMed1991

A genetic element that increases the frequency of gene amplification.

A repetitive mammalian genetic element, HSAG-1, has been shown to promote the amplification of the vector, pSV2-DHFR, containing the functional cDNA for dihydrofolate reductase (DHFR). LR-73 cells, a line of Chinese hamster ovary cells, were transfected with this recombinant construct or with the parent vector, then subjected to culture in selective medium containing steadily increasing concentrations of methotrexate, a drug which specifically inhibits DHFR. Cultures transfected with the HSAG-1-containing construct acquired drug resistance faster than those transfected with the parent vector. This acceleration of acquisition of drug resistance was due to an increased probability of the generation and subsequent selection of cellular variants with increased copy numbers of the vector. The effect has also been observed in CHO(DHFR-) and HeLa cell lines. Possible mechanisms for the effect of the HSAG-1 element on gene amplification are discussed.

Animals↗

PubMed1994

Size heterogeneity among antigenically related Giardia lamblia variant-specific surface proteins is due to differences in tandem repeat copy number.

Giardia lamblia undergoes antigenic variation by modulating the expression of the different genes that comprise the trophozoite's variant-specific surface protein (VSP) repertoire. We studied an epitope that is conserved among VSPs expressed by cloned trophozoite lines derived from the independent G. lamblia isolates WB, G3M, Be-2, and CAT. The epitope recognized by monoclonal antibody 6E7 lies entirely within the region of tandemly repeated 65-amino-acid units that is characteristic of these size-variant VSPs. Northern (RNA) hybridization, cDNA cloning, and DNA sequence analysis indicate that size heterogeneity among these VSPs is due to differences in the number of repetitive units.

Amino Acid Sequence↗

PubMed1997

PCR analysis of human telomeric repeats present on HHV-6A viral strains.

Human herpesvirus 6 (HHV-6) presents a perfect tandem array of human telomeric repeats (TRS) at both identical direct repeats (DR). Several researchers have reported a different TRS copy number by sequence analysis of HHV-6 DR's cloned fragments so it has been hypothesized that number of TRS is unstable. By PCR we show that the TRS copy number of U1102 HHV-6 variant A strains is stable during viral cultivation in cell lines and each HHV-6 variant A strain, detected in pathologic specimens, is characterized by a specific TRS copy number.

Cell Line↗

PubMed1992

Mitochondrial DNA length variation and heteroplasmy in populations of white sturgeon (Acipenser transmontanus).

Southern blot analysis was used to quantify the extent of mtDNA D-loop length variation in two populations of white sturgeon, Acipenser transmontanus. Over 42% of individuals were heteroplasmic for up to six different mtDNA length variants attributable to varying copy numbers of an 82-bp repeat sequence. Chi-square analyses revealed that the frequencies of length genotypes and the incidence of heteroplasmy were significantly different between Fraser and Columbia River sturgeon populations but not between restriction site haplotypes. Heteroplasmic fish have, on average, higher copy number than homoplasmic fish. Forty-five of 101 homoplasmic individuals carry only a single copy of the repeat, while none of the 73 heteroplasmic fish has the single repeat as the predominant variant. On the basis of differences in frequency distributions of copy number within and between fish, we suggest that (1) heteroplasmy is maintained by high recurrent mutation of multiple copy genomes, favoring increased copy number and (2) the mutation pressure toward higher copy number heteroplasmy is partially offset by selection to reduced genome size and segregation to the homoplasmic condition.

Animals↗

PubMed1978

Gene amplification and drug resistance in cultured murine cells.

Resistance of mouse cells to the folate analog, methotrexate, results from selection of increasingly resistant cells on progressive increases of methotrexate in the culture medium. High-level resistance is associated with high rates of synthesis of dihydrofolate reductase and correspondingly high numbers of reductase genes. In some variants high resistance and gene copy number are stable in the absence of selection pressure, whereas in others they are unstable. Analogies are made to antibiotic and insecticide resistance wherein selection of organisms with increased capacity to counteract the drug effect results in emergence of resistance. Gene amplification may underlie many such resistance phenomena.

Alleles↗

PubMed1994

Length variation in mitochondrial DNA of the minnow Cyprinella spiloptera.

Length differences in animal mitochondrial DNA (mtDNA) are common, frequently due to variation in copy number of direct tandem duplications. While such duplications appear to form without great difficulty in some taxonomic groups, they appear to be relatively short-lived, as typical duplication products are geographically restricted within species and infrequently shared among species. To better understand such length variation, we have studied a tandem and direct duplication of approximately 260 bp in the control region of the cyprinid fish, Cyprinella spiloptera. Restriction site analysis of 38 individuals was used to characterize population structure and the distribution of variation in repeat copy number. This revealed two length variants, including individuals with two or three copies of the repeat, and little geographic structure among populations. No standard length (single copy) genomes were found and heteroplasmy, a common feature of length variation in other taxa, was absent. Nucleotide sequence of tandem duplications and flanking regions localized duplication junctions in the phenylalanine tRNA and near the origin of replication. The locations of these junctions and the stability of folded repeat copies support the hypothesized importance of secondary structures in models of duplication formation.

Animals↗

PubMed2005

Different gvpC length variants are transcribed within single filaments of the cyanobacterium Planktothrix rubescens.

Transcripts of the gas vesicle genes gvpA and gvpC were detected in single filaments of the cyanobacterium Planktothrix rubescens using reverse transcription and quantitative real-time PCR. Primers were designed to amplify short sequences within gvpA and three length variants of gvpC. With genomic template DNA, and using Sybr Green to monitor product accumulation, similar amplification efficiencies were observed for each of these genes. The relative copy numbers of gvpC length variants in genomic DNA from five Planktothrix gas vesicle genotypes determined by real-time PCR were similar to those indicated by sequencing the gas vesicle gene clusters. The precipitation of gvp cDNA reverse-transcribed from cellular RNA from single filaments was required before amplification of the gene fragments; without this step it was not possible to detect the accumulation of the expected amplicons by dissociation analysis. Precipitation was also necessary to ensure the generation of product curves that allowed linear regression in an early stage of PCR, a prerequisite for the quantification of low-input cDNA amounts without the need for standard curves. This report shows that different gvpC length variants are transcribed within single Planktothrix filaments, both from laboratory cultures and from natural samples taken from Lake Zurich. This has implications for the efficiency of buoyancy provision by the possible production of gas vesicles of different strengths within individual cyanobacterial filaments. The hypothesis that post-transcriptional regulation may influence the type of protein (GvpC) present in gas vesicles is presented.

Bacterial Proteins↗

PubMed1999

Molecular evolution of a tandemly repeated trnF(GAA) gene in the chloroplast genomes of Microseris (Asteraceae) and the use of structural mutations in phylogenetic analyses.

We sequenced the first ca. 900 bp of the 5'-trnL(UAA)-trnV(UAC)/ndhJ region of the chloroplast DNA of different Microseris accessions in order to resolve homoplasious length variation detected in the trnL(UAA)-trnF(GAA) region. We found two to four tandemly repeated trnF genes in the species of Microseris (Asteraceae, Lactuceae) and two in their sister genus Uropappus. Sequences indicated nonhomologous transitions between two, three, and four trnF genes in different Microseris taxa. Independent origins of similar trnF copy numbers were inferred from a chloroplast phylogeny of Microseris. The taxa involved grow on separate continents, supporting parallel origins of similar length variants. The changes in trnF copy numbers were best explained by interchromosomal recombination with unequal crossing over. The 5' copies of the repeats showed the highest sequence conservation, suggesting that these copies are likely to be functional trnF genes, whereas the other ones probably represent pseudogenes. Our results show that length polymorphisms accumulate once a duplicated sequence has become incorporated. Due to parallel gains of similar trnF copy numbers, homoplasious length variation was introduced into the data matrix. The data demonstrate that length polymorphisms cannot be used as indicators for phylogenetic distance unless they can be analyzed at the sequence level.

Base Sequence↗

PubMed2025

In silico generation of synthetic cancer genomes using generative AI.

Understanding how genomic alterations drive cancer is key to advancing precision oncology. To detect these alterations, accurate algorithms are used; however, due to privacy concerns, few deeply sequenced cancer genomes can be shared, limiting benchmarking and representing a major obstacle to the improvement of analytic tools. To address this, we developed OncoGAN, a generative AI model combining adversarial networks and variational autoencoders to create realistic synthetic cancer genomes. Trained on large-scale genomic datasets, OncoGAN accurately reproduces somatic mutations, copy number alterations, and structural variants across cancer types while preserving donors' privacy. The synthetic genomes reflect tumor-specific mutational signatures and positional mutation patterns. Using DeepTumour, we validated the synthetic data's fidelity, showing high concordance between generated and predicted tumors. Moreover, augmenting the training data with synthetic genomes improved DeepTumour's accuracy, underscoring OncoGAN's potential to generate shareable datasets with known ground truths for benchmarking and enhancement of cancer genome analysis tools.

Humans↗