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PubMed2025

Structural variation detection and association analysis of whole-genome-sequence data from 16,543 Alzheimer's disease sequencing project subjects.

INTRODUCTION: The role of structural variations (SVs) in Alzheimer's disease (AD) remains understudied. METHODS: We analyzed whole-genome sequencing data from the Alzheimer's Disease Sequencing Project (N = 16,543) and identified 400,234 (168,223 high-quality) SVs. Laboratory validation yielded a sensitivity of 82% (85% for high-quality). RESULTS: We found a burden of singletons (odds ratio [OR] = 1.07, p = 0.0017) and homozygous deletions (OR = 1.14, p < 0.0001) in cases. On AD genes, we observed the ultra-rare SVs associated with the disease, including protein-altering SVs in ABCA7, APP, PLCG2, and SORL1. Twenty-one SVs are in linkage disequilibrium (LD) with known AD-risk variants, exemplified by a 5k deletion in LD (R2 = 0.99) with rs143080277 in NCK2. We identified a rare deletion near RNA5SP293 associated with AD (OR = 1.99, p = 1.3 × 10-5), which was replicated using an independent dataset. DISCUSSION: This study highlights the pivotal role of SVs in AD genetics. HIGHLIGHTS: Observed a significant burden of singletons and homozygous deletions in Alzheimer's disease (AD) patients. Identified rare protein-altering structural variations (SVs) in ABCA7, APP, PLCG2, and SORL1. Established linkages between SVs and AD risk-associated single nucleotide variants (SNVs). Discovered a novel deletion near RNA5SP293 linked to AD, replicated independently. Uncovered over-representation of SVs in neuronal function pathways.

Humans↗

PubMed2006

Regulated polyploidy in halophilic archaea.

Polyploidy is common in higher eukaryotes, especially in plants, but it is generally assumed that most prokaryotes contain a single copy of a circular chromosome and are therefore monoploid. We have used two independent methods to determine the genome copy number in halophilic archaea, 1) cell lysis in agarose blocks and Southern blot analysis, and 2) Real-Time quantitative PCR. Fast growing H. salinarum cells contain on average about 25 copies of the chromosome in exponential phase, and their ploidy is downregulated to 15 copies in early stationary phase. The chromosome copy number is identical in cultures with a twofold lower growth rate, in contrast to the results reported for several other prokaryotic species. Of three additional replicons of H. salinarum, two have a low copy number that is not growth-phase regulated, while one replicon even shows a higher degree of growth phase-dependent regulation than the main replicon. The genome copy number of H. volcanii is similarly high during exponential phase (on average 18 copies/cell), and it is also downregulated (to 10 copies) as the cells enter stationary phase. The variation of genome copy numbers in the population was addressed by fluorescence microscopy and by FACS analysis. These methods allowed us to verify the growth phase-dependent regulation of ploidy in H. salinarum, and they revealed that there is a wide variation in genome copy numbers in individual cells that is much larger in exponential than in stationary phase. Our results indicate that polyploidy might be more widespread in archaea (or even prokaryotes in general) than previously assumed. Moreover, the presence of so many genome copies in a prokaryote raises questions about the evolutionary significance of this strategy.

Archaea↗

PubMed2006

Relation of DNA ploidy to genetic aberrations detected by chromosomal CGH and FISH in gastric adenocarcinomas.

We analyzed DNA copy number aberrations (DCNAs) by chromosomal comparative genomic hybridization (CGH) in 93 consecutive sporadic gastric adenocarcinomas. In addition, numerical aberrations in chromosomes 7, 11, 17, and 18 were evaluated by fluorescence in situ hybridization (FISH). Gastric cancers were divided on the basis of nuclear DNA content measured by laser scanning cytometry (LSC) into two groups, 36 DNA diploid (1.0 or= 1.2) cancers. The most frequent gain and loss of DNA copy number were found at 8q21-23 and 19p13.3, respectively, in both diploid and aneuploid cancers. Diploid cancers were further divided on the basis of genetic aberrations into major type and subtype cancers. The diploid cancer group included nine subtype cancers that showed large numbers of DCNAs; the mean number of DCNAs detected by CGH was 26.7 per tumor. This value was much larger in these diploid subtype cancers than diploid major type cancers (mean, 5.2 per tumor, p<0.0001). These nine cancers were also characterized by large intercellular variations in chromosome copy numbers that were not detected in the 27 major diploid type cancers. The aneuploid cancer group included only three subtype tumors that showed only a small number of DCNAs (mean, 3 per tumor) and minimal intercellular variations in chromosomal copy number. These data indicate that gastric adenocarcinomas can be divided into three types; aneuploid, major diploid type and diploid subtype cancers. Large-scale studies are necessary to clarify the differences in biological characteristics and underlying genetic mechanisms between these types.

Adenocarcinoma↗

PubMed1997

DNA copy number changes associated with characteristic LOH in islet cell carcinomas of transgenic mice.

Comparative genomic hybridization (CGH) provides a method of surveying the entire tumor genome for regional variations in DNA sequence copy number. Such variations, if found recurrently, may indicate the locations of genes that contribute to tumor development through upregulation of oncogenes (copy number increase), inactivation of tumor-suppressor genes (copy number decrease), or changes in the level of expression through gene dosage effects. Thus, CGH is a powerful tool for screening for new cancer genes. Although CGH is widely applied to human genome analysis, application to the mouse is only beginning. The present study is designed to compare results obtained by CGH with those obtained by other techniques used for analysis of the murine genome. We report CGH analysis of several control cell lines with cytogenetically established regional copy number changes, as well as analysis of 16 primary insulinomas, four tumor-derived cell lines, and three hyperplasia-derived cell lines from transgenic mice expressing the SV40 large T antigen under control of the rat insulin promoter. Loss of heterozygosity (LOH) on chromosomes 9 and 16 had previously been found to be frequent in primary insulinomas, and specimens were selected for the present study based on the LOH status of these chromosomes. We found complete concordance of the CGH results with the cytogenetically described copy number changes in the control cell lines and with the LOH on chromosomes 9 and 16 in the tumors. Thus, CGH can provide accurate data in murine systems, and it reveals that the LOH in these islet cell tumors most frequently results from deletion of one of the alleles.

Adenoma, Islet Cell↗

PubMed2026

Distinct Effects of Complement C4A and C4B Copy Numbers in Systemic Sclerosis Serological and Clinical Subtypes.

OBJECTIVE: Complement component 4 (C4), encoded by C4A and C4B within the major histocompatibility complex (MHC) on chromosome 6, regulates the immune response and clears immune complexes. The variable copy number (CN) of C4 genes and retroviral human endogenous retrovirus K (HERV-K) element influence its function. Given the relationship of C4 CN with systemic sclerosis (SSc) risk, we assessed associations with SSc clinical and serologic subtypes. METHODS: We compared imputed C4 CNs across SSc subgroups (4,049 anticentromere positive [ACA+]; 2,200 anti-topoisomerase I [ATA+]; 577 anti-RNA polymerase [ARA+]; 1,078 triple-negative [TN] patients; 6,295 limited cutaneous SSc [lcSSc]; and 2,946 diffuse cutaneous SSc [dcSSc]) and 17,991 controls. We evaluated associations with SSc subtypes, identifying C4-independent HLA alleles. RESULTS: Lower C4 CN and higher HERV-K CN were associated with increased risk in all SSc subgroups. ATA+ patients showed the strongest association, particularly with C4A (odds ratio = 1.88), and differences in C4A CN association were more pronounced between autoantibody subgroups (ATA+ vs ACA+, P = 4 × 10-11) than between clinical subgroups (dcSSc vs lcSSc, P = 1 × 10-4). In ACA+ patients, only low C4B CN showed a significant association to SSc risk (P = 1.23 × 10-5). We also observed sex-biased associations: dcSSc, ATA+, and ARA+ male patients showed stronger effects for C4A and ACA+ and lcSSc female patients for C4B. Finally, our results suggest that the HLA alleles associated with SSc subgroups are independent of C4 CN. CONCLUSION: This study highlights distinct genetic contributions of C4A and C4B in SSc subtypes susceptibility. Our findings suggest that lower C4 CNs, particularly C4A, increase the risk of the severe dcSSc subtype, potentially through a mechanism involving immune complex clearance.

Humans↗

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↗

PubMed1994

Lymphocyte expression in transgenic trout by mouse immunoglobulin promoter/enhancer.

Two groups of transgenic rainbow trout (Oncorhynchus mykiss, Walbaum) have been produced and compared. One group harbored the reporter gene of chloramphenicol acetyltransferase (CAT) associated with mouse immunoglobulin (Ig) promoter/enhancer (pUCL-CAT-E). The other group carried the same reporter gene under the control of the cytomegalovirus promoter/enhancer (pCMV-CAT). Slot blot analysis of DNA from blood cells and other tissues from pUCL-CAT-E fish showed variation of copy number between the major tissues but not between red and white blood cells. Southern blot analysis indicated that multiple copies organized in concatemers were incorporated into the genome. The pCMV-CAT fish had a pronounced expression of CAT in both white and red blood cells. In contrast, activity of CAT was found in the white blood cells of all pUCL-CAT-E fish but not in their red blood cells. Expression in white blood cells was found preferentially in sIg+ cells, indicating that B cells are the major expressors. High expression was also found in spleen and kidney, but the activity found in thymocytes was equal to the background level. Analysis of some major tissues showed high white blood cell expression associated with low tissue expression, except that liver (known to contain lymphoid tissue in fish) was higher. Thus the regulatory elements of the Ig gene from mouse induce a tissue-specific expression in fish.

Animals↗

PubMed1994

Variation in human FCGR2C gene copy number.

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Antigens, CD↗

PubMed1993

Steroid 21-hydroxylase (P450c21): a new allele and spread of mutations through the pseudogene.

Lesions in the gene encoding the adrenal enzyme steroid 21-hydroxylase (P450c21) result in defective adrenal cortisol synthesis, often accompanied by aldosterone deficiency. The symptoms range from severe neonatal disease to inconspicuous symptoms in adulthood depending on the nature of the mutations. The 21-hydroxylase gene is present in close proximity to a highly homologous pseudogene, and both genes show variation in copy number between individuals. For complete DNA sequence characterization, we have applied selective polymerase chain reaction amplification and direct sequencing of all full-length steroid 21-hydroxylase genes present in individuals. Using healthy individuals with only one remaining steroid 21-hydroxylase allele as normal references, a new allele was found in two siblings, in whom clinical and laboratory findings demonstrated moderate enzyme deficiency. Full-length sequencing of this allele displayed an Arg 484 to Pro codon change in exon 10, in the same position as a previously identified GG to C mutation found in a patient with severe 21-hydroxylase deficiency. Arg 484 is located within a stretch of amino acids that are highly conserved between mammalian 21-hydroxylases. The finding of the presently reported 21-hydroxylase allele indicates that the GG to C mutation from the severely affected patient has arisen by a two-step mechanism, consisting of a G to C transversion accompanied by an adjacent G deletion. When sequencing 26 pseudogenes, both these mutations, which are not present in the pseudogenes hitherto reported, were found at low frequency together with a number of other polymorphisms. Thus, also rare mutations can spread via the pseudogene and can therefore be expected to arise independently in unrelated individuals.

Adrenal Hyperplasia, Congenital↗

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↗

PubMed1983

Distribution of insertion element IS1 in natural isolates of Escherichia coli.

Total DNAs from twelve natural isolates of Escherichia coli from animals and humans were examined by hybridization with a probe for IS1. Considerable variation in copy number was found. In the case of two strains isolated from the same individual, one strain contained no copies of IS1 and the other, much greater than 30. Evidence was also obtained for the existence of IS1-like elements (iso-IS1s) of greater than 15% sequence divergence relative to the IS1 from antibiotic resistance plasmid R100.

Animals↗

PubMed1985

Physical and genetic analysis of IS110, a transposable element of Streptomyces coelicolor A3(2).

On at least three independent occasions a 1.6 kb segment of Streptomyces coelicolor DNA was detected in apparently the same location in an attP-deleted derivative of the temperate phage phiC31 that carried a selectable viomycin resistance gene. This sequence (termed IS110) allowed integration of the phage (giving viomycin-resistant transductants) at homologous sequences (detected by Southern hybridisation) at several locations in the S. coelicolor genome. The inserted prophages facilitated genetic mapping of two IS110 copies in the chromosomal linkage map. A third copy did not exhibit simple segregation with chromosomal markers, and there appeared to be a frequent DNA rearrangement close to this copy. Some variation in the number of copies of IS110 and their location has taken place in the pedigree of S. coelicolor derivatives. IS110 did not hybridise to any known S. coelicolor plasmid, nor to any of several other IS-like elements previously described in other Streptomyces plasmids or phages. It hybridised strongly to DNA from only a small minority of other Streptomyces species and was absent from S. lividans, a close relative of S. coelicolor.

Bacteriophages↗

PubMed1994

Evaluation of an automated DNA profiling system employing multiplex amplification of four tetrameric STR loci.

We have examined the performance and reproducibility of an automated DNA profiling system which is based on the multiplex amplification of 4 tetrameric STR loci-HUMVWFA31/A. HUMTH01, HUMF13A1 and HUMFES/FPS. The system was able to type 100 pg of purified, undegraded, genomic DNA. At lower concentrations of DNA (below 100 pg), allelec drop-out occurred due to stochastic differences in allele copy number. Minor variation of individual PCR reagent concentrations or cycling temperatures did not result in a significant effect on the efficiency of amplification of any of the 4 loci in the quadruplex system. More substantial variation of reagent concentrations or cycling temperatures outside the optimum range of the system resulted in a reduction or complete loss of signal for one or more loci. This was also observed at high ionic strength or extreme pH. However, under all reagent concentrations and conditions studied, no artefact bands that could potentially result in the mistyping of a sample were apparent within the read region (130-240 bases) of the gel. Evaluation of both native and denaturing polyacrylamide gels revealed that, although native gels displayed faster run times, the sizing precision of such gels for certain STR loci was lower than that of denaturing gels. Also, artefact bands may be present within the read region of native gels. In conclusion the quadruplex amplification system described, coupled with automated fluorescence-based detection on denaturing polyacrylamide gels, appeared to be a robust and reliable system for individual identification.

Alleles↗

PubMed2026

Copy number variants in BRCA1 and BRCA2 genes in Polish patients with breast and ovarian cancer.

PURPOSE: BRCA1 and BRCA2 are key susceptibility genes in hereditary breast and ovarian cancer (HBOC), with mutational status guiding PARP inhibitor therapy. While single-nucleotide variants (SNVs) predominate, the prevalence of copy number variants (CNVs) varies significantly across different populations. This study aims to determine the incidence of BRCA1/2 CNVs in the Polish population, where data remain scarce due to non-mandatory CNV testing. METHODS: We retrospectively analysed the results of genetic tests assessing the presence of BRCA1/2 CNVs performed in 2720 individuals tested at the Lower Silesian Oncology Centre (2021-2024), including 2702 breast/ovarian cancer patients and 18 unaffected relatives. The mean age was 54.7 ± 15.15 years. Genetic testing involved DNA extraction, NGS, and MLPA for CNV confirmation. Variants were classified according to ACMG-AMP guidelines and verified through independent testing. RESULTS: In this study, no BRCA2 CNVs were identified, consistent with previous Central European findings. Pathogenic BRCA1 CNVs were detected in 0.85% of the analyzed cohort and in 0.52% of the cancer patient subgroup, affecting 23 individuals from 13 families. Eight distinct BRCA1 CNVs were detected, the most common being exon 21 deletion. Affected families exhibited a high incidence of HBOC-related cancers, with early-onset breast cancer and a notable proportion of triple-negative breast cancer cases. CONCLUSIONS: This study highlights the clinical significance of BRCA1 CNVs in Polish patients with HBOC-spectrum cancers and their families. Although rare, these variants were associated with aggressive cancer phenotypes and early onset. Given their diagnostic and therapeutic implications, BRCA1 CNVs should be routinely analysed in high-risk families to ensure accurate detection and personalised treatment planning.

Humans↗

PubMed2025

Ataxia and oculomotor apraxia caused by a large-scale deletion in the senataxin gene.

Senataxin, an RNA/DNA helicase, is a key protein providing genome stability and one of the best characterized R-loop-binding factors playing an important role in transcription and DNA repair processes. Pathogenic SETX gene variants cause autosomal recessive spinocerebellar ataxia with axonal neuropathy (AOA2, MIM #606002) and autosomal dominant juvenile amyotrophic lateral sclerosis (ALS4, MIM #602433), rare neurodegenerative disorders characterized by juvenile onset of progressive cerebellar ataxia, axonal sensorimotor peripheral neuropathy, combined upper and lower motor neuron symptoms, and increased serum alpha-fetoprotein (AFP; specific for AOA2). We report two cases of adult patients presenting with cerebellar syndrome, scanned speech, and exercise intolerance which started in the second/third decade of life and were followed by muscle weakness and impaired gait coordination. Whole exome sequencing (WES) was performed to analyze single nucleotide and copy number variants. A decreased coverage of a genomic region of around 16 kb on chromosome 9 (chr9:132,295,852-132,311,876), suggesting a deletion encompassing 5 exons of the SETX gene (exons 11-15, NM_015046.7) was observed. This homozygous SETX (9q34.13) deletion leads to a frame shift and consequently truncation of the helicase domain in the protein. Loss-of-function variants in the SETX gene are known to be pathogenic. Statistical analysis of NGS data from the Polish population identified a few heterozygous carriers, suggesting its region-specific origin.

Humans↗

PubMed1986

Close linkage of human chromosomal pepsinogen A genes.

We have obtained a clone containing two pepsinogen A genes in a single insert by screening a recombinant cosmid library for human genomic DNA. Restriction endonuclease mappings of this cloned DNA showed that these two genes are very similar, but distinct in structure, and that they are closely linked to one another in the human chromosome DNA. The close arrangement of the genes with very similar structures could facilitate the homologous recombination or the unequal crossing-over which accounts for high frequency of haplotype variation in copy number of pepsinogen A genes as reported by Taggart et al.

Cloning, Molecular↗

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↗

PubMed2026

Chromosome-scale genome remodeling in tumor evolution: Copy number alterations and structural variants as two sides of the same coin.

Chromosome-scale genomic rearrangements are a dominant force in tumor evolution. Copy-number alterations (CNAs) and structural variants (SVs) constitute two complementary axes of this process. Although detection technologies now deliver near-comprehensive catalogs, technical resolution has outpaced conceptual integration. In this review, we frame CNAs and SVs as inextricable facets of chromosomal aberrations. They reshape cancer genomes through altered gene dosage and three-dimensional regulatory rewiring. CNAs quantify the gene-dosage imbalance, yet arise through mechanistically distinct routes. Segmental CNAs typically require chromosomal breakage, and therefore often coincide with SV junctions. By contrast, whole-chromosome aneuploidy and whole-genome doubling (WGD) primarily reflect mitotic or cytokinetic failure and can occur without local breakpoints, while nevertheless reshaping the karyotypic landscape and seeding subsequent structural complexity. SVs, in turn, range from unbalanced events that alter copy number to ostensibly balanced exchanges that predominantly rewire regulatory architecture. Despite their diverse and sometimes catastrophic architectures, SVs are ultimately rooted in double-strand break formation and error-prone resolution. By integrating CNAs and SVs within a unified mechanistic and functional framework, we aim to convert catalogs into concepts and distill the organizing principles that govern tumor genome evolution.

Humans↗