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PubMed1989

Molecular population genetics of mtDNA size variation in crickets.

Nucleotide sequence analysis of a region of cricket (Gryllus firmus) mtDNA showing discrete length variation revealed tandemly repeated sequences 220 base pairs (bp) in length. The repeats consist of 206 bp sequences bounded by the dyad symmetric sequence 5'GGGGGCATGCCCCC3'. The sequence data showed that mtDNA size variation in this species is due to variation in the number of copies of tandem repeats. Southern blot analysis was used to document the frequency of crickets heteroplasmic for two or more different-sized mtDNAs. In New England populations of G. firmus and a close relative Gryllus pennsylvanicus approximately 60% of the former and 45% of the latter were heteroplasmic. From densitometry of autoradiographs the frequencies of mtDNA size classes were determined for the population samples and are shown to very different in the two species. However, in populations where hybridization between the two species has occurred, the frequencies of size classes and cytoplasmic genotypes in each species' distinct mtDNA lineage were shifted in a manner suggesting nuclear-cytoplasmic interactions. The data were applied to reported diversity indices and hierarchical statistics. The hierarchical statistics indicated that the greatest proportion of variation for mtDNA size was due to variation among individuals in their cytoplasmic genotypes (heteroplasmic or homoplasmic state). The diversity indices were used to estimate a per-generation mutation rate for size variants of 10(-4). The data are discussed in light of the relationship between genetic drift and mutation in maintaining variation for mtDNA size.

Animals↗

PubMed1997

Molecular evolution and host adaptation of Bordetella spp.: phylogenetic analysis using multilocus enzyme electrophoresis and typing with three insertion sequences.

A total of 188 Bordetella strains were characterized by the electrophoretic mobilities of 15 metabolic enzymes and the distribution and variation in positions and copy numbers of three insertion sequences (IS). The presence or absence of IS elements within certain lineages was congruent with estimates of overall genetic relationships as revealed by multilocus enzyme electrophoresis. Bordetella pertussis and ovine B. parapertussis each formed separate clusters, while human B. parapertussis was most closely related to IS1001-containing B. bronchiseptica isolates. The results of the analysis provide support for the hypothesis that the population structure of Bordetella is predominantly clonal, with relatively little effective horizontal gene flow. Only a few examples of putative recombinational exchange of an IS element were detected. Based on the results of this study, we tried to reconstruct the evolutionary history of different host-adapted lineages.

Adaptation, Biological↗

PubMed2025

LYCEUM: learning to call copy number variants on low-coverage ancient genomes.

MOTIVATION: Copy number variants (CNVs) are pivotal in driving phenotypic variation that facilitates species adaptation. They are significant contributors to various disorders, making ancient genomes crucial for uncovering the genetic origins of disease susceptibility across populations. However, detecting CNVs in ancient DNA (aDNA) samples poses substantial challenges due to several factors: (i) aDNA is often highly degraded; (ii) contamination from microbial DNA and DNA from closely related species introduces additional noise into sequencing data; and finally, (iii) the typically low-coverage of aDNA renders accurate CNV detection particularly difficult. Conventional CNV calling algorithms, which are optimized for high-coverage read-depth signals, underperform under such conditions. RESULTS: To address these limitations, we introduce LYCEUM, the first machine learning-based CNV caller for aDNA. To overcome challenges related to data quality and scarcity, we employ a two-step training strategy. First, the model is pre-trained on whole genome sequencing data from the 1000 Genomes Project, teaching it CNV-calling capabilities similar to conventional methods. Next, the model is fine-tuned using high-confidence CNV calls derived from only a few existing high-coverage aDNA samples. During this stage, the model adapts to making CNV calls based on the downsampled read depth signals of the same aDNA samples. LYCEUM achieves accurate detection of CNVs even in typically low-coverage ancient genomes. We also observe that the segmental deletion calls made by LYCEUM show correlation with the demographic history of the samples and exhibit patterns of negative selection inline with natural selection. AVAILABILITY AND IMPLEMENTATION: LYCEUM is available at https://github.com/ciceklab/LYCEUM.

DNA Copy Number Variations↗

PubMed2000

Evaluation of c-erbB-2 overexpression and Her-2/neu gene copy number heterogeneity in Barrett's adenocarcinoma.

Amplification of the Her-2/neu gene is accompanied by overexpression of its cell surface receptor product, c-erbB-2 protein. To investigate the degree of intratumoural heterogeneity we applied immunohistochemistry in primary Barrett's adenocarcinoma (BCA) (n = 6) and dysplasia adjacent to the carcinoma (n = 4). In addition, fluorescence in situ hybridisation (FISH) was performed in primary BCA (n = 5) and dysplastic areas (n = 4). For an objective evaluation digital image analysis and laser scanning microscopy were used. Five of six BCA showed a marked intratumoral heterogeneous staining pattern ranging from areas in which the tumour cells were negative or faintly positive to tumour areas with a strong staining of the entire membrane. Among the two dysplastic areas also a heterogeneous staining pattern was observed. FISH analysis revealed marked heterogeneity of intratumoral gene copy number changes in all BCA showing populations with different fractions of cells with polysomy, low level amplification and high level amplification. One dysplasia showed a minor population with Her-2/neu signal clusters. In conclusion, we observed marked intratumoural heterogeneity of c-erbB-2 protein overexpression and Her-2/neu gene copy number in the majority of the primary BCA analyzed. Digital image analysis and laser scanning microscopy were helpful in quantifying the variations in protein expression and DNA copy number in individual tumour cells. The observed heterogeneity could hamper the exact diagnostic determination of the c-erbB-2 status in small biopsies and possibly influence the effectiveness of a potential c-erbB-2 targeting therapy. Figures on http://www.esacp.org/acp/2000/20-1/walch.htm+ ++.

Adenocarcinoma↗

PubMed1984

Variation in V lambda genes in the genus Mus.

The complement of Ig V lambda genes in nine species of feral mice representing the four extant subgenera of the genus Mus was examined and compared with that of BALB/c inbred mice. Although all inbred strains examined have two V lambda genes, there is variation in the number of copies of V lambda genes in the wild mice. All feral representatives of M. musculus domesticus, from which inbred strains are derived, have at least three V lambda genes, indicating that a V lambda gene may have been lost during the inbreeding process. At least three V lambda genes are also found in representatives of three other M. musculus subspecies, including the stock of M. musculus musculus "Czech II" shown to have at least 12 C lambda genes. In comparing the complement of V lambda and C lambda genes in these animals, evidence is found that supports a mechanism of lambda gene reiteration involving duplication of a unit containing a V lambda and two C lambda genes. However, the possibility that C lambda gene amplification occurred independent of V lambda gene evolution cannot be ruled out. M. spicelegus and M. spretus, species that are semifertile with M. musculus, have one to three V lambda genes. Species more distantly related to M. musculus, such as M. cookii and M. platythrix, appear to have more (four to six) V lambda genes. Greater V lambda gene heterogeneity is also found in these animals. We propose that the ancestors of the subgenus Mus had more V lambda genes than are seen in modern species and that the paucity of V lambda genes in M. musculus, M. spicelegus, and M. spretus may be the result of V lambda gene deletion events that occurred since the divergence of the ancestor of these three species and those of the distantly related species.

Animals↗

PubMed1995

Comparative genomic hybridization analysis of human sarcomas: I. Occurrence of genomic imbalances and identification of a novel major amplicon at 1q21-q22 in soft tissue sarcomas.

Comparative genomic hybridization (CGH) was recently developed as a tool to survey entire genomes for variations in DNA sequence copy numbers. We have applied this technique to detect and map amplified regions in 54 soft tissue sarcomas. Aberrations were detected by visual analysis of hybridizations or contrast-enhanced digital images, followed by quantitative digital ratio imaging of the aberrant chromosomes. Several tumors showed increased DNA sequence copy number at 12q14, as expected. However, CGH analysis detected amplification of 12q14 also in some tumors where neither MDM2 nor CDK4 was amplified, suggesting that another as yet unknown gene(s) may drive amplification of this region in sarcomas. Furthermore, a novel recurring amplicon was detected at 1q21-q22. DNA amplifications coinciding with this segment were as frequent as those observed for 12q14, indicating that 1q21-q22-linked gene(s) may also play an important role in the development and/or progression of human soft tissue sarcomas.

Animals↗

PubMed1993

Characterization of the COL2A1 VNTR polymorphism.

The variable number of tandem repeat (VNTR) region 3' to the collagen type II gene (COL2A1) was amplified in vitro by the polymerase chain reaction. Subsequent high-resolution gel electrophoresis showed that the five earlier reported alleles could be further subtyped. A total of 17 allelic variants with a heterozygosity of 73.0% were found in 202 unrelated Norwegians. DNA sequencing of 19 COL2A1 alleles has been performed. The internal organization of the VNTR was common for all alleles, as previously shown for a few alleles. Moreover, the polymorphism in the COL2A1 locus is mainly due to variation in the numbers of copies of two repeat units, containing 34 and 31 bp, respectively, and/or to small deletions in either of the two units. DNA sequencing of alleles with the same electrophoretic size revealed no heterogeneity such as an alternating order of the different units, a feature that might have been expected to be the result of unequal crossing-over events. The observed ordered structure of the VNTR and the possibility of single-stranded DNA from the cores in the VNTR forming hairpins and loops suggest that the COL2A1 polymorphism may have evolved mainly by replication slippage mechanisms.

Adult↗

PubMed1977

Replication of prophage P1 during the cell cycle of Escherichia coli.

We have followed, by DNA-DNA hybridization, the variation in the number of copies of prophage P1 relative to two chromosomal markers when the doubling time of the host cells is modified by a change in carbon source. The ratio of P1/chromosome terminus undergoes a twofold decrease when the cell doubling time increases from 24 to 215 min, whereas the ratio of P1/chromosome origin increases 1.4 fold; both ratios tend towards unity at slow growth rates. This suggests that the replication of prophage P1 is not simultaneous with chromosome initiation or chromosome termination. The chromosome replication time is unaffected by the presence of P1, and remains constant over the range of doubling times studied, with a value of about 4o min. Following amino acid starvation, the P1/chromosome origin ratio increases from 0.7 to 0.9, suggesting that P1 retains the ability to replicate after chromosome initiation has stopped and in the absence of essential amino acids. The results are discussed with reference to similar studies done on F and R1.

Cell Division↗

PubMed1987

Translational regulation of the expression of zein cloned in yeast under an inducible GAL promoter.

Yeast cells transformed by a plasmid containing a zein sequence fused to an hybrid yeast promoter GAL1-10/CYC1 accumulate, during a batch growth in galactose minimal medium, large amounts of zein only during a growth-limited phase that precede the entering into the stationary phase. We found that zein is fairly stable in yeast cells and the increased accumulation of zein polypeptide depends mainly upon a marked increase of its rate of synthesis. The increase of the rate of heterologous protein synthesis is not dependent on variation in the plasmid copy number and it is not related to the relative level of zein mRNA, indicating the existence of a postranscriptional regulation that modulates the translatability of this messenger RNA in function of the growth conditions. A possible explanation of this modulation is discussed in terms of a codon bias effect that slow-down the translation of heterologous mRNAs during the exponential phase of growth.

Autoradiography↗

PubMed1999

Molecular structure and chromosomal localization of major repetitive DNA families in the chickpea (Cicer arietinum L.) genome.

Three major repetitive DNA sequences were isolated from a genomic library of chickpea (Cicer arietinum L.) and characterized with respect to their genomic organization and chromosomal localization. All repetitive elements are genus-specific and mostly located in the AT-rich pericentric heterochromatin. Two families are organized as satellite DNAs with repeat lengths of 162-168 bp (CaSat1) and 100 bp (CaSat2). CaSat1 is mainly located adjacent to the 18S rDNA clusters on chromosomes A and B, whereas CaSat2 is a major component of the pericentric heterochromatin on all chromosomes. The high abundance of these sequences in closely related species of the genus Cicer as well as their variation in structure and copy number among the annual species provide useful tools for taxonomic studies. The retrotransposon-like sequences of the third family (CaRep) display a more complex organization and are represented by two independent sets of clones (CaRep1 and CaRep2) with homology to different regions of Ty3-gypsy-like retrotransposons. They are distributed over the pericentric heterochromatin block on all chromosomes with extensions into euchromatic regions. Conserved structures within different crossability groups of related Cicer species suggest independent amplification or transposition events during the evolution of the annual species of the genus.

Amino Acid Sequence↗

PubMed1998

A large polymorphic repeat in the pericentromeric region of human chromosome 15q contains three partial gene duplications.

We report the identification of a partial duplication of GABRA5 , a gene within the imprinted 15q11-q13 region. The duplicated locus maps to the pericentromeric region of 15q, proximal to the large deletions associated with Angelman and Prader-Willi syndromes. We also observed variation in the number of copies of this locus in different individuals, indicating that the duplication is part of a variable repeat. Investigation of the duplication in individuals with a normal karyotype revealed between one and four copies of the repeat on each chromosome 15, whereas from eight to 20 copies were found in individuals possessing a cytogenetically detectable elongation of the 15q region. The variable region is roughly 1 Mb in size and contains two other non-processed duplications, the immunoglobulin heavy chain (IgH) D segment gene and the neurofibromatosis type 1 (NF1) gene. One unit of the pericentromeric repeat is thus composed of duplications of genes from different chromosomal regions. Moreover, we have found replication asynchrony across the GABRA5 duplication, suggesting for the first time that the imprinted part of chromosome 15q extends proximal of the region commonly deleted in Angelman and Prader-Willi syndromes.

Centromere↗

PubMed1991

Activity of clavulanate combinations against TEM-1 beta-lactamase-producing Escherichia coli isolates obtained in 1982 and 1989.

Recent reports of decreased susceptibility to amoxycillin/clavulanate and ticarcillin/clavulanate combinations amongst Escherichia coli isolates have been attributed to an increased frequency of hyperproduction of TEM-1 beta-lactamase. To test this claim we compared the activities of clavulanate combinations against consecutive E. coli isolates producing TEM-1 beta-lactamase that were obtained from clinical material at The London Hospital during 1982 (n = 50) and 1989 (n = 46). Enzyme production was quantified and related to the level of clavulanate required to potentiate amoxycillin and ticarcillin. The levels of TEM-1 enzyme production varied 150-fold amongst the isolates, partly because of variation in the gene copy number. A clear correlation existed between enzyme quantity and levels of resistance to the clavulanate combinations. However, there was no significant difference (P greater than 0.05, Mann-Whitney U test) between the isolates obtained in 1982 and 1989 in terms of the clavulanate concentrations required to potentiate the penicillins, or in the distribution of beta-lactamase activities present.

Amoxicillin↗

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↗

PubMed1986

Variation in the number of alpha-globin loci in sheep.

Southern blot analysis was used to compare sheep and goat restriction-endonuclease maps of the DNA region containing the alpha-globin genes. The identical digestion patterns observed in both species with three endonucleases (BamHI, BstEII, and PstI) show that in sheep a single chromosome normally bears two nonallelic alpha-globin genes positioned at the same distance as in goat. Variant digestion patterns with enzymes that cleave outside (BamHI and HindIII) and within (EcoRI) the alpha-globin loci allowed us to infer that chromosomes with different numbers of alpha-globin loci are also present in sheep. In particular, in the 60 sheep considered, four individuals were heterozygous (alpha alpha/alpha alpha alpha) and one was homozygous (alpha alpha alpha/alpha alpha alpha) for chromosomes with three loci and one individual was heterozygous for a chromosome with four loci (alpha alpha/alpha alpha alpha alpha). This variation in the number of copies of alpha-globin loci can be explained by means of unequal crossovers.

Animals↗

PubMed2002

Determination of bacterial load by real-time PCR using a broad-range (universal) probe and primers set.

The design and evaluation of a set of universal primers and probe for the amplification of 16S rDNA from the Domain Bacteria to estimate total bacterial load by real-time PCR is reported. Broad specificity of the universal detection system was confirmed by testing DNA isolated from 34 bacterial species encompassing most of the groups of bacteria outlined in Bergey's Manual of Determinative Bacteriology. However, the nature of the chromosomal DNA used as a standard was critical. A DNA standard representing those bacteria most likely to predominate in a given habitat was important for a more accurate determination of total bacterial load due to variations in 16S rDNA copy number and the effect of generation time of the bacteria on this number, since rapid growth could result in multiple replication forks and hence, in effect, more than one copy of portions of the chromosome. The validity of applying these caveats to estimating bacterial load was confirmed by enumerating the number of bacteria in an artificial sample mixed in vitro and in clinical carious dentine samples. Taking these parameters into account, the number of anaerobic bacteria estimated by the universal probe and primers set in carious dentine was 40-fold greater than the total bacterial load detected by culture methods, demonstrating the utility of real-time PCR in the analysis of this environment.

Bacteria, Aerobic↗

PubMed1976

Synethesis and integration of viral DNA in chicken cells at different time after infection with various multiplicities of avian oncornavirus.

To see if integration of the provirus resulting from RNA tumor virus infection is limited to specific sites in the cell DNA, the variation in the number of copies of virus-specific DNA produced and integrated in chicken embryo fibroblasts after RAV-2 infection with different multiplicities has been determined at short times, long times, and several transfers after infection. The number of copies of viral DNA in cells was determined by initial hybridization kinetics of single-stranded viral complementary DNA with a moderate excess of cell DNA. The approach took into account the different sizes of cell DNA and complementary DNA in the hybridization mixture. It was found that uninfected chicken embryo fibroblasts have approximately seven copies, part haploid genome of DNA sequences homologous to part of the Rous-association virus 2 (RAV-2) genome. Infection with RAV-2 adds additional copies, and different sequences, of RAV -2- specific DNA. By 13 h postinfection, there are 3 to 10 additional copies per haploid genome. This number can not be increased by increasing the multiplicity of infection, and stays relatively constant up to 20 h postinfection, when some of the additional viral DNA is integrated. Between 20 and 40 h postinfection, the cells accumulated up to 100 copies per haploid genome of viral DNA. Most of these are unintegrated. This number decreases with cell transfer, until cells are left with one to three copies of additional viral DNA sequences per haploid genome, of which most are integrated. The finding that viral infection causes the permanent addition of one to three copies of integrated viral DNA, despite the cells being confronted with up to 100 copies per haploid genome after infection, is consistent with a hypothesis that chicken cells contain a limited number of specific integration sites for the oncornavirus genome.

Animals↗

PubMed2003

Quantitative detection of low-copy-number mRNAs differing at single nucleotide positions.

Accurate analysis of mRNA expression levels of SNPs, highly homologous genes, and splicing variants requires techniques capable of quantifying low-copy-number mRNAs differing at single nucleotide positions. We have used an RT-PCR-based technique based on co-amplification of closely related target mRNA transcripts and assessed the effect of the stochastic distribution of low-copy-number templates on sampling variation when quantifying rare mRNA transcripts. The technique was optimized for maximal sensitivity to enable the analysis of samples containing a subpopulation of target cells and small microdissected samples. We demonstrate that the input level of template molecules is a critical determinant of the achievable assay precision. A minimum of approximately 50 molecules of template is required to discriminate between 2-fold differences in the expression levels of two transcripts. At levels above 1000 molecules of input template, the stochastic effects on sampling variation become negligible.

Antigens, Neoplasm↗

PubMed2026

MarkerMatch: a proximity-based probe-matching algorithm for joint analysis of copy-number variants from different genotyping arrays.

MOTIVATION: Copy-number variants (CNVs) are a form of genetic structural variation with increasing importance in complex human disorders. Both DNA sequencing and microarray data can be used to detect CNVs, which can be used in genetic association tests. Unlike genotypes, CNV detection in microarrays requires the use of observed intensity signals at each probe, which limits the imputability for analyses that span multiple array types. Thus far, a consensus set of probes (those present on all arrays) has been used to circumvent the problem of differing array-specific sensitivities. This has led to excessive reduction in overall sensitivity since arrays can have an undesirably low probe overlap. To overcome this limitation, we developed MarkerMatch, a proximity-based algorithm that matches probes across different genotyping microarrays to maximize the number of probes considered in the CNV calling algorithm, thereby increasing the resolution and sensitivity while preserving precision. RESULTS: By analyzing CNV calls from 4906 individuals genotyped across three different arrays, we show that the MarkerMatch approach improves sensitivity by increasing the density of probes available for CNV calling while maintaining precision or improving it relative to the current practice (e.g. use of consensus probes only). We further demonstrate that MarkerMatch matches the CNV detection from current practice in terms of F1 score and PPV for larger CNVs. We also optimize MarkerMatch parameters, DMAX and Method, and find an optimal DMAX setting at 10 kb, with no clear optimal candidate based on Method, indicating that parameters for this metric should be determined on a use case basis. AVAILABILITY: The R package for MarkerMatch is available at: https://github.com/FranjoIM/MarkerMatch. The code used for analysis and implementation is available at: https://doi.org/10.5281/zenodo.18460979. The live notebook is available at https://fivankovic.notion.site/2026-markermatch.

DNA Copy Number Variations↗