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At least 289 records · Page 16Linked to original sources
PubMed2024

Copy number variant scan in more than four thousand Holstein cows bred in Lombardy, Italy.

Copy Number Variants (CNV) are modifications affecting the genome sequence of DNA, for instance, they can be duplications or deletions of a considerable number of base pairs (i.e., greater than 1000 bp and up to millions of bp). Their impact on the variation of the phenotypic traits has been widely demonstrated. In addition, CNVs are a class of markers useful to identify the genetic biodiversity among populations related to adaptation to the environment. The aim of this study was to detect CNVs in more than four thousand Holstein cows, using information derived by a genotyping done with the GGP (GeneSeek Genomic Profiler) bovine 100K SNP chip. To detect CNV the SVS 8.9 software was used, then CNV regions (CNVRs) were detected. A total of 123,814 CNVs (4,150 non redundant) were called and aggregated into 1,397 CNVRs. The PCA results obtained using the CNVs information, showed that there is some variability among animals. For many genes annotated within the CNVRs, the role in immune response is well known, as well as their association with important and economic traits object of selection in Holstein, such as milk production and quality, udder conformation and body morphology. Comparison with reference revealed unique CNVRs of the Holstein breed, and others in common with Jersey and Brown. The information regarding CNVs represents a valuable resource to understand how this class of markers may improve the accuracy in prediction of genomic value, nowadays solely based on SNPs markers.

Cattle↗
PubMed2025

Absolute Quantification of Cellular and Cell-Free Mitochondrial DNA Copy Number from Human Blood and Urinary Samples Using Real Time Quantitative PCR.

Mitochondrial DNA copy number (mtDNA-CN) in human body fluids is widely used as a biomarker of mitochondrial dysfunction in common metabolic diseases. Here we describe protocols to measure cellular and/or cell free (cf)-mtDNA-CN in human peripheral blood and urine. Cellular mtDNA is located inside the mitochondria where it encodes key subunits of the respiratory complexes in mitochondria and is usually normalized with reference to the nuclear genome as the mitochondrial genome to nuclear genome ratio (Mt/N) in either whole blood, peripheral blood mononuclear cells (PBMCs), or whole urine. Cf -mtDNA is usually found outside of the mitochondria, often released following mitochondrial damage, can trigger inflammatory pathways, and is usually measured as mtDNA-CN per volume of the starting material. Here we describe how to (1) separate whole blood into PBMCs, plasma, and serum fractions and whole urine into urinary supernatant and pellet, (2) prepare DNA from each of these fractions, (3) prepare reference standards for absolute quantification, (4) carry out qPCR for either relative or absolute quantification from test samples, (5) analyze qPCR data, and (6) calculate the sample size to adequately power studies. The protocol presented here is suitable for high throughput use and can be modified to quantify mtDNA from other body fluids, human cells, and tissues.

Humans↗
PubMed2025

The Fire Ant Social Chromosome Exerts a Major Influence on Genome Regulation.

Supergenes underlying complex trait polymorphisms ensure that sets of coadapted alleles remain genetically linked. Despite their prevalence in nature, the mechanisms of supergene effects on genome regulation are poorly understood. In the fire ant Solenopsis invicta, a supergene containing over 500 individual genes influences trait variation in multiple castes to collectively underpin a colony level social polymorphism. Here, we present results of an integrative investigation of supergene effects on gene regulation. We present analyses of ATAC-seq data to investigate variation in chromatin accessibility by supergene genotype and STARR-seq data to characterize enhancer activity by supergene haplotype. Integration with gene co-expression analyses, newly mapped intact transposable elements (TEs), and previously identified copy number variants (CNVs) collectively reveals widespread effects of the supergene on chromatin structure, gene transcription, and regulatory element activity, with a genome-wide bias for open chromatin and increased expression in the presence of the derived supergene haplotype, particularly in regions that harbor intact TEs. Integrated consideration of CNVs and regulatory element divergence suggests each evolved in concert to shape the expression of supergene encoded factors, including several transcription factors that may directly contribute to the trans-regulatory footprint of a heteromorphic social chromosome. Overall, we show how genome structure in the form of a supergene has wide-reaching effects on gene regulation and gene expression.

Animals↗
PubMed1999

Transposon dynamics and the breeding system.

The selfish DNA hypothesis predicts that natural selection is responsible for preventing the unregulated build up of transposable elements in organismal genomes. Accordingly, between-species differences in the strength and effectiveness of selection against transposons should be important in driving the evolution of transposon activity and abundance. We used a modeling approach to investigate how the rate of self-fertilization influences the population dynamics of transposable elements. Contrasting effects of the breeding system were observed under selection based on transposon disruption of gene function versus selection based on element-mediated ectopic exchange. This suggests that the comparison of TE copy number in organisms with different breeding systems may provide a test of the relative importance of these forces in regulating transposon multiplication. The effects of breeding system also interacted with population size, particularly when there was no element excision. The strength and effectiveness of selection against transposons was reflected not only in their equilibrium abundance, but also in the per-site element frequency of individual insertions and the coefficient of variation in copy number. These results are discussed in relation to evidence on transposon abundance available from the literature, and suggestions for future data collection.

Breeding↗
PubMed1988

Tandem array of human visual pigment genes at Xq28.

Unequal crossing-over within a head-to-tail tandem array of the homologous red and green visual pigment genes has been proposed to explain the observed variation in green-pigment gene number among individuals and the prevalence of red-green fusion genes among color-blind subjects. This model was tested by probing the structure of the red and green pigment loci with long-range physical mapping techniques. The loci were found to constitute a gene array with an approximately 39-kilobase repeat length. The position of the red pigment gene at the 5' edge of the array explains its lack of variation in copy number. Restriction maps of the array in four individuals who differ in gene number are consistent with a head-to-tail configuration of the genes. These results provide physical evidence in support of the model and help to explain the high incidence of color blindness in the human population.

Color Vision Defects↗
PubMed1996

Characterization of the maize OHP1 gene: evidence of gene copy variability among inbreds.

The maize proteins Opaque-2 (O2) and OHP1 are members of the bZIP class of transcriptional regulatory proteins. The genomic organizations of the O2 and OHP1 genes are conserved in terms of the number and placement of introns which suggests a common evolutionary origin. The organization of O2 and OHP1 contrasts with the maize bZIP protein gene OBF1, which lacks introns, suggesting that there exist at least two evolutionary paths for bZIP genes in maize. The OHP1 gene is located on chromosome 1L and a duplicate gene, OHP2, is located on 5S. Interestingly, the OHP1 gene, but not OHP2, has been amplified within recent history. Two out of ten maize inbreds analyzed contain multiple linked copies of OHP1, and in one of these lines at least two copies of the OHP1 genes are expressed. This variation in copy number among inbreds may prove useful in understanding the role of OHP1 in maize growth and development and yield insights into the evolution of this group of bZIP DNA binding proteins.

Amino Acid Sequence↗
PubMed2001

Instability of chromosome 8 as an indicator of aggressive tumor phenotype in pancreatic cancer.

BACKGROUND AND OBJECTIVES: Chromosomal instability is a common feature of pancreatic carcinoma, but its biological significance remains unclear. In this study, we investigated the association between chromosomal instability and biological aggressiveness in human pancreatic cancer cells. METHODS: Fluorescence in situ hybridization was performed to examine changes in chromosomal numbers in a total of 13 pancreatic cancer cell lines. We also assessed the potential for tumor aggressiveness within cancer cells by in vitro migration and invasion assay and by subcutaneous implantation into nude mice. RESULTS: Chromosomal instability, characterized by numerical variations in copy numbers of chromosome 8, was observed in most cell lines, and the magnitude of instability was correlated well with both motility (P < 0.001) and invasion rate (P < 0.001) of these cells. Furthermore, a significant positive correlation existed between chromosome instability and tumor growth in vivo (P < 0.01). CONCLUSIONS: These results suggest that the increased level of chromosomal instability may play a critical role in the development of aggressive tumor phenotype during pancreatic cancer progression. J. Surg. Oncol. 2001;76:181-187.

Animals↗
PubMed2001

Mhc class I genes of swordtail fishes, Xiphophorus: variation in the number of loci and existence of ancient gene families.

Swordtail fishes and platies in the genus Xiphophorus (order Cyprinodontiformes, Teleostei) encompass 22 closely related species which are the products of a recent adaptive radiation in the streams of Central America. To investigate the evolution of the major histocompatibility complex (Mhc) genes in the period immediately following speciation, the class I genes from 20 of the 22 species were cloned and characterized by sequencing. The analysis revealed the existence of multiple loci (at least seven in some individuals) whose numbers vary among the different species and probably also among individuals of the same species. The variation does not seem to bear any relationship to the taxonomy of the genus. Genes at the different loci are distinguished by their intron sequences and by the presence of characteristic motifs in exons 2 and 3. The variation in copy number of loci may have been effected in part by unequal crossing over occurring between introns of misaligned closely related genes. The sequences of the genes fall into two groups, A and B, which represent ancient lineages. The groups define two families of loci, which diverged from each other an estimated 85 million years ago, before the separation of the Acanthopterygii from the Paracanthopterygii of the advanced bony fishes. Evolution of the genes within each family can be explained by the birth-and-death process driven by gene duplications and mutational differentiation.

Amino Acid Sequence↗
PubMed2004

Induction of aneuploidy by increasing chromosomal instability during dedifferentiation of hepatocellular carcinoma.

To gain more insight into the role of chromosomal instability (CIN), the cytogenetic hallmark of most solid tumors, we performed fluorescence in situ hybridization (FISH) on interphase nuclei of cytological specimens enabling the correct detection of chromosome copies in intact tumor cells of 18 well (G1), moderately (G2), or poorly (G3) differentiated hepatocellular carcinomas (HCCs). A close correlation between the morphological dedifferentiation and increasing copy numbers and variation of FISH signals was seen for chromosomes 1 and 8, respectively (P < or = 0.0002). Four HCC G1 had constant chromosome patterns for chromosomes 1 and/or 8 with a mean of signals per nucleus < or =5.08 and < or =3 different signal combinations, indicating a low level of CIN, as confirmed by FISH using probes for centromeres of chromosomes 3, 7, and 17. In contrast to this, five HCC G2-3 revealed > or =8.46 signals per nucleus and 23-41 different signal combinations, indicating high levels of CIN. In the remaining cases, signal counts from 5.96-8.46 and 7-15 combinations were seen. Here, nuclei with constant aberration patterns and low copy numbers occurred alongside nuclei with inconstant patterns and high copy numbers. It is evident that in these cases a transition from well to moderately differentiated HCC developed in parallel to an increase in CIN, possibly induced by a major dysregulation of mitotic control mechanisms. In conclusion, CIN may induce a stepwise increase of aneuploidy in HCC that is mirrored by the morphological dedifferentiation of tumor cells.

Aged↗
PubMed1996

Variation in topoisomerase I gene copy number as a mechanism for intrinsic drug sensitivity.

DNA topoisomerase I (topo I) is the principle target for camptothecin and its derivatives such as SN38. Levels of topo I expression vary widely between and within tumour types and the basis for this is poorly understood. We have used fluorescence in situ hybridisation to detect the topo I locus in a panel of breast and colon cancer cell lines. This approach has identified a range of topo I gene copies from 1 to 6 between the cell lines as a result of DNA amplification, polysomy and isochromosome formation. Topo I gene copy number was highly correlated with topo I expression, (rs = 0.92), and inversely correlated to sensitivity to a 1 h exposure to SN38 (rs = -0.904). This illustrates the significant impact of altered topo I gene copy number on intrinsic drug sensitivity and influences potential mechanisms for acquisition of drug resistance.

Antineoplastic Agents, Phytogenic↗
PubMed2004

Distribution and characterization of staphylococcal interspersed repeat units (SIRUs) and potential use for strain differentiation.

Variable-number tandem repeats (VNTRs) have been shown to be a powerful tool in the determination of evolutionary relationships and population genetics of bacteria. The sequencing of a number of Staphylococcus aureus genomes has allowed the identification of novel VNTR sequences in S. aureus, which are similar to those used in the study of the evolution of Mycobacterium tuberculosis clades. Seven VNTRs, termed staphylococcal interspersed repeat units (SIRUs), distributed around the genome are described, occurring in both unique and multiple sites, and varying in length from 48 to 159 bp. Variations in copy numbers were observed in all loci, within both the sequenced genomes and the UK epidemic methicillin-resistant S. aureus (EMRSA) isolates. Clonally related UK EMRSA isolates were clustered using SIRUs, which provided a greater degree of discrimination than multi-locus sequence typing, indicating that VNTRs may be a more appropriate evolutionary marker for studying transmission events and the geographical spread of S. aureus clades.

Bacterial Typing Techniques↗
PubMed1999

Sequence variation and evolution of the mitochondrial DNA control region in the musk shrew, Suncus murinus.

The complete mitochondrial DNA (mtDNA) control region was cloned and sequenced in the musk shrew, Suncus murinus, Insectivora. The general aspect was similar to that found in other mammals. We have found in two locations of this region the presence of arrays of tandem repeats like those in other shrew species. One array was located in the left domain containing the termination-associated sequences (TAS) and the length of a copy was 77 bp. The other repeats were situated upstream from the recognition site for the end of H-strand replication in the right domain and were 20 bp long. The left halves of the control region containing the former repeats were sequenced and compared in several laboratory lines and wild animals from different localities, variations in copy number of repeated sequences were found both among individuals and within an individual. A comparative study of repeated sequences provides useful indication for the origin and evolution of tandem repeated sequences. Strand slippage and mispairing during replication of mtDNA with concerted manner is currently regarded as a dominant theory to account molecular mechanism for tandemly repeated sequences, and the pattern of sequence and length variation in our study supports this theory. Our results, however, suggest that the evolution of the repeated sequences containing the TAS in the musk shrew might go through the process of two steps; at the first step one complete repeated and several incomplete repeated sequences had reproduced in common ancestor of the shrew, and the second stage step-up of complete repeated sequences occurred with concerted evolution after differentiation into continental and insular groups.

Animals↗
PubMed2006

Clinical findings in 33 subjects with large supernumerary marker(15) chromosomes and 3 subjects with triplication of 15q11-q13.

We present clinical data on 33 subjects with additional copies of the Prader-Willi-Angelman critical region (PWACR) contained in a supernumerary marker chromosome (SMC). Twenty-three subjects had a typical large non-mosaic SMC(15) containing two copies of the PWACR. They showed a variable but generally severe phenotype of learning disability and autism, with seizures in approximately two-thirds. The other 10 differed from this typical pattern in respect of mosaicism, variation in copy number, or arrangement of the PWACR within the SMC or number of SMC per cell. Clinical severity increased with the number of additional copies of the PWACR and decreased with mosaicism for a normal cell line. There was a trend for a larger number of seizures to be associated with more severe learning disability. Three subjects with interstitial triplications of 15q11-q13 showed a range of phenotypes similar to those of the typical large SMC(15). All additional copies of the PWACR in this series were maternally-derived. FISH and molecular data localizing the breakpoints of the rearrangements have been previously published or are included in this report. No correlations were found between specific clinical features and variations in breakpoints proximal and distal to the PWACR.

Abnormalities, Multiple↗
PubMed2000

Structure of chromosomal duplicons and their role in mediating human genomic disorders.

Chromosome-specific low-copy repeats, or duplicons, occur in multiple regions of the human genome. Homologous recombination between different duplicon copies leads to chromosomal rearrangements, such as deletions, duplications, inversions, and inverted duplications, depending on the orientation of the recombining duplicons. When such rearrangements cause dosage imbalance of a developmentally important gene(s), genetic diseases now termed genomic disorders result, at a frequency of 0.7-1/1000 births. Duplicons can have simple or very complex structures, with variation in copy number from 2 to >10 repeats, and each varying in size from a few kilobases in length to hundreds of kilobases. Analysis of the different duplicons involved in human genomic disorders identifies features that may predispose to recombination, including large size and high sequence identity between the recombining copies, putative recombination promoting features, and the presence of multiple genes/pseudogenes that may include genes expressed in germ cells. Most of the chromosome rearrangements involve duplicons near pericentromeric regions, which may relate to the propensity of such regions to accumulate duplicons. Detailed analyses of the structure, polymorphic variation, and mechanisms of recombination in genomic disorders, as well as the evolutionary origin of various duplicons will further our understanding of the structure, function, and fluidity of the human genome.

Animals↗
PubMed1993

The effects of unequal sister chromatid exchange on length of arrays of repeated sequences.

Models of homogenization of repeated sequences by unequal sister chromatid exchange (USCE) assume that no significant changes in array length occur. The effects of successive USCEs on the lengths of arrays of repeated sequences has been examined mathematically and by simulation, assuming misalignment to be greater in longer arrays, a condition necessary for homogenization. The series of duplications and deletions gives a wide, asymmetric variation in copy number. Frequencies follow a binomial distribution, but if misalignment increases with array length, lengths become logarithmically distributed, most arrays being shorter than the original, counterbalanced by a few very long arrays. The median length, which is also the modal length, decreases exponentially or asymptotically. Given a proportional misalignment of a, the median (mode) decreases by a2/2 per unequal crossover. Since drift is a random transmission of available alleles in the population, it follows that fixation of common short arrays is much more probable than fixation of rare long arrays. This process will continue inexorably until each array is too short to undergo further unequal crossing over, and no more variation is generated. The number of unequal crossovers required by some published models of homogenization would almost certainly cause dramatic reduction in number, or complete loss, of repeats. Frequent unequal sister chromatid exchanges are not compatible with survival of arrays unless counteracted by an independent amplification mechanism or selection, so are unlikely to be important as a long-term homogenization mechanism in non-essential repeated sequences.

DNA↗
PubMed1998

Rapid reorganization of resistance gene homologues in cereal genomes.

We used conserved domains in the major class (nucleotide binding site plus leucine-rich repeat) of dicot resistance (R) genes to isolate related gene fragments via PCR from the monocot species rice and barley. Peptide sequence comparison of dicot R genes and monocot R-like genes revealed shared motifs but provided no evidence for a monocot-specific signature. Mapping of these genes in rice and barley showed linkage to genetically characterized R genes and revealed the existence of mixed clusters, each harboring at least two highly dissimilar R-like genes. Diversity was detected intraspecifically with wide variation in copy number between varieties of a particular species. Interspecific analyses of R-like genes frequently revealed nonsyntenic map locations between the cereal species rice, barley, and foxtail millet although tight collinear gene order is a hallmark of monocot genomes. Our data suggest a dramatic rearrangement of R gene loci between related species and implies a different mechanism for nucleotide binding site plus leucine-rich repeat gene evolution compared with the rest of the monocot genome.

Chromosome Mapping↗
PubMed2004

Chromosomal polymorphism, gene synteny and genome size in T. cruzi I and T. cruzi II groups.

Pulsed-field gel electrophoresis and DNA hybridization were used to establish and compare some parameters of the molecular karyotype of nine stocks classified into Trypanosoma cruzi I and T. cruzi II groups. The isolates showed a variable number of chromosomal bands (17-22) comprised between 0.4 and 3.3 Mbp. The total number of chromosomes and the genome size were estimated based on the fluorescence intensity of SYBR Green I-stained chromosomal bands. Differences in the length of the telomeric regions among the stocks and between chromosomes of the same stock were observed. No correlation was found between the length of the telomeric region and the group to which the isolate belongs. Hybridization of 54 genetic markers revealed extensive chromosome size polymorphism. Nevertheless, the most represented pattern was the hybridization of the probes in larger chromosomes in stocks of T. cruzi II as compared to T. cruzi I. Eight putative syntenic groups, encompassing 29 non-redundant genetic markers and distributed in 11 CL Brener chromosomal bands were disclosed. The syntenic groups were conserved in all the stocks. The relative abundance of repetitive DNA sequences was determined. C6, B11/L1Tc and E12 elements presented maximum 1.7-fold variation in copy number, whereas 195-bp satellite DNA (120,000 copies in Y strain) was four- to nine-fold more abundant in T. cruzi II stocks. The novel aspects of T. cruzi karyotype here presented contribute to the comprehension of the genome organization of this parasite and will assist the assignment of scaffold to the CL Brener chromosomal bands.

Animals↗
PubMed2004

Gene conversion and the evolution of protocadherin gene cluster diversity.

The synaptic cell adhesion molecules encoded by the protocadherin gene cluster are hypothesized to provide a molecular code involved in the generation of synaptic complexity in the developing brain. Variation in copy number and sequence content of protocadherin cluster genes among vertebrate species could reflect adaptive differences in protocadherin function. We have completed an analysis of zebrafish protocadherin cluster genes. Zebrafish have two unlinked protocadherin clusters, DrPcdh1 and DrPcdh2. Like mammalian protocadherin clusters, DrPcdh1 has both alpha and gamma variable and constant region exons. A consensus protocadherin promoter motif sequence identified in mammals is also conserved in zebrafish. Few orthologous relationships, however, are apparent between zebrafish and mammalian protocadherin proteins. Here we show that protocadherin cluster genes in human, mouse, rat, and zebrafish are subject to striking gene conversion events. These events are restricted to regions of the coding sequence, particularly the coding sequences of ectodomain 6 and the cytoplasmic domain. Diversity among paralogs is restricted to particular ectodomains that are excluded from conversion events. Conversion events are also strongly correlated with an increase in third-position GC content. We propose that the combination of lineage-specific duplication, restricted gene conversion, and adaptive variation in diversified ectodomains drives vertebrate protocadherin cluster evolution.

Animals↗