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At least 1,459 records · Page 81Linked to original sources
PubMed1998

Test of candidate gene--quantitative trait locus association applied to fatness in mice.

We test for the contribution of five strong candidate genes for obesity to quantitative variation for fatness in mice. The candidate loci are known through their major mutant phenotypes. We propose a randomization test for overall contribution of candidate genes, based on the empirical distribution of LOD scores from a quantitative trait locus (QTL) genome scan. The test is applied to data on body fat content and male gonadal fatpad weight from a QTL genome scan with an F2 population of C57BL/6J and DBA/2J inbred mice. The test is nonsignificant in this experiment for overall body fat content. QTLs detected at an experiment-wide significance level on chromosome 4, 6, 13 and 15 have effects on mean fatness of up to 19% between the homozygotes, but map to locations where there is no strong candidate gene. The test is significant for gonadal fat pad weight in males, and gives weak support for an association with the diabetes gene.

Adipose Tissue↗
PubMed2004

Assessment of environmental stress by the micronucleus test and the Comet assay on the genome of teleost populations from two natural environments.

The aim of the present paper was to assess the biological damage caused by exposure of the test organism (Gambusia holbrooki: Cyprinodontiformes, Poecilidae) to various mutagenic agents present in the polluted waters of the Sarno River. For this purpose, we performed a micronuclei (MN) test and single cell gel electrophoresis (the Comet assay), testing DNA migration in an electrophoretic field using erythrocytes of G. holbrooki specimens both from the Sarno River and from the waters of the crater of the Astroni natural reserve as negative controls. The results indicate statistically higher values for both MN and DNA migration in the samples from the Sarno River compared with those from Astroni and point to a strong genotoxic action of the mixture of pollutants present in the Sarno River. These data were compared with the values found in the G. holbrooki specimens from the Sarno River kept under laboratory conditions for 100 days in clean water.

Animals↗
PubMed2000

[Mucoviscidosis screening of newborn infants in the Dresden district. Results from 1 June 1996 to 31 March 2000].

PROBLEM: Cystic fibrosis (CF) is the most common congenital defect of metabolism in Europe. Therefore we tried to detect this disease as early as possible before clinical symptoms occur. Thus early diagnosis can be the basis for an early start of treatment. PATIENTS AND METHODS: As part of a complete neonatal screening program in our region we investigated the concentration of immuno-reactive trypsin (IRT) in dried blood samples. Genomic investigation of the same blood sample for the most common CF mutations was performed when a critical value of IRT was exceeded. RESULTS: From 6/1996 until 3/2000 (46 months) we investigated the blood of 49,926 newborn children. Due to a high IRT value (> 70 ng/ml) in 579 cases, a genomic investigation was performed. In 38 children we detected one of the three most frequent CF mutations (delta F508, G551D, R553X) by polymerase chain reaction (PCR). The sweat test (pilocarpine iontophoresis) confirmed cystic fibrosis in 8 newborns. Four times a homocygocity for the mutation delta F508 was found and four times a compound heterocygocity (one time delta F508/R553X und three times delta F508/others). Only three of these eight CF patients already had clinical symptoms of the disease at this time, only in one case had this diagnosis been considered. An additional newborn with meconium ileus had been diagnosed as cystic fibrosis before performing the screening. Up to now we have not found any case of false negative testing. CONCLUSION: We found this procedure of neonatal testing practicable and therefore recommend its continuation. The genomic test should include the search for additional CF mutations. As alternative method a second IRT-test should be considered at the end of the first month of life for those children with initial IRT-concentrations above 150 ng/ml and without evidence of the three tested CFTR-mutations.

Cystic Fibrosis↗
PubMed2004

Occult hepatitis B virus infection: implications in transfusion.

Hepatitis B virus (HBV) presents a higher residual risk of transmission by transfusion than hepatitis C virus (HCV) or human immunodeficiency virus (HIV). While most infectious blood units are removed by screening for hepatitis B surface antigen (HBsAg), there is clear evidence that transmission by HBsAg-negative components occurs, in part, during the serologically negative window period, but more so during the late stages of infection. Donations negative for HBsAg, but positive for HBV DNA, with or without the presence of HBV antibodies, correspond to 'occult' HBV infection (OBI). The frequency of OBI depends on the relative sensitivity of both HBsAg and HBV DNA assays. It also depends on the prevalence of HBV infection in the population. OBI may follow recovery from infection, displaying antibody to hepatitis B surface antigen (anti-HBs) and persistent low-level viraemia, escape mutants undetected by the HBsAg assays, or healthy carriage with antibodies to hepatitis B e antigen (anti-HBe) and to hepatitis B core antigen (anti-HBc). Over time, in the latter situation, anti-HBe and, later, anti-HBc may become undetectable. The critical question is whether or not OBI is infectious by transfusion. All forms have been shown to be infectious in immunocompromised individuals, such as organ- or bone marrow-transplant recipients. In immunocompetent recipients, there is no evidence that anti-HBs-containing components (even at low titre) are infectious. Anti-HBc only, with HBV DNA, can be associated with infectivity, as can rare cases of HBV DNA without any serological HBV marker. If HBV nucleic acid amplification technology (NAT) is considered, the OBI viral load would usually be < 500 IU/ml, making testing of plasma pools unsuitable unless the sensitivity of NAT significantly increases by genome enrichment or test improvement.

Adult↗
PubMed2000

Adeno-associated virus in normal and myositis human skeletal muscle.

The normal tissue tropism of adeno-associated virus (AAV) is poorly defined, although the majority of humans test seropositive for this virus. Eighty-five muscle biopsy specimens were tested for AAV genomes; AAV DNA was identified in 17% of normal and 10% of Duchenne muscular dystrophy muscle biopsy specimens, but in only 3% of peripheral blood samples. AAV genomes were absent from all 37 muscle biopsy specimens from patients with myositis tested. Muscle is a major target organ for AAV, and infection is associated with autoimmune disease of muscle.

Adolescent↗
PubMed2026

Phylogenomics reveals persistent gene-tree discordance in the Chenopodium album aggregate.

BACKGROUND AND AIMS: Complex genomic histories shaped by hybridisation and polyploidy can influence traits related to plant defence, stress tolerance and toxicity, particularly in Amaranthaceae, which includes crops such as quinoa and spinach. Within this family, white goosefoot (Chenopodium album), a widespread agricultural weed and traditional food resource, belongs to a diploid-polyploid aggregate with extensive phylogenetic discordance. Clarifying its evolutionary history provides context for interpreting ecologically and agronomically relevant trait variation across the aggregate. Building on the established genome-lineage framework, we tested whether discordance persists when constituent genome-lineage components are represented separately and whether the remaining signal is compatible with reticulate evolution. METHODS: We analysed 2,298 conserved nuclear BUSCO families across 27 assembly-level terminals using tree- and network-based approaches. Genome-lineage-aware analyses used 2,156 families after separating polyploid Chenopodium into A-H components, with Dysphania ambrosioides as outgroup. HyDe tested site-pattern asymmetry under global false-discovery-rate correction. KEY RESULTS: Assembly-level analyses grouped the Danish C. album aggregate accession Ca6-1 with hexaploid C. album sensu stricto dcCheAlbu1.1, whereas relationships among surrounding Chenopodium taxa were less stable. Genome-lineage-aware analyses recovered the expected B-, C- and D-affinity relationships, but substantial gene-family heterogeneity persisted. Reticulate network models fitted the assembly-level data better than bifurcating models, although inferred patterns differed between methods. HyDe detected significant site-pattern asymmetry in a small subset of loci, with most retained signal shared between the focal assemblies. CONCLUSIONS: Gene-tree discordance persists in the C. album aggregate after genome-lineage separation. The established genome-lineage framework captures the dominant phylogenomic structure, while residual heterogeneity is compatible with both tree-like and reticulate processes without identifying direct progenitors or a unique hybridisation history. This framework supports future analyses of lineage-specific and trait-associated loci related to plant defence, food quality and toxicity in C. album and related Amaranthaceae.

Chenopodium album↗
PubMed2003

Extracting phylogenetic information from whole-genome sequencing projects: the lactic acid bacteria as a test case.

The availability of an ever increasing number of complete genome sequences of diverse prokaryotic taxa has led to the introduction of novel approaches to infer phylogenetic relationships among bacteria. In the present study the sequences of the 16S rRNA gene and nine housekeeping genes were compared with the fraction of shared putative orthologous protein-encoding genes, conservation of gene order, dinucleotide relative abundance and codon usage among 11 genomes of species belonging to the lactic acid bacteria. In general there is a good correlation between the results obtained with various approaches, although it is clear that there is a stronger phylogenetic signal in some data sets than in others, and that different parameters have different taxonomic resolutions. It appears that trees based on different kinds of information derived from whole-genome sequencing projects do not provide much additional information about the phylogenetic relationships among bacterial taxa compared to more traditional alignment-based methods. Nevertheless, it is expected that the study of these novel forms of information will have its value in taxonomy, to determine which genes are shared, when genes or sets of genes were lost in evolutionary history, to detect the presence of horizontally transferred genes and/or confirm or enhance the phylogenetic signal derived from traditional methods. Although these conclusions are based on a relatively small data set, they are largely in agreement with other studies and it is anticipated that similar trends will be observed when comparing other genomes.

Bacterial Proteins↗
PubMed2026

Whole-Genome Analysis Reveals Antimicrobial Resistance and Population Structure of Environmental and Veterinary Acinetobacter baumannii.

Acinetobacter (A.) baumannii is an important multidrug-resistant pathogen increasingly recognized across animal and environmental settings, and carbapenem-resistant A. baumannii (CRAB) is classified as a critical-priority pathogen by the World Health Organization. This study investigated the antimicrobial resistance (AMR) and genomic characteristics of 122 A. baumannii isolates comprising 72 veterinary and 50 environmental isolates collected in Andhra Pradesh, India. Antimicrobial susceptibility testing, whole-genome sequencing (WGS), resistance and virulence gene profiling, multilocus sequence typing (MLST), core-genome analysis, single nucleotide polymorphism (SNP) phylogeny, and pan-genome analysis were performed. Overall, 58.2% of isolates were multidrug-resistant (MDR), and 41.8% were extensively drug-resistant (XDR). Sequence type (ST) 52 predominated among veterinary isolates, whereas ST2 was more frequent among environmental isolates. The presence of carbapenem-resistant isolates along with the ST2 lineage enhances the similarity to clinical A. baumannii. Several intrinsic resistance genes, including blaOXA-23, armA, aph(3&#x2033;)-Ib, aph(6)-Id, tet(B), mph(E), and msr(E), were more prevalent in the ST2-associated population. Virulence-associated determinants were widely conserved. Core-genome MLST (cgMLST) and core-genome SNP (cgSNP) analyses identified highly related isolates within both lineages, while pairwise SNP differences were 0-7. Pan-genome analysis identified 4204 gene clusters and distinct accessory gene patterns between ST2 and ST52. These findings indicate that resistance gene distribution was closely associated with lineage structure and support integrated genomic surveillance of A. baumannii across animal and environmental reservoirs.

Acinetobacter baumannii↗
PubMed2006

A public health approach to pharmacogenomics and gene-based diagnostic tests.

While the human genome project is likely to lead to fundamental changes in our understanding of disease causation and our ability to screen for disease predisposition and treatment responsiveness, the current healthcare system is not properly aligned to ensure the proper use of these advances. As the pace of genetic technology development increases and new pharmacogenetic drugs and gene-based diagnostic tests increasingly impact providers, patients, health plans, payers and employers, it will be crucial to develop an evidence-based framework by which to evaluate these new tests and treatments. In order to increase the level of evidence available and allow for informed decisions in the face of strong marketing and advocacy forces, the authors suggest the development of one (or more) large clinical networks with the purpose of systematically evaluating the clinical effectiveness of new genomic applications, including pharmaceuticals and gene-based diagnostic tests, in 'real world' settings.

Evidence-Based Medicine↗
PubMed1993

Ethical and practical implications of the human genome initiative for family medicine.

Major advances in predictive genetic testing resulting from the Human Genome Initiative could change significantly the routine practice of family medicine. Family physicians should be aware that increased genetic information may affect patients' abilities to acquire and maintain insurance and employment and that interested parties will have incentives to seek this information. The social consequences of genetic information, as well as increased health promotion efforts, may raise problems of informed consent and confidentiality. In addition to their ethical implications, these developments will also affect the practice of family physicians in practical ways such as record keeping. We discuss cases that illustrate the potential impact of these emerging technologies on the practice of family medicine.

Adult↗
PubMed1997

Genetic markers of bone metabolism and bone disease.

Genetic factors play an important role in the pathogenesis of several bone diseases. The the most important of these is osteoporosis-a common condition characterised by reduced bone mass and increased fracture risk, which affects up to 40% of women and 12% of men at some point during life. Twin and family studies suggest that up to 85% of the variance in bone mineral density is genetically determined. Clinical studies have identified several candidate genes which may be involved in this process. The vitamin D receptor gene (VDR) has been most widely studied, but the relationship between polymorphisms of the VDR and bone density has been found to be inconsistent and poorly reproducible in different populations. Polymorphisms in and around the genes encoding interleukin-6, tumour necrosis factor beta and the oestrogen receptor have also been associated with bone mass in some populations, but these have not been widely studied. In contrast, a functional polymorphism has been identified at a binding site for the transcription factor Sp1 in the collagen type I alpha I gene, which is associated with bone mass and osteoporotic fracture in several populations, suggesting that genotyping at this site may be of potential clinical value in the assessment of fracture risk. The importance of genetic factors in the regulation of bone mass, coupled with the ability to test for candidate polymorphisms in genomic DNA, indicates that genetic testing may play a role in the future assessment of osteoporotic fracture risk. The clinical value of this approach is at present unclear, but is likely to be an important area for future development as new polymorphisms are identified by genome wide searches and further analysis of candidate genes.

Bone Diseases↗
PubMed2025

Lentiviral-mediated gene complementation rescues pathogenic ABCA3 variants.

The ATP-binding cassette subfamily A member 3 (ABCA3) protein on the limiting membrane of lamellar bodies in alveolar type 2 (AT2) cells transports phospholipids required for pulmonary surfactant assembly. ABCA3 deficiency results from biallelic pathogenic variants in ABCA3 and causes progressive neonatal respiratory failure or childhood interstitial lung disease (chILD). Supportive/compassionate care or lung transplantation are the only current definitive treatments for ABCA3 deficiency and progressive respiratory failure. Complementing dysfunctional ABCA3 by gene addition has therapeutic potential. Previous studies show that repairing or complementing ABCA3 in induced pluripotent stem cell (iPSC)-derived AT2 cells rescues lamellar body morphology and surfactant phospholipid composition. Pathogenic variants disrupt ABCA3 function through altered protein trafficking (type 1) or by impaired phospholipid transport (type 2) into lamellar bodies. Here we tested ABCA3 gene complementation using a human pulmonary epithelial cell line (A549) with a genomically silenced ABCA3 locus (ABCA3 KO). From this line, additional cell lines that stably express individual ABCA3 variant cDNA constructs from a single genomic locus were tested: L101P (type 1), E292V (type 2), E690K (type 2), or wild-type ABCA3. Lentiviral-mediated ABCA3 delivery to each cell line partially rescued localization to LAMP3+ vesicles, lamellar body-like structure morphology, and cell proliferation. A functional assay measuring NF-&#x3ba;B signaling suggested that ABCA3 complementation ameliorated aberrant inflammatory signaling in E292V or E690K (type 2) mutant lines, but not in L101P (type 1) or knockout lines. These studies highlight the therapeutic potential of gene addition as well as differences between ABCA3 pathogenic variants that may influence genetic therapy outcomes.

ABCA3 deficiency↗
PubMed2005

Comparison of various microbiological tests including polymerase chain reaction for the diagnosis of osteoarticular tuberculosis.

PURPOSE: To evaluate the utility of the polymerase chain reaction (PCR) test for diagnosing osteoarticular tuberculosis (TB). METHODS: Clinical samples (synovial tissue and synovial fluid) obtained from 23 cases of suspected osteoarticular tuberculosis were subjected to Ziehl Neelsen (ZN) smear examination, radiometric BACTEC culture and PCR test for tuberculosis by amplifying 65 kDa antigen coding region of Mycobacterium tuberculosis (M.tb) genome. RESULTS: PCR test was found to be much sensitive than the ZN smear examination and BACTEC culture (p<0.05) in the diagnosis of osteoarticular TB. In synovial fluid samples, PCR was positive in 73.9%, ZN smear examination in 17.39% and BACTEC culture in 39.13% of cases. The positivities were relatively lower with synovial tissue samples, the corresponding figures being 60.8, 8.6 and 26.08% respectively. Moreover, on combining the results of synovial fluid and tissues, the corresponding figures further increased to 78.2, 21.7 and 43.3% respectively. Further, sensitivity and specificity for PCR employing BACTEC culture as the "gold standard" was 100% respectively. Using BACTEC culture, the earliest positivity was seen in three days using synovial tissue specimen and 13 days with synovial fluid, the average detection times being 23.2 days and 32.6 days respectively. On the other hand, PCR test gave a positive result within 24 hours. CONCLUSIONS: PCR test was shown to be much more sensitive than ZN smear examination and BACTEC culture test for diagnosing osteoarticular tuberculosis.

Bacteriological Techniques↗
PubMed1983

Expression of the yeast CYC genes and CYC1/GalK fusion genes on yeast plasmids.

We have presented the results of our studies of the expression of the CYC genes from plasmids. All our data indicate that the levels of expression and the regulation of expression are very similar for the plasmid-borne genes and the chromosomal genes when care is taken to construct the appropriate plasmids. The usefulness of these plasmids has been demonstrated: mutations affecting regulatory sites adjacent to genes of interest have been constructed [such as the Xho I deletion and inversion in the YCpCYC1(2.4) plasmid] and selected [as in the case of the IS1 insertion into the YCpCYC7(2) plasmid], and these mutations have led us to some tentative conclusions about the location and nature of the regulatory sites of these genes. Furthermore, transformation with plasmids containing modified genes or fusions has permitted isolation of genomic regulatory mutants, as in the selection of lac+ suppressors of the lac- CYC1 1/x inversion carried on the YCpCYC1(2.4) 1/x plasmid. Although we cannot rule out the possibility that use of plasmids might cause us to miss a class of regulatory effects that can be propagated only along a chromosomal structure, we believe that the regulatory effects that we do observe can be more quickly and completely defined by working with plasmids. If any regulatory effects occur only on chromosomes, they can be studied more easily once the basic regulatory phenomena have been analyzed. The regulatory regions of the CYC1, CYC7, and TR2 genes that we have crudely mapped so far all exert their effects 100-300 bp away from the putative transcriptional starting sites. How the information in these regions is transmitted along the DNA is an intriguing question. We are engaged in a mutational analysis of these sites to locate them more precisely, to map second-site mutations that moderate the effects of the original mutations, to obtain genomic mutations that define the genes whose products interact with these sites, and to test combinations of genomic and plasmid mutations to define the sites with which regulatory elements interact. This approach should aid our understanding of the spatial relationships between yeast regulatory sites and transcriptional signals. Ultimately, obtaining mutations in regulatory genes, such as the mutations described here for the anaerobic regulation of TR2, will allow the cloning of these genes by complementation. This will lead to the isolation of the protein encoded and ultimately to an approach to the molecular mechanism of regulation through study of protein-DNA interactions.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1992

Identification of Selenomonas species by whole-genomic DNA probes, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, biochemical tests and cellular fatty acid analysis.

Nonisotopic, whole-genomic DNA probes, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), biochemical tests in microtiter trays and cellular fatty acid (CFA) analysis were compared for the identification of 5 oral Selenomonas species. DNA probes were prepared by biotin-labeling DNA extracted from the type strains of Selenomonas noxia, Selenomonas flueggei, Selenomonas artemidis, Selenomonas infelix and Selenomonas sputigena. The probes were hybridized with DNA from 21 reference strains, 18 fresh isolates of Selenomonas species, and 21 strains of other oral gram-negative species. Target DNAs were obtained by in situ extraction of colonies blotted onto filter paper. Streptavidin-linked alkaline phosphatase was used to detect homologous reactions of probe and target DNA. Each Selenomonas species DNA probe reacted with reference strains of only that species. All Selenomonas strains that reacted with the DNA probe for a particular species gave similar biochemical test results, SDS-PAGE protein profiles, and CFA profiles to those of the type strain of the corresponding species. All the methods tested were useful for identifying the species, and all yielded similar identifications of the fresh isolates. The DNA probes, however, had the potential for identifying Selenomonas species directly from primary isolation plates or plaque samples.

Bacteroidaceae↗
PubMed2006

REEF: searching REgionally Enriched Features in genomes.

BACKGROUND: In Eukaryotic genomes, different features including genes are not uniformly distributed. The integration of annotation information and genomic position of functional DNA elements in the Eukaryotic genomes opened the way to test novel hypotheses of higher order genome organization and regulation of expression. RESULTS: REEF is a new tool, aimed at identifying genomic regions enriched in specific features, such as a class or group of genes homogeneous for expression and/or functional characteristics. The method for the calculation of local feature enrichment uses test statistic based on the Hypergeometric Distribution applied genome-wide by using a sliding window approach and adopting the False Discovery Rate for controlling multiplicity. REEF software, source code and documentation are freely available at http://telethon.bio.unipd.it/bioinfo/reef/. CONCLUSION: REEF can aid to shed light on the role of organization of specific genomic regions in the determination of their functional role.

Algorithms↗
PubMed2000

Genomic control for association studies: a semiparametric test to detect excess-haplotype sharing.

Individuals who share a disease mutation from a common ancestor often share alleles at genetic markers adjacent to the mutation, even if the common ancestor is remote. The alleles at these adjacent markers, called the haplotype, can be visualized as a string of realizations of random variables, which may be dependent when individuals are related in some fashion. Ideally, for a sample of individuals all having the same (genetic) disease, this dependence-measured as haplotype-sharing-will be greater in the vicinity of disease genes than in other regions of the genome. In this paper we present a semiparametric test for haplotype-sharing. We begin by developing a model assuming that the ancestral haplotype is known and thus the extent of haplotype-sharing from a common ancestor can be determined unambiguously. The amount of overlap at markers far from the disease is treated as a random variable with an unknown distribution F, which we estimate non-parametrically. Overlap of markers surrounding disease genes are modeled as a mixture pF(x - theta) + (1 - p)F(x), in which p is the fraction of subjects with the disease mutation. Testing for a disease gene then amounts to testing whether p = 0. Next we drop the assumption that the ancestral haplotype is known. To detect excess clustering of haplotypes, we measure the pairwise overlap of a set of haplotypes. As in the simpler scenario, this distribution is modeled as a location-shift mixture. To test the hypothesis we construct a score test with a simple limiting distribution.

Journal Article↗
PubMed2003

Array rank order regression analysis for the detection of gene copy-number changes in human cancer.

cDNA microarray technology has been applied to the detection of DNA copy-number changes in malignant tumors. Test and control genomic DNA samples are differentially labeled and cohybridized to a spotted cDNA microarray. The ratio of test to control fluorescence intensities for each spot reflects relative gene copy number. The low signal-to-noise ratios of this assay and the variable levels of gene amplification and deletion among tumors hamper the detection of deviations from the diploid complement. We describe a regression-based statistical method to test for altered copy number on each gene and apply the technique to copy-number profiles in 10 thyroid tumors. We show that a novel transformation of fluorescence ratios into array rank order efficiently normalizes the heterogeneity among copy-number profiles and improves the reproducibility of the results. Array rank order regression analysis enhances the detection of consistent changes in gene copy number in solid tumors by cDNA microarray-based comparative genome hybridization.

Fluorescence↗