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At least 865 records · Page 48Linked to original sources
PubMed2002

The APG8/12-activating enzyme APG7 is required for proper nutrient recycling and senescence in Arabidopsis thaliana.

The vacuole/lysosome serves an important recycling function during starvation and senescence in eukaryotes via a process called autophagy. Here bulk cytosolic constituents and organelles become sequestered in specialized autophagic vesicles, which then deliver their cargo to the vacuole for degradation. In yeasts, genetic screens have identified two novel post-translational modification pathways remarkably similar to ubiquitination that are required for autophagy. From searches of the Arabidopsis genome, we have identified gene families encoding proteins related to both the APG8 and -12 polypeptide tags and orthologs for all components required for their attachment. A single APG7 gene encodes the ATP-dependent activating enzyme that initiates both conjugation pathways. Phenotypic analysis of an APG7 disruption indicates that it is not essential for normal growth and development in Arabidopsis. However, the apg7-1 mutant is hypersensitive to nutrient limiting conditions and displays premature leaf senescence. mRNAs for both APG7 and APG8 preferentially accumulate as leaves senesce, suggesting that both conjugation pathways are up-regulated during the senescence syndrome. These findings show that the APG8/12 conjugation pathways have been conserved in plants and may have important roles in autophagic recycling, especially during situations that require substantial nitrogen and carbon mobilization.

Adenosine Triphosphate↗
PubMed1999

Comparative genomic hybridization analysis of hepatoblastomas: additional evidence for a genetic link with Wilms tumor and rhabdomyosarcoma.

We applied the technique of comparative genomic hybridization (CGH) to a series of 16 hepatoblastomas. Our goals were (1) to identify all quantitative chromosome abnormalities that appear in this type of tumor and (2) to compare the results with data from similar studies on other tumors associated with the Beckwith-Wiedemann syndrome (BWS). We found that the most commonly detected (> 30%) chromosome abnormalities were gains of chromosomes 1, 2, 7, 8, and 17. Losses of chromosomes were found in only a few cases. On comparing our results with those from studies on the BWS-associated tumors, Wilms tumor and rhabdomyosarcoma, it became clear that three chromosome regions, namely, 7q, 8q, and 17q, were the ones most commonly involved in all three types of tumors. These regions, therefore, may harbor genes that play a role in the etiology of BWS-associated tumors in general.

Age of Onset↗
PubMed1999

Evaluation of replication studies, combined data analysis, and analytical methods in complex diseases.

Due to genetic heterogeneity, phenocopies, incomplete penetrance, misdiagnosis, and unknown mode of inheritance, linkage studies of most complex diseases are unlikely to provide conclusive findings with unambiguously high lod scores. Typically, several marginally significant lod scores or elevated lod scores are observed in a genome-wide screen. However, it is usually difficult to differentiate these findings from false positives (type I errors). Two approaches are commonly used to guard against false positives: replication studies in independent samples and combined data analysis. In the current paper, we evaluated these two common approaches using simulated data where data from multiple groups were available and locations of disease genes were known. We found replication studies and combined data analysis performed similarly in terms of their ability to identify true and false positive linkages. Both approaches confirmed two true linkages and did not confirm any false positive linkages. The results also indicated that it is not appropriate to apply the criteria proposed for confirming significant evidence for linkage to confirm regions with only suggestive evidence for linkage. The current results support previous findings that parametric analysis using an incorrect genetic model can still identify a true linkage.

Environment↗
PubMed2002

Complete reconstitution of the human coenzyme A biosynthetic pathway via comparative genomics.

The biosynthesis of CoA from pantothenic acid (vitamin B5) is an essential universal pathway in prokaryotes and eukaryotes. The CoA biosynthetic genes in bacteria have all recently been identified, but their counterparts in humans and other eukaryotes remained mostly unknown. Using comparative genomics, we have identified human genes encoding the last four enzymatic steps in CoA biosynthesis: phosphopantothenoylcysteine synthetase (EC ), phosphopantothenoylcysteine decarboxylase (EC ), phosphopantetheine adenylyltransferase (EC ), and dephospho-CoA kinase (EC ). Biological functions of these human genes were verified using a complementation system in Escherichia coli based on transposon mutagenesis. The individual human enzymes were overexpressed in E. coli and purified, and the corresponding activities were experimentally verified. In addition, the entire pathway from phosphopantothenate to CoA was successfully reconstituted in vitro using a mixture of purified recombinant enzymes. Human recombinant bifunctional phosphopantetheine adenylyltransferase/dephospho-CoA kinase was kinetically characterized. This enzyme was previously suggested as a point of CoA biosynthesis regulation, and we have observed significant differences in mRNA levels of the corresponding human gene in normal and tumor cells by Northern blot analysis.

Blotting, Northern↗
PubMed2006

Autoregulation of ribosome biosynthesis by a translational response in fission yeast.

Maintaining the appropriate balance between the small and large ribosomal subunits is critical for translation and cell growth. We previously identified the 40S ribosomal protein S2 (rpS2) as a substrate of the protein arginine methyltransferase 3 (RMT3) and reported a misregulation of the 40S/60S ratio in rmt3 deletion mutants of Schizosaccharomyces pombe. For this study, using DNA microarrays, we have investigated the genome-wide biological response of rmt3-null cells to this ribosomal subunit imbalance. Whereas little change was observed at the transcriptional level, a number of genes showed significant alterations in their polysomal-to-monosomal ratios in rmt3Delta mutants. Importantly, nearly all of the 40S ribosomal protein-encoding mRNAs showed increased ribosome density in rmt3 disruptants. Sucrose gradient analysis also revealed that the ribosomal subunit imbalance detected in rmt3-null cells is due to a deficit in small-subunit levels and can be rescued by rpS2 overexpression. Our results indicate that rmt3-null fission yeast compensate for the reduced levels of small ribosomal subunits by increasing the ribosome density, and likely the translation efficiency, of 40S ribosomal protein-encoding mRNAs. Our findings support the existence of autoregulatory mechanisms that control ribosome biosynthesis and translation as an important layer of gene regulation.

Base Sequence↗
PubMed2000

HIV-1 genome nuclear import is mediated by a central DNA flap.

HIV-1 and other lentiviruses have the unique property among retroviruses to replicate in nondividing cells. This property relies on the use of a nuclear import pathway enabling the viral DNA to cross the nuclear membrane of the host cell. In HIV-1 reverse transcription, a central strand displacement event consecutive to central initiation and termination of plus strand synthesis creates a plus strand overlap: the central DNA flap. We show here that the central DNA flap acts as a cis-determinant of HIV-1 DNA nuclear import. Wild-type viral linear DNA is almost entirely imported into the nucleus where it integrates or circularizes. In contrast, mutant viral DNA, which lacks the DNA flap, accumulates in infected cells as unintegrated linear DNA, at the vicinity of the nuclear membrane. Consistently, HIV-1 vectors devoid of DNA flap exhibit a strong defect of nuclear import, which can be corrected to wild-type levels by reinsertion of the DNA flap sequence.

Amino Acid Sequence↗
PubMed2000

Synteny and regional marker order assignment of 26 type I and microsatellite markers to the horse X- and Y-chromosomes.

The hypothesis that the conservation of sex-chromosome-linked genes among placental mammals could be extended to the horse genome was tested using the UCDavis horse-mouse somatic cell hybrid (SCH) panel. By exploiting the fluorescence in-situ hybridization (FISH) technique to localize an anchor locus, X-inactivation-specific transcript (XIST) on the horse X chromosome, together with the fragmentation and translocation of the X- and Y-chromosome fragments in a somatic cell hybrid panel, we regionally assigned 13 type I and 13 type II (microsatellite) markers to the horse X- and Y-chromosomes. The synteny groups that correspond to horse X- and Y-chromosomes were identified by synteny mapping of sex-specific loci zinc finger protein X-linked (ZFX), zinc finger protein Y-linked (ZFY) and sex-determining region Y (SRY) on the SCH panel. A non-pseudoautosomal gene in the human steroid sulfatase (STS) was identified in both X- and Y-chromosome-containing clones. The regional order of the X-linked type I markers examined in this study, from Xp- to Xq-distal, was [STS-X, the voltage-gated chloride channel 4 (CLCN4)], [ZFX, delta-aminolevulinate synthase 2 (ALAS2)], XIST, coagulation factor IX (F9) and [biglycan (BGN), equine F18, glucose-6-phosphate dehydrogenase (G6PD)] (precise marker order could not be determined for genes within the same brackets). The order of the Y-linked type I markers was STS-Y, SRY and ZFY These orders are the same arrangements as reported for the human X- and Y-chromosomes, supporting the conservation of genomic organization between the human and the horse sex chromosomes. Regional ordering of X-linked type I and microsatellite markers provides the first integration of type I and type II markers in the horse X chromosome.

Animals↗
PubMed2026

Genomic Analysis and Clinical Correlation of Non-Small Cell Lung Cancer with Special Reference to Brain Metastasis.

BACKGROUND: Next-generation sequencing (NGS) has improved genomic analysis depth in precision oncology. This study analyzed genomic biomarker testing in stage IV NSCLC, focusing on brain metastasis and clinicopathological correlations. OBJECTIVE: To study molecular markers and clinicopathological correlations in stage IV NSCLC patients, with and without brain metastasis. METHODS: A total of 169 stage IV NSCLC patients were studied from April 2023 to May 2025. Demographic data, clinical presentations, and mutation analyses were assessed using NGS on tissue blocks or liquid biopsies. RESULTS: Among 169 patients, 41.42% (n = 70) had brain metastasis (NSCLC-BM), while 58.58% (n = 99) had no brain metastasis (mNSCLC). Median ages were 51.5 and 56 years, respectively. Adenocarcinoma comprised 95.27% (n = 161) of cases. The cerebral hemisphere was the most common intracranial metastatic site, while skeletal involvement was the most common extracranial site. Headache was the predominant neurological symptom. EGFR mutations were the most common overall. EGFR > TP53 > ALK > other mutations were observed in NSCLC-BM, while EGFR > TP53 > KRAS > other mutations were seen in mNSCLC. Mutation analysis stratified by smoking history (χ²(1) = 1.347, p = 0.245) and sex (χ²(1) = 0.0302, p = 0.862) was not statistically significant. The benefit of gefitinib plus chemotherapy in EGFR exon 19 and exon 21 L858R mutations was greater in mNSCLC (log-rank χ²(1) = 10.813, p = 0.001) than in NSCLC-BM (log-rank χ²(1) = 3.100, p = 0.078). Median survival was 11 months (95% CI: 7.506-14.494) for NSCLC-BM versus 21 months (95% CI: 8.365-33.635) for mNSCLC, with a statistically significant difference (log-rank χ²(1) = 8.639, p = 0.003). CONCLUSION: NSCLC-BM showed higher genomic biomarker enrichment (80% vs. 68.68%) but poorer outcomes than mNSCLC. EGFR was the most common targetable mutation, followed by ALK in NSCLC-BM and KRAS in mNSCLC.

Humans↗
PubMed2003

STRP screening sets for the human genome at 5 cM density.

BACKGROUND: Short tandem repeat polymorphisms (STRPs) are powerful tools for gene mapping and other applications. A STRP genome scan of 10 cM is usually adequate for mapping single gene disorders. However mapping studies involving genetically complex disorders and especially association (linkage disequilibrium) often require higher STRP density. RESULTS: We report the development of two separate 10 cM human STRP Screening Sets (Sets 12 and 52) which span all chromosomes. When combined, the two Sets contain a total of 782 STRPs, with average STRP spacing of 4.8 cM, average heterozygosity of 0.72, and total sex-average coverage of 3535 cM. The current Sets are comprised almost entirely of STRPs based on tri- and tetranucleotide repeats. We also report correction of primer sequences for many STRPs used in previous Screening Sets. Detailed information for the new Screening Sets is available from our web site: http://research.marshfieldclinic.org/genetics. CONCLUSION: Our new human STRP Screening Sets will improve the quality and cost effectiveness of genotyping for gene mapping and other applications.

Base Sequence↗
PubMed1999

A genome-wide search for loci contributing to smoking and alcoholism.

Using the Collaborative Study on the Genetics of Alcoholism (COGA) data, we performed a sib-pair linkage analysis of two smoking-related traits and one alcoholism phenotype. The first trait, EVRNVR, was a dichotomous one we constructed based on epidemiological definitions of smoking. The second trait, PKYRS, used the quantitative pack-year history provided, and the third trait was the COGA alcoholism classification, ALDX1. There was some evidence for linkage of the EVRNVR trait to regions-on chromosomes 6, 9, and 14. Smaller numbers of loci provided nominal evidence for linkage to PKYRS, although some candidate gene regions were identified. The number of loci identified using EVRNVR suggests that a threshold-based phenotype may better identify loci affecting smoking history. Approximately one-third of the loci that showed evidence for linkage to EVRNVR at a nominal significance level (p < 0.01) also showed evidence for linkage to ALDX1. Some of these regions may represent loci increasing vulnerability to both smoking and alcoholism.

Age Factors↗
PubMed2000

A two-stage, genome-wide screen for susceptibility loci in primary Raynaud's phenomenon.

OBJECTIVE: To identify chromosomal regions containing genes involved in the susceptibility to primary Raynaud's phenomenon (RP). METHODS: Six extended families with multiple individuals affected with primary RP (n = 37) were examined for linkage in a 2-stage, whole-genome screen, using a total of 298 microsatellite markers. RESULTS: Multipoint, nonparametric linkage analysis identified 5 areas of possible linkage, with a nominal level of significance of P < or = 0.05. Analysis of a finer map of markers in these regions defined the regions of linkage as 21.4 cM on 6q13-6q23.3 (D6S261; P = 0.0004), 10.2 cM on 7p22-7p15 (D7S664; P = 0.014), 1.6 cM on 9p23-9p22 (D9S156; P = 0.0075), 5.1 cM on 17p13.1-17p12 (D17S1791; P = 0.036), and 11.8 cM on Xp11.4-Xp11.23 (DXS8054; P = 0.006). Three potential candidate genes map to these regions: the beta subunit of the muscle acetylcholine receptor and the serotonin 1B and 1E receptors. CONCLUSION: These results provide evidence of the presence and location of genes that are involved in the genetic susceptibility to primary RP.

Adolescent↗
PubMed2006

Bacterial type I glutamine synthetase of the rifamycin SV producing actinomycete, Amycolatopsis mediterranei U32, is the only enzyme responsible for glutamine synthesis under physiological conditions.

The structural gene for glutamine synthetase, glnA, from Amycolatopsis mediterranei U32 was cloned via screening a genomic library using the analog gene from Streptomyces coelicolor. The clone was functionally verified by complementing for glutamine requirement of an Escherichia coli glnA null mutant under the control of a lac promoter. Sequence analysis showed an open reading frame encoding a protein of 466 amino acid residues. The deduced amino acid sequence bears significant homologies to other bacterial type I glutamine synthetases, specifically, 71% and 72% identical to the enzymes of S. coelicolor and Mycobacterium tuberculosis, respectively. Disruption of this glnA gene in A. mediterranei U32 led to glutamine auxotrophy with no detectable glutamine synthetase activity in vivo. In contrast, the cloned glnA gene can complement for both phenotypes in trans. It thus suggested that in A. mediterranei U32, the glnA gene encoding glutamine synthetase is uniquely responsible for in vivo glutamine synthesis under our laboratory defined physiological conditions.

Actinobacteria↗
PubMed2004

Effect of host species on recG phenotypes in Helicobacter pylori and Escherichia coli.

Recombination is a fundamental mechanism for the generation of genetic variation. Helicobacter pylori strains have different frequencies of intragenomic recombination, arising from deletions and duplications between DNA repeat sequences, as well as intergenomic recombination, facilitated by their natural competence. We identified a gene, hp1523, that influences recombination frequencies in this highly diverse bacterium and demonstrate its importance in maintaining genomic integrity by limiting recombination events. HP1523 shows homology to RecG, an ATP-dependent helicase that in Escherichia coli allows repair of damaged replication forks to proceed without recourse to potentially mutagenic recombination. Cross-species studies done show that hp1523 can complement E. coli recG mutants in trans to the same extent as E. coli recG can, indicating that hp1523 has recG function. The E. coli recG gene only partially complements the hp1523 mutation in H. pylori. Unlike other recG homologs, hp1523 is not involved in DNA repair in H. pylori, although it has the ability to repair DNA when expressed in E. coli. Therefore, host context appears critical in defining the function of recG. The fact that in E. coli recG phenotypes are not constant in other species indicates the diverse roles for conserved recombination genes in prokaryotic evolution.

Amino Acid Sequence↗
PubMed1997

Regulation of the transposable element mariner.

The mariner/Tcl superfamily of transposable elements is widely distributed in animal genomes and is especially prevalent in insects. Their wide distribution results from their ability to be disseminated among hosts by horizontal transmission and also by their ability to persist in genomes through multiple speciation events. Although a great deal is known about the molecular mechanisms of transposition and excision, very little is known about the mechanisms by which transposition is controlled within genomes. The issue of mariner/Tcl regulation is critical in view of the great interest in these elements as vectors for germline transformation of insect pests and vectors of human disease. Several potentially important regulatory mechanisms have been identified in studies of genetically engineered mariner elements. One mechanism is overproduction inhibition, in which excessive wild-type transposase reduces the rate of excision of a target element. A second mechanism is mediated by certain mutant transposase proteins, which antagonize the activity of the wild-type transposase. The latter process may help explain why the vast majority of MLEs in nature undergo 'vertical inactivation' by multiple mutations and, eventually, stochastic loss. Another potential mechanism of regulation may result from transposase titration by defective elements that retain their DNA binding sites and ability to transpose. There is also evidence that some mariner/Tcl elements can be mobilized in a type of hybrid dysgenesis.

Animals↗
PubMed1997

Utilization of host iron sources by Corynebacterium diphtheriae: identification of a gene whose product is homologous to eukaryotic heme oxygenases and is required for acquisition of iron from heme and hemoglobin.

Corynebacterium diphtheriae was examined for the ability to utilize various host compounds as iron sources. C. diphtheriae C7(-) acquired iron from heme, hemoglobin, and transferrin. A siderophore uptake mutant of strain C7 was unable to utilize transferrin but was unaffected in acquisition of iron from heme and hemoglobin, which suggests that C. diphtheriae possesses a novel mechanism for utilizing heme and hemoglobin as iron sources. Mutants of C. diphtheriae and Corynebacterium ulcerans that are defective in acquiring iron from heme and hemoglobin were isolated following chemical mutagenesis and streptonigrin enrichment. A recombinant clone, pCD293, obtained from a C7(-) genomic plasmid library complemented several of the C. ulcerans mutants and three of the C. diphtheriae mutants. The nucleotide sequence of the gene (hmuO) required for complementation was determined and shown to encode a protein with a predicted mass of 24,123 Da. Sequence analysis revealed that HmuO has 33% identity and 70% similarity with the human heme oxygenase enzyme HO-1. Heme oxygenases, which have been well characterized in eukaryotes but have not been identified in prokaryotes, are involved in the oxidation of heme and subsequent release of iron from the heme moiety. It is proposed that the HmuO protein is essential for the utilization of heme as an iron source by C. diphtheriae and that the heme oxygenase activity of HmuO is involved in the release of iron from heme. This is the first report of a bacterial gene whose product has homology to heme oxygenases.

Amino Acid Sequence↗
PubMed2003

Genome-wide scan on plasma triglyceride and high density lipoprotein cholesterol levels, accounting for the effects of correlated quantitative phenotypes.

BACKGROUND: Plasma triglyceride and high density lipoprotein cholesterol levels are inversely correlated and both are genetically related. Two correlated traits may be influenced both by shared and unshared genes. The power to detect unshared trait-specific genes may be increased by incorporating correlated traits as covariates. The power to localize the shared genes may be improved by bivariate analysis. Univariate genome scans were carried out on triglyceride (high density lipoprotein cholesterol) with and without using high density lipoprotein cholesterol (triglyceride) as a covariate, and bivariate linkage analysis on triglyceride and high density lipoprotein cholesterol using the 330 Framingham pedigrees of the Genetic Analysis Workshop 13 data. The results of five genome scans were compared to determine the chromosomal regions which may harbor the genes influencing variation specific to triglycerides, specific to high density lipoprotein cholesterol, or the covariation of both triglyceride and high density lipoprotein cholesterol. RESULTS: The results of our five genome scans identified some chromosomal regions with possible quantitative trait loci (QTL) that may specifically influence one trait, such as the regions on chromosome 1 (at 1 cM near marker 280we5), on high density lipoprotein cholesterol, or control the covariation of both traits, such as the regions on chromosome 7 (at 169 cM near marker GATA30D09), chromosome 12 (at 3 cM near marker GATA4H03), chromosome 20 (at 49 cM near marker GATA29F06), chromosome 2 (at 146 cM near marker GATA8H05), and chromosome 6 (at 148 cM near marker GATA184A08) on triglyceride and high density lipoprotein cholesterol. The one on chromosome 6 had a LOD score of 3.1 with the bivariate linkage analysis. CONCLUSION: There is strong evidence for a QTL on chromosome 6 near marker GATA184A08 appearing to influence the variation of high density lipoprotein cholesterol and triglycerides in the Framingham population.

Adult↗
PubMed2004

A highly informative SNP linkage panel for human genetic studies.

We have developed a highly informative set of single-nucleotide polymorphism (SNP) assays designed for linkage mapping of the human genome. These assays were developed on a robust multiplexed assay system to provide a combination of very high accuracy and data completeness with high throughput for linkage studies. The linkage panel is comprised of approximately 4,700 SNPs with 0.39 average minor allele frequency and 624-kb average spacing. Based on almost 2 million genotypes, data quality was shown to be extremely high, with a 99.94% call rate, >99.99% reproducibility and 99.995% genotypes consistent with mendelian inheritance. We constructed a genetic map with an average 1.5-cM resolution using series of 28 CEPH pedigrees. The relative information content of this panel was higher than those of commonly used STR marker panels. The potent combination of this SNP linkage panel with the multiplexed assay system provides a previously unattainable level of performance for linkage studies.

Algorithms↗
PubMed2006

Identification of cryptic aberrations and characterization of translocation breakpoints using array CGH in high hyperdiploid childhood acute lymphoblastic leukemia.

High hyperdiploidy, characterized by non-random trisomies, is the largest cytogenetic subgroup in childhood acute lymphoblastic leukemia (ALL). It is not known whether the gained chromosomes are sufficient for leukemogenesis or if additional genetic aberrations are necessary. However, the suboptimal chromosome morphology of hyperdiploid ALLs makes detection of structural abnormalities difficult if using cytogenetic techniques; alternative methods are, therefore, needed. We performed array comparative genome hybridization (CGH) analyses, with a resolution of 100 kb, of eight cases of high hyperdiploid childhood ALL to characterize structural abnormalities found with G-banding/multicolor fluorescence in situ hybridization (FISH) and to detect novel changes. The non-centromeric breakpoints of four rearrangements, including three translocations and one 1q duplication, were narrowed down to <0.2 Mb. Furthermore, four submicroscopic imbalances involving 0.6-2.7 Mb were detected, comprising two segmental duplications involving 1q22 and 12q24.31 in one case and two hemizygous deletions in 12p13.2-31 - including ETV6 - and in 13q32.3-33.1 in another case. Notably, FISH analysis of the latter revealed an associated reciprocal t(3;13)(q?;32.2-33.1). In conclusion, the array CGH analyses revealed putative leukemia-associated submicroscopic imbalances and rearrangements in 2/8 (25%) hyperdiploid ALLs. The detection and characterization of these additional genetic aberrations will most likely increase our understanding of the pathogenesis of high hyperdiploid childhood ALL.

Adolescent↗