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Results for “structural genomics”

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PubMed2025

Genomic structural equation modeling elucidates the shared genetic architecture of allergic disorders.

BACKGROUND: The intricate shared genetic architecture underlying allergic disorders-including allergic asthma, atopic dermatitis, contact dermatitis, allergic rhinitis, allergic conjunctivitis, allergic urticaria, anaphylaxis, and eosinophilic esophagitis-remains incompletely characterized. METHODS: Our study employed genomic structural equation modeling (Genomic SEM) to define the common factor representing the shared genetic architecture of allergic disorders. Coupled with diverse post-GWAS analytical methods, we aimed to discover susceptible loci and investigate genetic associations with external traits. Furthermore, we explored enriched genetic pathways, cellular layers, and genomic elements, and investigated putative plasma protein biomarkers. Polygenic risk score (PRS) analyses, leveraging our integrated GWAS data, were conducted to assess chromosomal-level risk associations for allergic disorders. RESULTS: A well-fitted genomic SEM integrated GWAS data, revealing the shared genetic architecture of allergic disorders. We identified a total of 2038 genome-wide significant SNP loci (p < 5e-8), including 31 previously unreported loci. Fine-mapping of variants and gene sets pinpointed 2 causal variants and 31 candidate susceptible genes. Genetic correlation analyses further illuminated the shared genetic architecture underlying multiple traits, notably psychiatric disorders. Preliminary findings identified four putative causal plasma protein biomarkers. CONCLUSION: Notably, this study presents the first comprehensive genetic characterization of allergic disorders through a GWAS analysis of an unmeasured composite phenotype, providing novel insights into shared etiological pathways across these conditions.

Humans↗

PubMed2006

A normalised scale for structural genomics target ranking: the OB-Score.

Target selection and ranking is fundamental to structural genomics. We present a Z-score scale, the "OB-Score", to rank potential targets by their predicted propensity to produce diffraction-quality crystals. The OB-Score is derived from a matrix of predicted isoelectric point and hydrophobicity values for nonredundant PDB entries solved to or=1 member with a high OB-Score, presenting favourable candidates for structural studies.

Databases, Protein↗

PubMed1999

The human BARX2 gene: genomic structure, chromosomal localization, and single nucleotide polymorphisms.

The BARX genes 1 and 2 are Bar class homeobox genes expressed in craniofacial structures during development. In this report, we present the genomic structure, chromosomal localization, and polymorphic markers in BARX2. The gene has four exons, ranging in size from 85 to 1099 bp. BARX2 is localized on human chromosome 11q25, as determined by radiation hybrid mapping. In the mouse, Barx2 is coexpressed with Pitx2 in several tissues. Based on the coexpression, BARX2 was assumed to be a candidate gene for those cases of Rieger syndrome that cannot be associated with mutations of PITX2. Mutations in PITX2 cause some cases of Rieger syndrome, an autosomal dominant disorder affecting eyes, teeth, and umbilicus. DNA from Rieger patients was subjected to single-strand conformation polymorphism screening of the BARX2 coding region. Three single nucleotide polymorphisms were found in a normal population, although no etiologic mutations were detectable in over 100 cases of Rieger syndrome or in individuals with related ocular disorders.

Alleles↗

PubMed2002

Genome structures embossed by oligonucleotide-stickiness.

MOTIVATION: An unmanageably large amount of data on genome sequences is accumulating, prompting researchers to develop new methods to analyze them. We have devised a novel method designated oligostickiness, a measure roughly proportional to the binding affinity of an oligonucleotide to a DNA of interest, in order to analyze genome sequences as a whole. RESULTS: Fifteen representative genomes such as Bacillus subtilis, Escherichia coli, Saccharomyces cerevisiae, Caenorhabditis elegans, H. sapiens and others were analyzed by this method using more than 50 probe dodecanucleotides, offering the following findings: (i) Genome sequences can be specifically featured by way of oligostickiness maps. (ii) Oligostickiness analysis, which is similar to but more informative than (G + C) content or repetitive sequence analysis, can reveal intra-genomic structures such as mosaic structures (E. coli and B. subtilis) and highly sticky/non-sticky regions of biological meanings. (iii) Some probe oligonucleotides such as dC(12) and dT(12) can be used for classifying genomes, clearly discriminating prokaryotes and eukaryotes. (iv) Based on global oligostickiness, which is the average value of the local oligostickinesses, the features of a genome could be visualized in spider web mode. The pattern of a spider web as well as a set of oligostickiness maps is highly characteristic to each genome or chromosome. Thus, we called it as chromosome texture, leading to a finding that all the chromosomes contained in a cell, so far investigated, have a common texture. AVAILABILITY: Oligostickinesses maps used in this work are available at http://gp.fms.saitama-u.ac.jp/ CONTACT: koichi@fms.saitama-u.ac.jp

Algorithms↗

PubMed2002

Comparative genomics in the grass family: molecular characterization of grass genome structure and evolution.

The genomes of grasses are very different in terms of size, ploidy level and chromosome number. Despite these significant differences, it was found by comparative mapping that the linear order (colinearity) of genetic markers and genes is very well conserved between different grass genomes. The potential of such conservation has been exploited in several directions, e.g. in defining rice as a model genome for grasses and in designing better strategies for positional cloning in large genomes. Recently, the development of large insert libraries in species such as maize, rice, barley and diploid wheat has allowed the study of large stretches of DNA sequence and has provided insight into gene organization in grasses. It was found that genes are not distributed randomly along the chromosomes and that there are clusters of high gene density in species with large genomes. Comparative analysis performed at the DNA sequence level has demonstrated that colinearity between the grass genomes is retained at the molecular level (microcolinearity) in most cases. However, detailed analysis has also revealed a number of exceptions to microcolinearity, which have given insight into mechanisms that are involved in grass-genome evolution. In some cases, the use of rice as a model to support gene isolation from other grass genomes will be complicated by local rearrangements. In this Botanical Briefing, we present recent progress and future prospects of comparative genomics in grasses.

Chromosome Mapping↗

PubMed1998

Genome structure and gene content in protist mitochondrial DNAs.

Although the collection of completely sequenced mitochondrial genomes is expanding rapidly, only recently has a phylogenetically broad representation of mtDNA sequences from protists (mostly unicellular eukaryotes) become available. This review surveys the 23 complete protist mtDNA sequences that have been determined to date, commenting on such aspects as mitochondrial genome structure, gene content, ribosomal RNA, introns, transfer RNAs and the genetic code and phylogenetic implications. We also illustrate the utility of a comparative genomics approach to gene identification by providing evidence that orfB in plant and protist mtDNAs is the homolog of atp8 , the gene in animal and fungal mtDNA that encodes subunit 8 of the F0portion of mitochondrial ATP synthase. Although several protist mtDNAs, like those of animals and most fungi, are seen to be highly derived, others appear to be have retained a number of features of the ancestral, proto-mitochondrial genome. Some of these ancestral features are also shared with plant mtDNA, although the latter have evidently expanded considerably in size, if not in gene content, in the course of evolution. Comparative analysis of protist mtDNAs is providing a new perspective on mtDNA evolution: how the original mitochondrial genome was organized, what genes it contained, and in what ways it must have changed in different eukaryotic phyla.

Amino Acid Sequence↗

PubMed2003

Ab-initio prediction and reliability of protein structural genomics by PROPAINOR algorithm.

We have formulated the ab-initio prediction of the 3D-structure of proteins as a probabilistic programming problem where the inter-residue 3D-distances are treated as random variables. Lower and upper bounds for these random variables and the corresponding probabilities are estimated by nonparametric statistical methods and knowledge-based heuristics. In this paper we focus on the probabilistic computation of the 3D-structure using these distance interval estimates. Validation of the predicted structures shows our method to be more accurate than other computational methods reported so far. Our method is also found to be computationally more efficient than other existing ab-initio structure prediction methods. Moreover, we provide a reliability index for the predicted structures too. Because of its computational simplicity and its applicability to any random sequence, our algorithm called PROPAINOR (PROtein structure Prediction by AI an Nonparametric Regression) has significant scope in computational protein structural genomics.

Algorithms↗

PubMed2005

An hypothesis about genome structures in mammalian polyploid cells based on a new concept that genome is fractal of six hierarchies.

A new model for the spatial configurations of DNA is proposed to solve the problem of DNA loss in mammalian polyploid cells. The ordinary concept that chromosomes are situated independently in nuclei cannot account well for the DNA loss in polyploid cells. A new concept about the DNA configurations in diploid cells is constructed based on observations that have been reported. Briefly, the DNA structure is self-similar fractal with a unit of opposite-handed twin-circles. In human diploid cells, DNA is constructed with six hierarchies whose sizes are 32(5), 32(4), 32(3), 32(2), 32(1) and 32(0) with a unit of 200 DNA base pairs, corresponding to a genome, a chromosome, a chromosome band, a replicon, a rosette loop (a gene) and a nucleosome, respectively. A model assuming particular spatial configurations of chromosomes in polyploid cells is deduced from this new concept about chromosome configurations in diploid cells. It can account satisfactorily for the problem of DNA loss in polyploid cells. When cell division is inhibited and DNA synthesis progresses, replicated DNA will be stacked. When inhibitors are removed, the polyploidized cells may return to the initial ploidy, because the stacked DNA loops have not been linked. When the stacked DNA twin-loops are linked with a proper configuration, the cells may become polyploid cells. There is a distinct difference in genome structure between polyploidized and polyploid cells. The homologous chromosomes of polyploid cells are arrayed mirror-symmetrically and they can come close to each other in the folded structure. If DNA synthesis is bypassed at the paired homologous chromosomes, DNA content is lost at every cell division. As the DNA loss progresses, the chromosome configuration of polyploid cells deviates gradually from mirror-symmetry and the DNA loss ceases, resulting in the establishment of semi-stable hypoploid.

Animals↗

PubMed2002

Molecular epidemiology and diagnosis of Leishmania: what have we learnt from genome structure, dynamics and function?

This paper reviews our exploration of the dynamics of the Leishmania genome and its contribution to epidemiology and diagnosis. We used as a model Peruvian populations of L. (Viannia) braziliensis and L. (V.) peruviana, 2 species very close phylogenetically, but phenotypically very different in biotope and pathology. We initially focused on karyotype analysis. Our data showed that chromosomes were subject to a fast rate of evolution, and were sensitive indicators of genetic drift. Therefore, molecular karyotyping appeared an adequate tool for monitoring (i) emergence of close species, (ii) ecogeographical differentiation at the intraspecific level, and (iii) strain 'fingerprinting'. Chromosome size variation was mostly due to the number of tandemly repeated genes (rDNA, mini-exon, gp63, and cysteine proteinase genes), and could involve the deletion of unique genes (L. (V.) braziliensis-specific gp63 families). Considering the importance of these genes in parasitism, their rearrangement might have functional implications: adaptation to different environments and pleomorphic pathogenicity. Our knowledge of genome structure and dynamics was used to develop new polymerase chain reaction (PCR) techniques. Amplification of gp63 genes followed by cleavage with restriction enzymes and study of restriction fragment length polymorphism (gp63 PCR-RFLP) allowed the discrimination of all species tested, even directly in biopsies with 95% sensitivity (compared with PCR amplification of kinetoplast deoxyribonucleic acid). At the intra-specific level, RFLP was also observed and corresponded to mutations in major immunogen domains of gp63. These seem to be under strong selection pressure, and the technique should facilitate addressing how the host's immune pressure may modulate parasite population structure. Altogether, gp63 PCR-RFLP represents a significant operational improvement over the other techniques for molecular epidemiology and diagnosis: it combines sensitivity, discriminatory power and prognostic value.

Animals↗

PubMed2000

Creating a structural genomics consortium.

A group of multinational companies, together with the Wellcome Trust, is attempting to form a charitable organization, the Structural Genomics Consortium. The goal will be to obtain X-ray structures for a broad representation across families of human proteins and to place the structural coordinates in the public database.

Computational Biology↗

PubMed1992

Genomic structure of the ME491/CD63 antigen gene and functional analysis of the 5'-flanking regulatory sequences.

Genomic structure of the ME491/CD63 antigen gene and promoter activity of the 5'-flanking regulatory sequences were studied. The antigen gene consists of eight exons that span 4 kilobase-pairs. Primer extension analysis with RNA from cultured human cells identified three major transcription initiation sites. The 5'-flanking region of exon 1 has features characteristic to promoters of many house-keeping genes and growth-regulating genes. The region is highly GC rich and contains potential binding sites for transcription factors such as Sp1 and ETF, but not a TATA box. The 5'-flanking sequence exerted strong promoter activity when linked to a reporter gene. Deletion mutant analysis of the 5'-flanking sequence has strongly suggested that a potential binding site for AP-1 plays an important role in positively regulating the gene expression.

Amino Acid Sequence↗

PubMed1997

Genomic structure and embryonic expression of the rat type 1 vasoactive intestinal polypeptide receptor gene.

The genomic structure of the rat vasoactive intestinal polypeptide type 1 receptor (VIPR I) gene was characterized using polymerase chain reactions (PCR) and DNA sequencing. These studies show that the rat VIPR I gene spans more than 20 kb of DNA sequence and includes thirteen exons separated by twelve introns, ranging from 0.2 to 4.5 kb. VIP is known to play an important role early in embryonic development. To elucidate the receptor-mediated biological functions of VIP in development, the temporal and spatial expression of VIPR I during rat embryonic development was examined in this study. Using in situ hybridization histochemistry with 35S-labeled riboprobe, VIPR I mRNA was detected as early as embryonic day 11 (E11), in the neuroepithelium, foregut, heart and in cells lining the blood vessels. From E14 through E18, VIPR I mRNA was detected in multiple tissues derived from all three germ layers. These include neuronal cells in brain and spinal cord (ectoderm); smooth muscle cells of intestines, cells lining the wall of the heart and blood vessels, kidney, adrenal gland (mesoderm); epithelial cells of airway and of liver (endoderm). The early onset and wide tissue expression of VIPR I suggests that binding of VIP to this receptor may play an important role in rat embryonic development.

Animals↗

PubMed2004

New methods for EXAFS analysis in structural genomics.

Data analysis is one of the remaining bottlenecks in high-throughput EXAFS for structural genomics. Here some recent developments in methodology are described that offer the potential for rapid and automated XAS analysis of metalloproteins.

Genes↗

PubMed2002

Structural genomics of proteins from conserved biochemical pathways and processes.

During the past year, X-ray crystallographers and solution NMR spectroscopists have made significant progress towards the complete structural characterization of conserved biochemical pathways and processes. Some of these advances were made in the context of nascent structural genomics programs, which promise to accelerate structural studies of biologically and medically important proteins. The results of high-throughput protein production, crystallization, structure determination, homology modeling and functional annotation published by two such programs have provided insight into the evolution and function of enzymes in the isoprenoid biosynthesis and ribulose monophosphate pathways.

Biological Evolution↗

PubMed2006

SGCEdb: a flexible database and web interface integrating experimental results and analysis for structural genomics focusing on Caenorhabditis elegans.

The SGCEdb (http://sgce.cbse.uab.edu) database/interface serves the primary purpose of reporting progress of the Structural Genomics of Caenorhabditis elegans project at the University of Alabama at Birmingham. It stores and analyzes results of experiments ranging from solubility screening arrays to individual protein purification and structure solution. External databases and algorithms are referenced and evaluated for target selection in the human, C.elegans and Pneumocystis carinii genomes. The flexible and reusable design permits tracking of standard and custom experiment types in a scientist-defined sequence. The database coordinates efforts between collaborators and is adaptable to a wide range of biological applications.

Animals↗

PubMed1993

Genomic structure of rat liver aryl sulfotransferase IV-encoding gene.

This report contains the first description of the genomic structure for a sulfotransferase (ST). The gene (ASTIV) encodes rat hepatic aryl ST IV, also known as tyrosine-ester ST (EC 2.8.2.9). A phage genomic clone containing 70% of the 3' AST gene coding sequence was isolated after screening a rat genomic library with an ASTIV cDNA. The remaining 5' sequence was determined from a PCR product obtained from rat genomic DNA and ASTIV cDNA-specific primers. ASTIV spans 3.5 kb and contains eight exons and seven introns. The fourth intron of this gene contains sequences homologous to rodent B1 repetitive elements and an Alu repeat found in rat. An alignment of the primary structures of ten different ST revealed several conserved regions, as well as a putative binding site for the cofactor for enzymatic sulfation reactions, 3'-phosphoadenosine-5'-phosphosulfate.

Amino Acid Sequence↗

PubMed2006

A large-scale, high-efficiency and low-cost platform for structural genomics studies.

A large-scale, high-efficiency and low-cost platform based on a Beckman Coulter Biomek FX and custom-made automation systems for structural genomics has been set up at Peking University, Beijing, People's Republic of China. This platform has the capacity to process up to 2000 genes per year for structural and functional analyses. Bacillus subtilis, a model organism for Gram-positive bacteria, and Streptococcus mutans, a major pathogen of dental caries, were selected as the main targets. To date, more than 470 B. subtilis and 1200 S. mutans proteins and hundreds of proteins from other sources, including human liver proteins, have been selected as targets for this platform. The selected genes are mainly related to important metabolism pathways and/or have potential relevance for drug design. To date, 40 independent structures have been determined; of these 11 are in the category of novel structures by the criterion of having less than 30% sequence identity to known structures. More than 13 structures were determined by SAD/MAD phasing. The macromolecular crystallography beamline at the Beijing Synchrotron Radiation Facility and modern phasing programs have been crucial components of the operation of the platform. The idea and practice of the genomic approach have been successfully adopted in a moderately funded structural biology program and it is believed this adaptation will greatly improve the production of protein structures. The goal is to be able to solve a protein structure of moderate difficulty at a cost about US 10,000 dollars.

Bacillus subtilis↗

PubMed2004

Dramatic effects of 2-bromo-5,6-dichloro-1-beta-D-ribofuranosyl benzimidazole riboside on the genome structure, packaging, and egress of guinea pig cytomegalovirus.

The halogenated benzimidazoles BDCRB (2-bromo-5,6-dichloro-1-beta-D-riborfuranosyl benzimidazole riboside) and TCRB (2,5,6-trichloro-1-beta-D-riborfuranosyl benzimidazole riboside) were the first compounds shown to inhibit cleavage and packaging of herpesvirus genomes. Both inhibit the formation of unit length human cytomegalovirus (HCMV) genomes by a poorly understood mechanism (M. R. Underwood et al., J. Virol. 72:717-715, 1998; P. M. Krosky et al., J. Virol. 72:4721-4728, 1998). Because the simple genome structure of guinea pig cytomegalovirus (GPCMV) provides a useful model for the study of herpesvirus DNA packaging, we investigated the effects of BDCRB on GPCMV. GPCMV proved to be sensitive to BDCRB (50% inhibitory concentration = 4.7 microM), although somewhat less so than HCMV. In striking contrast to HCMV, however, a dose of BDCRB sufficient to reduce GPCMV titers by 3 logs (50 microM) had no effect on the quantity of GPCMV genomic DNA that was formed in infected cells. Electron microscopy revealed that this DNA was in fact packaged within intranuclear capsids, but these capsids failed to egress from the nucleus and failed to protect the DNA from nuclease digestion. The terminal structure of genomes formed in the presence of BDCRB was also altered. Genomes with ends lacking a terminal repeat at the right end, which normally exist in an equimolar ratio with those having one copy of the repeat at the right end, were selectively eliminated by BDCRB treatment. At the left end, BDCRB treatment appeared to induce heterogeneous truncations such that 2.7 to 4.9 kb of left-end-terminal sequences were missing. These findings suggest that BDCRB induces premature cleavage events that result in truncated genomes packaged within capsids that are permeable to nuclease. Based on these and other observations, we propose a model for duplication of herpesvirus terminal repeats during the cleavage and packaging process that is similar to one proposed for bacteriophage T7 (Y. B. Chung, C. Nardone, and D. C. Hinkle, J. Mol. Biol. 216:939-948, 1990).

Animals↗