Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Structural variants”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 217 records · Page 12Linked to original sources
PubMed1997

Properties of intraepithelial neoplasia relevant to the development of cancer chemopreventive agents.

Cancer chemoprevention is concerned with the development of drugs or diet supplements that will avert the onset or stop the progression of the intraepithelial neoplasia which precedes invasive cancer. Two basic processes underlie the onset and development of intraepithelial neoplasia. First is genomic instability (often associated with chronic diffuse epithelial hyperplasia), which is the increased production of genomic structural variants due to unrepaired DNA breaks with secondary formation of abnormal structures, including "mutator" mutations in genes responsible for genomic stability, gene copy amplification or loss from DNA breakage-fusion-anaphase bridge cycles, unequal sister chromatid exchange, and accumulation of double minutes. Second is the development within an epithelium having genomic instability of multicentric neoplastic lesions that independently progress through each of the following processes at a continuously accelerating rate: clonal evolution, hyperproliferation, production of genomic structural variants, and apoptosis. Recommended chemoprevention strategies based on these mechanisms are (1) early diagnosis and treatment of genomic instability before the appearance of intraepithelial neoplasia, i.e., during the "predysplastic" or "premorphologic" phase, (2) development of multiple agents that block intralesional proliferation at steps along the "command" pathways of mitotic signal transduction and along the "execute" pathways of synthesis of daughter cell components, (3) development of nontoxic antiinflammatory agents, antioxidants, antimutagens, and proapoptotics, (4) avoidance of "clonal escape" through use of drug combinations, and (5) use of computer-assisted quantitative image analysis to assay modulation of surrogate endpoints in chemoprevention clinical trials.

Carcinoma in Situ↗
PubMed2000

New insights into the thyroid-stimulating hormone receptor. The major antigen of Graves' disease.

The receptor for thyroid-stimulating hormone is one of the most interesting hormone-binding sites because of its close association with common human diseases, including thyroid nodules and Graves' hyperthyroidism. This article discusses the structure and biosynthetic processing of this elusive glycoprotein, whose paucity and instability have impeded its isolation from natural sources. Topics include cleavage and subunit structure, variant species, and structural modeling, the thyroid-stimulating hormone receptor as the major autoantigen in Graves' disease, and a summary of recent efforts to replicate the symptoms of this uniquely human disease in animal models.

Alternative Splicing↗
PubMed1998

Mycobacterial lipoarabinomannan: an extraordinary lipoheteroglycan with profound physiological effects.

Detailed structural and functional studies over the last decade have led to current recognition of the mycobacterial lipoarabinomannan (LAM) as a phosphatidylinositol anchored lipoglycan with diverse biological activities. Fatty acylation has been demonstrated to be essential for LAM to maintain its functional integrity although the focus has largely been on the arabinan motifs and the terminal capping function. It has recently been shown that the mannose caps may be involved not only in attenuating host immune response, but also in mediating the binding of mycobacteria to and subsequent entry into macrophages. This may further be linked to an intracellular trafficking pathway through which LAM is thought to be presented by CD1 to subsets of T-cells. The implication of LAM as major histocompatibility complex (MHC)-independent T-cell epitope and the ensuing immune response is an area of intensive studies. Another recent focus of research is the biosynthesis of arabinan which has been shown to be inhibitable by the anti-tuberculosis drug, ethambutol. The phenomenon of truncated LAM as synthesized by ethambutol resistant strains provides an invaluable handle for dissecting the array of arabinosyltransferases involved, as well as generating much needed structural variants for further structural and functional studies. It is hoped that with more systematic investigations based on clinical isolates and human cell lines, the true significance of LAM in the immunopathogenesis of tuberculosis and leprosy can eventually be explained.

Animals↗
PubMed2002

Multiplex gene expression analysis for high-throughput drug discovery: screening and analysis of compounds affecting genes overexpressed in cancer cells.

Drug discovery strategies are needed that can rapidly exploit multiple therapeutic targets associated with the complex gene expression changes that characterize a polygenic disease such as cancer. We report a new cell-based high-throughput technology for screening chemical libraries against several potential cancer target genes in parallel. Multiplex gene expression (MGE) analysis provides direct and quantitative measurement of multiple endogenous mRNAs using a multiplexed detection system coupled to reverse transcription-PCR. A multiplex assay for six genes overexpressed in cancer cells was used to screen 9000 chemicals and known drugs in the human prostate cancer cell line PC-3. Active compounds that modulated gene expression levels were identified, and IC50 values were determined for compounds that bind DNA, cell surface receptors, and components of intracellular signaling pathways. A class of steroids related to the cardiac glycosides was identified that potently inhibited the plasma membrane Na(+)K(+)-ATPase resulting in the inhibition of four of the prostate target genes including transcription factors Hoxb-13, hPSE/PDEF, hepatocyte nuclear factor-3alpha, and the inhibitor of apoptosis, survivin. Representative compounds selectively induced apoptosis in PC-3 cells compared with the nonmetastatic cell line BPH-1. The multiplex assay distinguished potencies among structural variants, enabling structure-activity analysis suitable for chemical optimization studies. A second multiplex assay for five toxicological markers, Hsp70, Gadd153, Gadd45, O6-methylguanine-DNA methyltransferase, and cyclophilin, detected compounds that caused DNA damage and cellular stress and was a more sensitive and specific indicator of potential toxicity than measurement of cell viability. MGE analysis facilitates rapid drug screening and compound optimization, the simultaneous measurement of toxicological end points, and gene function analysis.

Actins↗
PubMed1998

High-resolution structures of variant Zif268-DNA complexes: implications for understanding zinc finger-DNA recognition.

BACKGROUND: Zinc fingers of the Cys2-His2 class comprise one of the largest families of eukaryotic DNA-binding motifs and recognize a diverse set of DNA sequences. These proteins have a relatively simple modular structure and key base contacts are typically made by a few residues from each finger. These features make the zinc finger motif an attractive system for designing novel DNA-binding proteins and for exploring fundamental principles of protein-DNA recognition. RESULTS: Here we report the X-ray crystal structures of zinc finger-DNA complexes involving three variants of Zif268, with multiple changes in the recognition helix of finger one. We describe the structure of each of these three-finger peptides bound to its corresponding target site. To help elucidate the differential basis for site-specific recognition, the structures of four other complexes containing various combinations of these peptides with alternative binding sites have also been determined. CONCLUSIONS: The protein-DNA contacts observed in these complexes reveal the basis for the specificity demonstrated by these Zif268 variants. Many, but not all, of the contacts can be rationalized in terms of a recognition code, but the predictive value of such a code is limited. The structures illustrate how modest changes in the docking arrangement accommodate the new sidechain-base and sidechain-phosphate interactions. Such adaptations help explain the versatility of naturally occurring zinc finger proteins and their utility in design.

Amino Acid Sequence↗
PubMed1980

Structure of a newly isolated variant of Simian virus 40 DNA containing monkey DNA and its similarity to previously isolated variants.

The structure of a newly and independently isolated defective variant of simian virus 40 that contains covalently linked monkey and SV40 DNA sequences is described. This variant, termed 290, has a structure essentially identical with a previously isolated and characterized variant named CVP8/1/P2 (Eco RI res). The structural similarities include the monkey (host) DNA segment that is combined with viral DNA sequences, the particular viral DNA segment that is present, and the arrangement of these within the defective genome. The monkey DNA segment contains sequences derived from both low and high reiteration frequency monkey DNA. The viral sequences include the origin of replication. The separate isolation of essentially identical variants suggests a high level of specificity in the events leading to the formation and amplification of this type of defective genome.

Animals↗
PubMed1990

A new member of a secretory protein gene family in the dipteran Chironomus tentans has a variant repeat structure.

We describe the structure of a gene expressed in the salivary gland cells of the dipteran Chironomus tentans and show that it encodes 1 of the approximately 15 secretory proteins exported by the gland cells. This sp115,140 gene consists of approximately 65 copies of a 42-bp sequence in a central uninterrupted core block, surrounded by short nonrepetitive regions. The repeats within the gene are highly similar to each other, but divergent repeats are present in a pattern which suggests that the repeat structure has been remodeled during evolution. The 42-bp repeat in the gene is a simple variant of the more complex repeat unit present in the Balbiani ring genes, encoding four of the other secretory proteins. The structure of the sp115,140 gene suggests that related repeat structures have evolved from a common origin and resulted in the set of genes whose secretory proteins interact in the assembly of the secreted protein fibers.

Amino Acid Sequence↗
PubMed2026

Pangenomic analyses in the cultivated grapevine confirm high genomic collinearity and extensive dispensable gene content likely involved in adaptation.

Pangenomes have now been developed for several horticultural crops, yet the extent to which genome diversity in sequence and organization contribute to plant adaptation and major agronomic traits remains poorly understood. Here, we assembled the genomes of 9 cultivated grapevine varieties and compared the genomes of 15 cultivated grapevine varieties for variation in gene and TE content. We found that genomic collinearity is highly conserved among varieties. We still observed substantial variation across genomes. Notably, we identified across varieties 55,662 orthologous genes, of which 55.3% appears to be dispensable. Dispensable genes are enriched for functions related to adaptation to biotic and abiotic constraints, suggesting that they may play a role in adaptation. Comparing our results with a recently published study, we found substantial differences with ∼12.6% of the genes we classified as core genes being classified as dispensable genes in this other study. We then constructed a pangenome graph and used it to performed genome-wide association studies for 3 important traits in grapevine production, which allowed us to include large structural variants as markers in the analyses. We identified 32 loci that we did not detect when we used the PN40024 genome as a reference, 20 of which are newly reported associations. Overall, our results indicates that despite recent advances in characterizing plant pangenomes, current gene classification into core and dispensable gene categories should be taken with caution. They also highlight the value of incorporating structural variants into GWAS, to better characterize the genetic architecture of agronomic traits.

Vitis↗
PubMed1988

Mapping of segmental antigenic determinants on structurally related variant surface glycoproteins of Trypanosoma brucei.

To study common and variant specific antigenic determinants on variant surface glycoproteins from Trypanosoma brucei, we have selected four serologically cross-reacting variant populations. Monoclonal antibodies were raised against the purified variant surface glycoproteins from each variant trypanosome population. Six monoclonal antibodies bind to segmental epitopes and one binds to a topographically assembled epitope. Amino acid compositions of these variant surface glycoproteins reveal striking conservation of certain residues including cysteine and charged amino acids. We also find that all seven monoclonal antibodies used in this study bind to protein determinants not exposed on the surface of the living trypanosome. Only one monoclonal antibody exhibits homologous specificity, while the remainder display cross-reactivity for three or all four variant surface glycoproteins. In addition, polyacrylamide gel electrophoresis peptide mapping and Western blots probed with each monoclonal antibody reveal significant peptide homologies. Furthermore, two pairs of monoclonal antibodies recognize two epitopes that are possibly immunodominant. The significance of these findings is discussed in terms of the structural similarities and differences among variant surface glycoproteins.

Amino Acids↗
PubMed1996

Dynamics of Fusarium solani cutinase investigated through structural comparison among different crystal forms of its variants.

In characterizing mutants and covalently inhibited complexes of Fusarium solani cutinase, which is a 197-residue lipolytic enzyme, 34 variant structures, crystallizing in 8 different crystal forms, have been determined, mostly at high resolution. Taking advantage of this considerable body of information, a structural comparative analysis was carried out to investigate the dynamics of cutinase. Surface loops were identified as the major flexible protein regions, particularly those forming the active-site groove, whereas the elements constituting the protein scaffold were found to retain the same conformation in all the cutinase variants studied. Flexibility turned out to be correlated with thermal motion. With a given crystal packing environment, a high flexibility turned out to be correlated with a low involvement in crystal packing contacts. The high degree of crystal polymorphism, which allowed different conformations with similar energy to be detected, made it possible to identify motions which would have remained unidentified if only a single crystal form had been available. Fairly good agreement was found to exist between the data obtained from the structural comparison and those from a molecular dynamics (MD) simulation carried out on the native enzyme. The crystallographic approach used in this study turned out to be a suitable tool for investigating cutinase dynamics. Because of the availability of a set of closely related proteins in different crystal environments, the intrinsic drawback of a crystallographic approach was bypassed. By combining several static pictures, the dynamics of the protein could be monitored much more realistically than what can be achieved on the basis of static pictures alone.

Carboxylic Ester Hydrolases↗
PubMed1995

Candidate genes in alcoholism.

Individual alleles identified by candidate gene analysis have been shown to profoundly influence certain complex behavioral syndromes including vulnerability to alcoholism. The alcohol and aldehyde dehydrogenase polymorphisms, ADH2(2) and ALDH2(2), respectively, are associated with lower vulnerability to alcoholism both in the Orient and also in North America among populations of Taiwanese and Koreans who have immigrated there. Protein structural variants have recently been identified for a series of genes involved in dopamine and serotonin function. Three dopamine receptors exhibit such structural variants, and these include the DRD2 dopamine receptor, which has three relatively rare amino acid substitutions. Structural polymorphisms were detected in five serotonin receptors (5HT1A, 5HT1Db, 5HT2A, 5HT2C, and 5HT7). Association studies between neurotransmitter gene variants and alcoholism are at an earlier stage than with ADH2(2)/ALDH2(2), but results are thus far negative (dopamine DRD4 receptor), equivocal (dopamine DRD2 receptor), or preliminary (tryptophan hydroxylase, 5HT2C and 5HT1Db).

Alcoholism↗
PubMedDate not supplied

[The influence of genes on the development of personality].

Antisocial behavior and personality disorders are both heterogeneous and the product of interacting genetic and environmental factors acting at different levels of causation. Heritability studies show that individual differences in predisposition to antisocial behavior are transmitted by genetic mechanisms in families. Direct gene analysis and genetic linkage analysis have identified structural variants in genes involved in neurotransmitter function, and some progress has been made towards relating these genetic variants to antisocial personality and other behaviors. The monoamine oxidase-A variant leads to aggressive behavior in one family. Direct gene analyses have revealed amino acid substitutions and structural variants at DRD2, DRD3 and DRD4 dopamine receptors and 5-HT2A, 5-HT2C serotonin receptors, serotonin transporter gene, and genes for enzymes, metabolizing biogenic amines MAO-A, MAO-B. The stage is set to identify the phenotypic significance of these as well as genetic variants at other loci which may be relevant as candidate genes for antisocial behavior and related behavioral differences.

Dopamine↗
PubMed2006

Beyond HLA: the significance of genomic variation for allogeneic hematopoietic stem cell transplantation.

The last 2 years have seen much excitement in the field of genetics with the identification of a formerly unappreciated level of "structural variation" within the normal human genome. Genetic structural variants include deletions, duplications, and inversions in addition to the recently discovered, copy number variants. Single nucleotide polymorphisms are the most extensively evaluated variant within the genome to date. Combining our knowledge from these studies with our rapidly accumulating understanding of structural variants, it is apparent that the extent of genetic dissimilarity between any 2 individuals is considerable and much greater than that which was previously recognized. Clearly, this more diverse view of the genome has significant implications for allogeneic hematopoietic stem cell transplantation, not least in the generation of transplant antigens but also in terms of individual susceptibility to transplant-related toxicities. With advances in DNA sequencing technology we now have the capacity to perform genome-wide analysis in a high throughput fashion, permitting a detailed genetic analysis of patient and donor prior to transplantation. Understanding the significance of this additional genetic information and applying it in a clinically meaningful way will be one of the challenges faced by transplant clinicians in the future.

Genetic Predisposition to Disease↗
PubMed1999

Structural basis for the activity of two muconate cycloisomerase variants toward substituted muconates.

We have refined to 2.3 A resolution two muconate cycloisomerase (MCIase) variant structures, F329I and I54V, that differ from each other and from wild-type in their activity toward cis,cis-muconate (CCM) and substituted CCMs. The working and free R-factors for F329I are 17.4/21.6% and for I54V, 17.6/22.3% with good stereochemistry. Except for the mutated residue, there are no significant changes in structure. To understand the differences in enzymatic properties we docked substituted CCMs and CCM into the active sites of the variants and wild type. The extra space the mutations create appears to account for most of the enzymatic differences. The lack of other structural changes explains why, although structurally equivalent changes occur in chloromuconate cycloisomerase (CMCIase), the changes in themselves do not convert a MCIase into a dehalogenating CMCIase. Reanalysis of the CMCIase structure revealed only one general acid/base, K169. The structural implication is that, in 2-chloro-CCM conversion by CMCIase, the lactone ring of 5-chloromuconolactone rotates before dehalogenation to bring the acidic C4 proton next to K169. Therefore, K169 alone performs both required protonation and deprotonation steps, the first at C5 as in MCIase, and the second, after ring rotation, at C4. This distinguishes CMCIase from alpha/beta barrel isomerases and racemases, which use two different bases.

Binding Sites↗
PubMed1996

Direct analysis of candidate genes in impulsive behaviours.

Antisocial behaviour is both heterogeneous and the product of interacting genetic and environmental factors acting at different levels of causation. Heritability studies show that individual differences in predisposition to antisocial behaviour are transmitted vertically in families by genetic mechanisms. Owing to aetiological heterogeneity and complexity, study of a variety of other behavioural phenotypes may shed more light on the antecedents of antisocial behaviour than direct studies on antisocial behaviour. Identification of genetic vulnerability factors would clarify mechanisms of vulnerability and the role of the environment. Direct gene analysis and genetic linkage analysis have identified structural variants in genes involved in neurotransmitter function, and some progress has been made towards relating these genetic variants to antisocial personality and other behaviours. Thyroid hormone receptor variants can cause attention deficit/hyperactivity disorder, and a monoamine oxidase A variant leads to aggressive behaviour in one family. Direct gene analyses have revealed non-conservative amino acid substitutions and structural variants (generally rare) at DRD2, DRD3 and DRD4 dopamine receptors and 5-HT1A, 5-HT2A, 5-HT2C and 5-HT7 serotonin receptors. The stage is set to identify the phenotypic significance of these as well as genetic variants at other loci which may be relevant as candidate genes for antisocial behaviour and related behavioural differences.

Animals↗
PubMed1987

A human-human hybridoma antibody (TrB12) defining subgroups of HLA-DQw1 and -DQw3.

We have constructed an IgG, kappa human--human hybridoma Ab(TrB12), which precipitates a molecule consisting of two polypeptides of about 33 and 27 kD in size. TrB12 reacted with; (1) 7 out of 10 DQw1-positive cell lines in IIF, and all 10 in a rosette-assay; (2) 5 out of 12 DQw3-positive cells, both in IIF and the rosette-assay; (3) none of 4 DQw2 homozygous cells. Detergent cell lysate of DQw1 homozygous cell lines contained antigens that cross-linked the mouse monoclonal antibody Genox 353 G2a-5 (anti-DQw1) and TrB12. TrB12 competed with the mouse DQw3-specific monoclonal antibody IVD-12 for binding to DQw3 homozygous cells. The data imply that the TrB12 epitope is associated with molecules that carry DQw1 and DQw3 serological specificities. By radioimmunoassay, TrB12 and the mouse monoclonal antibody IIB3 divided both DQw1- and DQw3- bearing cell lines into three phenotypic groups: (1) TrB12+IIB3hi, (2) TrB12-IIB3lo, and (3) TrB12-IIB3-. For DQw1 the results suggest that the first two groups represent structural variants but the third group may reflect low expression of DQw1. For DQw3 the evidence suggests that all three phenotypes represent structural variants. DQw3 has previously been divided into two serologically defined alleles, TA10+IIB3- and TA10-IIB3+. The TrB12+IIB3hi and TrB12-IIB3lo variants of DQw3 described in this study probably represent novel subgroups of the TA10-IIB3+ allele.

Alleles↗
PubMed2002

Structure of variant 2 scorpion toxin from Centruroides sculpturatus Ewing.

Centruroides sculpturatus Ewing variant 2 toxin (CsE-v2) is a neurotoxin isolated from the venom of a scorpion native to the Arizona desert. The structure of CsE-v2 was solved in two different crystal forms using a combination of molecular replacement and multiple isomorphous replacement techniques. Crystals of CsE-v2 display a temperature-dependent, reversible-phase transition near room temperature. At lower temperature the space group changes from P3(2)21 to P3(1)21 with an approximate doubling of the C-axis. The small-cell structure, which has one molecule per asymmetric unit, has an R factor of 0.229 at 2.8 A resolution. The large-cell structure has two molecules per asymmetric unit and was refined at 2.2 A resolution to an R factor of 0.255. CsE-v2 is a rigid, compact structure with four intrachain disulfide bonds. The structure is similar to other long-chain beta neurotoxins, and the largest differences occur in the last six residues. The high-resolution structure of CsE-v2 corrects an error in the reported C-terminal sequence; the terminal tripeptide sequence is Ser 64-Cys 65-Ser 66 rather than Ser 64-Ser 65-Cys 66. Comparison of CsE-v2 with long-chain alpha toxins reveals four insertions and one deletion, as well as additional residues at the N and C termini. Structural alignment of alpha and beta toxins suggests that the primary distinguishing feature between the two classes is the length of the loop between the second and third strands in a three-strand beta sheet. The shorter loop in alpha toxins exposes a critical lysine side chain, whereas the longer loop in beta toxins buries the corresponding basic residue (either arginine or lysine).

Amino Acid Sequence↗
PubMed1999

[Familial apolipoprotein A-I variants].

Apolipoprotein (apo) A-I is the major apolipoprotein of HDL and is a single polypeptide chain with 243 amino acid residues. Familial apo A-I deficiency is a rare metabolic disorder of which 13 cases have been characterized at the molecular level. However, in subjects with apo A-I deficiency, coronary artery disease is not always present. To date, more than 40 genetically determined structural variants of apo A-I have been identified. Seven apo A-I mutations have been identified to cause hereditary amyloidosis. In our laboratory, we characterized ten apo A-I variants, including apo A-I(Vall56Glu) Oita. A minority of structural variants were associated with altered HDL cholesterol levels or increased risk for cardiovascular disease.

Amyloidosis↗