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Results for “Variant interpretation”

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PubMed1980

Double one-dimensional electrophoresis of human serum transferrin: a new high-resolution screening method for genetically determined variation.

With one-dimensional electrophoresis or electrofocusing the selective demonstration of proteins and their genetically determined variants from complex compositions like the physiological body fluids often is possible only with specific staining techniques or immunofixation. By the method described here samples are separated by PAG electrophoresis and a selected detail of the electropherogram is further resolved by PAG electrofocusing. The resulting pattern of bands after a usual protein stain can easily be interpreted due to the reduction of the number of bands. Informative bands hidden in a one-dimensional pherogram by overlapping with one or more other bands can be selectively visualized by the one-dimensional combination of two electrophoretic methods. With the double one-dimensional technique several hundred samples can be analyzed per person day. Thus the application in electrophoretic screening studies appears to be of special interest. The method is demonstrated by using the polymorphism of human serum transferrin as an example. A new variant of Tf-C with a high incidence in the German population is demonstrated.

Adult↗

PubMed1980

Computed tomography of the nasopharynx: normal and variants of normal.

In 52 normal nasopharyngeal computed tomographic (CT) scans the various tissue planes deep to the mucosa were always seen and appeared symmetric. The superficial structures were more often asymmetric; however, by using physiologic maneuvers, coronal scanning, and this very reliable deep plane anatomy, a highly accurate interpretation is possible. A knowledge of these simple scanning techniques and of the range of normal anatomy will help radiologists avoid the equivocal and false-positive interpretations that plague other radiographic studies of this area. Because of its deep plane information, CT best complements the clinical evaluation of the nasopharynx, and should be the radiographic examination of choice.

Adenoids↗

PubMed2000

Complex chromosome rearrangements may locate the bcr/abl fusion gene sites other than 22q11.

BACKGROUND AND OBJECTIVE: From 5-8% of Philadelphia (Ph) positive patients with chronic myeloid leukemia (CML) show variant translocations in which at least a third chromosome in addition to 9q34 and 22q11 is involved. The formation mechanisms and clinical significance of variant Ph translocations are still unclear. The BCR/ABL chimeric gene encoding for chimeric proteins is always present and maps on the 22q- regardless of the type of translocation. We studied two apparently Ph negative CML patients with unusual karyotypes both showing a typical b3a2 rearrangement. DESIGN AND METHODS: Dual-color fluorescence in situ hybridization (FISH) can visualize BCR and ABL genes and localize the BCR/ABL fusion gene. We used FISH to study the formation mechanisms of variant Ph translocations in two patients. RESULTS: The chimeric BCR/ABL gene was located on a locus other than the expected 22q11 in both patients. In the first case the fusion signal was present on the 9q34 band whereas in the second patient it was detected on chromosome 8, involved in masked Ph formation. INTERPRETATION AND CONCLUSIONS: The location of the hybrid BCR/ABL gene on chromosomes other than 22q- is a rare event which can only be observed using the FISH technique. When these unusual translocations occur the hypothesis most often put forward is that several consecutive cytogenetic events have taken place. The factors which regulate the formation of these breakpoints have yet to be clarified. The FISH technique allows the identification of chromosome rearrangements that could not otherwise be detected by conventional banding procedures. The location of the hybrid BCR/ABL gene on sites other than 22q11 represents a rare type of variant Ph translocation. The real frequency and clinical significance of such rearrangements need to be investigated.

Aged↗

PubMed2000

A catalytically deficient active site variant of PvuII endonuclease binds Mg(II) ions.

In efforts to understand the mechanisms of many nucleic acid enzymes, the first site-directed mutations are made at conserved acidic active residues. Almost without exception, the low or null activities of the resulting variants are attributed to the importance of the acidic residue(s) to the ligation of required metal ions. Using (25)Mg NMR spectroscopy as a direct probe of metal ion binding and the homodimeric PvuII restriction endonuclease as a model system, this interpretation is examined and clarified. Our results indicate that Mg(II) binds wild-type PvuII endonuclease in the absence of DNA with a K(d,app) of 1.9 mM. Hill analysis yields an n(H) coefficient of 1.4, a value consistent with the binding of more than one Mg(II) ion per monomer active site. Variable pH studies indicate that two ionizable groups are responsible for Mg(II) binding by wild-type PvuII endonuclease near physiological pH. The pK(a,app) for these ionizations is 6.7, a value which is unusual for acidic residues but consistent with data obtained for critical groups in MunI endonuclease and a number of other hydrolases. To assign residues critical to ligating Mg(II), binding measurements were performed on the low activity catalytic site mutants E68A and D58A. As expected, E68A binds Mg(II) ions very weakly (K(d,app) approximately 40 mM), implicating Glu68 as critical to Mg(II) binding. Interestingly, while D58A has only residual specific activity, it retains an affinity for Mg(II) with a K(d,app) of 3.6 mM and exhibits a Hill coefficient of 0.7. Moreover, in this variant, multiple ionizable groups with pK(a,app) of 7.2 are involved in Mg(II) binding, suggesting a shuffling of Mg(II) ligands in the active site. These data indicate that Asp58 is important for the critical positioning of metal ion(s) required for catalysis.

Binding Sites↗

PubMed2004

Sampling the disparity space image.

A central issue in stereo algorithm design is the choice of matching cost. Many algorithms simply use squared or absolute intensity differences based on integer disparity steps. In this paper, we address potential problems with such approaches. We begin with a careful analysis of the properties of the continuous disparity space image (DSI) and propose several new matching cost variants based on symmetrically matching interpolated image signals. Using stereo images with ground truth, we empirically evaluate the performance of the different cost variants and show that proper sampling can yield improved matching performance.

Algorithms↗

PubMed1999

Trichotillomania and the mourning process: a case report and review of the psychodynamics.

We present our theory of trichotillomania (hair pulling) as a manic phenomenon, complementary to its classic comprehension as a mourning response. Under certain conditions, separation or threat of separation can generate sadness or grief, while in pathological cases, when the loss is experienced as unbearable, the response might be depressive or manic. We suggest that in trichotillomania (TR), like in mania, manic defenses are used to cope with separation. We believe hair pulling is an expression of primary magical thinking, offering the subject an illusion of control and victory over the object. A representative case of a young woman suffering from bipolar disorder with TR is described. Based on our case analysis, we argue that TR may not necessarily be a variant of OCD, but rather classified among the affective disorders.

Adult↗

PubMed1995

Histone phosphorylation during sea urchin development.

Studies on histone phosphorylation during transitions in chromatin structure occurring in vivo during spermatogenesis and early embryogenesis in sea urchins are reviewed and evaluated in the light of recent studies on histone phosphorylation occurring during chromatin synthesis in frog egg extracts in vitro and evidence that protein kinases and phosphatases play direct roles in the regulation of cellular structure. Sperm-specific histone variants Sp H1 and Sp H2B are maintained as phosphorylated derivatives N and O/P throughout spermatogenesis and early embryogenesis and egg specific histone variants CS H1 and CS H2A are phosphorylated during early embryogenesis. These developmental correlations provide clues about the roles of histone phosphorylation in control of chromatin structure in vivo and provide a basis for the interpretation of data obtained from in-vitro sperm chromatin remodeling in egg extracts and from biochemical studies on the effects of histone phosphorylation on DNA binding. The potential consequences for chromatin structure of the various histone phosphorylation events observed in sea urchins and frog egg extracts are discussed.

Animals↗

PubMed2004

Regulatory polymorphisms underlying complex disease traits.

There is growing evidence that genetic variation plays an important role in the determination of individual susceptibility to complex disease traits. In contrast to coding sequence polymorphisms, where the consequences of non-synonymous variation may be resolved at the level of the protein phenotype, defining specific functional regulatory polymorphisms has proved problematic. This has arisen for a number of reasons, including difficulties with fine mapping due to linkage disequilibrium, together with a paucity of experimental tools to resolve the effects of non-coding sequence variation on gene expression. Recent studies have shown that variation in gene expression is heritable and can be mapped as a quantitative trait. Allele-specific effects on gene expression appear relatively common, typically of modest magnitude and context specific. The role of regulatory polymorphisms in determining susceptibility to a number of complex disease traits is discussed, including variation at the VNTR of INS, encoding insulin, in type 1 diabetes and polymorphism of CTLA4, encoding cytotoxic T lymphocyte antigen, in autoimmune disease. Examples where regulatory polymorphisms have been found to play a role in mongenic traits such as factor VII deficiency are discussed, and contrasted with those polymorphisms associated with ischaemic heart disease at the same gene locus. Molecular mechanisms operating in an allele-specific manner at the level of transcription are illustrated, with examples including the role of Duffy binding protein in malaria. The difficulty of resolving specific functional regulatory variants arising from linkage disequilibrium is demonstrated using a number of examples including polymorphism of CCR5, encoding CC chemokine receptor 5, and HIV-1 infection. The importance of understanding haplotypic structure to the design and interpretation of functional assays of putative regulatory variation is highlighted, together with discussion of the strategic use of experimental tools to resolve regulatory polymorphisms at a transcriptional level. A number of examples are discussed including work on the TNF locus which demonstrate biological and experimental context specificity. Regulatory variation may also operate at other levels of control of gene expression and the modulation of splicing at PTPRC, encoding protein tyrosine phosphatase receptor-type C, and of translational efficiency at F12, encoding factor XII, are discussed.

Autoimmune Diseases↗

PubMed1997

Type-4 pili of Kingella denitrificans.

Kingella denitrificans possess type-4 pili, and the type strain, ATCC 33394, contains at least four complete copies of type-4 pilin-encoding genes. Previously reported hybridization patterns of K. denitrificans chromosomal DNA seen using a Neisseria gonorrhoeae pilin gene region probe, had been interpreted as representing possible partial, silent gene loci. This now appears to be due to cross-reaction to multiple copies of 18-bp inverted repeat structures. Data are presented on a variety of colony variants which have changed from a spreading-corroding (SC) phenotype to a nonspreading-noncorroding (N) phenotype. Interestingly, while the SC to N transition is most often associated with loss of piliation in other bacteria containing type-4 pili, many of the K. denitrificans N variants still produce pilin, and some still produce pili.

Bacterial Outer Membrane Proteins↗

PubMed2006

Sequence variations in the 5' upstream regions of the FBN1 gene associated with Marfan syndrome.

Marfan syndrome (MFS; OMIM#154700) is a connective tissue disorder characterized by manifestations in the ocular, skeletal and cardiovascular systems. MFS is caused by mutation in the fibrillin-1 gene (FBN1; OMIM#134797) and more than 550 mutations have been identified so far. FBN1 is approximately 230 kb in size and contains three evolutionarily conserved alternatively spliced exons B, A and C at the 5'end. In a first systematic attempt to associate sequence variations in the FBN1 5' alternatively spliced exons with MFS, we investigated 41 individuals fulfilling the diagnostic criteria of Ghent nosology or with features of MFS including at least one major criterion or involvement of two organ systems but not fulfilling a strict interpretation of the Ghent nosology, and known to be negative for mutations in the FBN1 exons 1-65 as well as the TGFBR2 and TGFBR1 coding regions. We identified five novel and one previously reported variants in the six unrelated probands and provide preliminary evidence for their role in pathogenesis.

5' Flanking Region↗

PubMed2006

Signatures of strong population differentiation shape extended haplotypes across the human CD28, CTLA4, and ICOS costimulatory genes.

The three members of the costimulatory receptor family, CD28, CTLA-4, and ICOS, have complementary effects on T cell activation, and their balance controls the overall outcome of immune and autoimmune responses. They are encoded in a short genomic interval, and overall activity may result from interplay between allelic variants at each locus. With multiethnic DNA panels that represent a wide spectrum of human populations, we demonstrate long-range linkage disequilibrium among the three genes. A large fraction of the variation found in the locus can be explained by the presence of extended haplotypes encompassing variants at CD28, CTLA4, and the ICOS promoter. There are unusual differences in the distribution of some variants and haplotypes between geographic regions. The differences may reflect demographic events and/or the adaptation to diverse environmental and microbial challenges encountered in the course of human migrations and will be important to consider when interpreting association to immune/autoimmune responsiveness.

Antigens, CD↗

PubMed1998

Dating the origin of the CCR5-Delta32 AIDS-resistance allele by the coalescence of haplotypes.

The CCR5-Delta32 deletion obliterates the CCR5 chemokine and the human immunodeficiency virus (HIV)-1 coreceptor on lymphoid cells, leading to strong resistance against HIV-1 infection and AIDS. A genotype survey of 4,166 individuals revealed a cline of CCR5-Delta32 allele frequencies of 0%-14% across Eurasia, whereas the variant is absent among native African, American Indian, and East Asian ethnic groups. Haplotype analysis of 192 Caucasian chromosomes revealed strong linkage disequilibrium between CCR5 and two microsatellite loci. By use of coalescence theory to interpret modern haplotype genealogy, we estimate the origin of the CCR5-Delta32-containing ancestral haplotype to be approximately 700 years ago, with an estimated range of 275-1,875 years. The geographic cline of CCR5-Delta32 frequencies and its recent emergence are consistent with a historic strong selective event (e.g. , an epidemic of a pathogen that, like HIV-1, utilizes CCR5), driving its frequency upward in ancestral Caucasian populations.

Acquired Immunodeficiency Syndrome↗

PubMed1999

Monoclonal antibodies recognize at least five epitopes on the SIV Nef protein and identify an in vitro-induced mutation.

Eleven monoclonal antibodies (MAbs) to SIV Nef were produced and characterized. Five antibody-binding sites on SIV Nef were identified on the basis of the reactivity of the antibodies with recombinant proteins. Two of the five epitopes were defined using overlapping peptides. A further three epitopes could not be defined with peptides but all antibodies reacted in Western blot, suggesting that the epitopes were at least partially conformation dependent. Antibodies in two of the five epitope groups were further differentiated by competition analysis. The panel of MAbs described is able to distinguish between a number of recombinant Nef proteins currently under investigation in vivo in macaques. Two of the MAbs described are able to distinguish between the Nef protein from pathogenic (J5) and attenuated (C8) strains of SIV, thus providing useful tools for studying the relevance of the Nef protein in the pathogenesis of SIV infection. In FACScan analysis two of the MAbs, KK70 and KK75, were used to identify an in vitro-induced mutation in J5 Nef grown in C8166 cells. Sequence analysis of the phenotypic variants identified a mutation of the tryptophan (TGG) at amino acid 214 to a stop codon (TGA), thus truncating the Nef protein. The functional significance of this observation remains unclear but highlights the need to interpret data with caution if virus has been cultured in vitro even for a short period of time.

Animals↗

PubMed1998

Strategies for mutational analysis of the large multiexon ATM gene using high-density oligonucleotide arrays.

Mutational analysis of large genes with complex genomic structures plays an important role in medical genetics. Technical limitations associated with current mutation screening protocols have placed increased emphasis on the development of new technologies to simplify these procedures. High-density arrays of >90,000-oligonucleotide probes, 25 nucleotides in length, were designed to screen for all possible heterozygous germ-line mutations in the 9.17-kb coding region of the ATM gene. A strategy for rapidly developing multiexon PCR amplification protocols in DNA chip-based hybridization analysis was devised and implemented in preparing target for the 62 ATM coding exons. Improved algorithms for interpreting data from two-color experiments, where reference and test samples are cohybridized to the arrays, were developed. In a blinded study, 17 of 18 distinct heterozygous and 8 of 8 distinct homozygous sequence variants in the assayed region were detected accurately along with five false-positive calls while scanning >200 kb in 22 genomic DNA samples. Of eight heterozygous sequence changes found in more than one sample, six were detected in all cases. Five previously unreported sequence changes, not found by other mutational scanning methodologies on these same samples, were detected that led to either amino acid changes or premature truncation of the ATM protein. DNA chip-based assays should play a valuable role in high throughput sequence analysis of complex genes.

Ataxia Telangiectasia Mutated Proteins↗

PubMed1986

Genomic hybridization of bovine class II major histocompatibility genes: 1. Extensive polymorphism of DQ alpha and DQ beta genes.

Class II genes of the bovine major histocompatibility complex (MHC) were investigated by Southern blot analysis using human cDNA probes for DQ alpha, DQ beta, DR alpha and DR beta. The presence of a DQ-like and a DR-like subregion in cattle was clearly indicated. Highly polymorphic restriction fragment patterns were obtained when genomic DNA, digested with any one of the BamHI, EcoRI or PvuII restriction enzymes, was hybridized with the DQ alpha and the DQ beta probe. The polymorphisms were interpreted genetically by analysing five paternal half-sib families of the Swedish Red and White breed. The material comprised, besides the bulls, 28 offspring and their dams. The analysis resolved 9 and 12 allelic variants of DQ alpha and DQ beta respectively. Thus, this investigation establishes a method for routine typing of MHC class II gene polymorphism in cattle. The results were entirely consistent with close linkage of DQ alpha and DQ beta since no recombinant was found and since alleles at these loci occurred in complete linkage disequilibrium in the material investigated. Close linkage between DQ and the blood group locus M, which has previously been found to be closely linked to the serologically defined BoLA-A locus, was also indicated. In this study DNA was isolated from frozen semen samples of dead bulls, which shows that this type of analysis will be useful in genetic investigations in cattle breeds, where artificial insemination is practised.

Animals↗

PubMed1995

Perspectives and future directions. Immunogenetics.

An outline of the history of immunogenetics is presented. The usefulness of the Rh, HLA and Gm systems in disease prediction and prevention will increase with our capacity precisely to relate polymorphic variants to particular functions and pathophysiological events. Alloimmunization to Gm markers is common in rheumatoid arthritis, an allegedly autoimmune disease. This paradox and the paradox of nonnominal allotypes, disobeying Mendelian rules, are resolved by the interpretation that herpesviruses may transfer nonself polymorphic genes. Transduction of such genes may be important also in AIDS pathogenesis.

Autoimmune Diseases↗

PubMed2026

Global disparities in COVID-19 vaccine coverage associated with trajectories of SARS-CoV-2 adaptation.

BACKGROUND: Vaccination serves as an effective intervention for health promotion and disease prevention across the socioecological systems and has played an important role during the COVID-19 pandemic. However, global disparities in vaccine coverage have increased uncertainty about the trajectories of viral adaptation, and the potential interplay between SARS-CoV-2 adaptation and vaccine rollout warrants further quantification. METHODS: Using over 13 million SARS-CoV-2 genomes across 86 countries from March 2020 to September 2022, we analyzed nonlinear associations between SARS-CoV-2 adaptation and vaccination coverage, considering public health and social measures, international travel, and infection dynamics, before and after the emergence of Omicron. Additionally, we examined the relationship between SARS-CoV-2 adaptation and COVID-19 mortality. RESULTS: During the pre-Omicron period, we found positive associations between nonsynonymous to synonymous divergence (dN/dS) ratios in the S1 subunit and medium levels of adjusted vaccine coverage (effect size: 0.96 [95% CI 0.47, 1.45]), while the association became insignificant at high levels (effect size: -1.89 [95% CI -4.20, 0.43]). However, no significant associations were found when Omicron dominated, possibly due to the immune escape ability of Omicron variants and the complex immune landscape shaped by mass hybrid immunity. Moreover, we observed evidence of dynamic interdependence and positive correlations between COVID-19 mortality and SARS-CoV-2 adaptation, with COVID-19 mortality interpreted as a proxy for uncontrolled viral spread. CONCLUSIONS: Our findings suggest a complex nonlinear relationship between vaccine-induced immunity and SARS-CoV-2 adaptation, with high vaccine coverage potentially linked to lower positive selection. We also observed directional coupling between COVID-19 mortality and SARS-CoV-2 adaptation. This may have implications for fair and fast vaccination in pandemic preparedness and response. CLINICAL TRIAL NUMBER: Not applicable.

Humans↗

PubMed2026

Multimodal atlas of human atherosclerosis links granular vascular cell states to coronary artery disease risk.

Advances in single-cell and spatial assays have revolutionized the scale and resolution of molecular tissue profiling. Here we present MetaPlaq, a multimodal atlas of human atherosclerotic arterial beds comprising over a million cells across single-cell transcriptomics, epigenomics and high-resolution spatial expression assays. We map granular cell states and disease-relevant transcriptional programs within the native tissue context of coronary arteries. Furthermore, we map cardiovascular GWAS signals to smooth muscle cells (SMCs) and endothelial cells (ECs) and uncover the cis-regulatory architecture governing their phenotypic transitions. Our comprehensive epigenomic reference allowed us to build cell-specific enhancer-gene link maps and multimodal gene regulatory networks (GRNs) underlying disease-relevant states such as osteogenic SMCs and ECs undergoing mesenchymal transition. We also integrate SMC and EC disease-associated gene sets with GRNs to nominate key transcription factors such as PRRX1, BNC2 and ELK3 regulating atherosclerosis-relevant transcriptional programs. Finally, we layer single-cell and spatial modalities to fine-map GWAS variants with improved cell and anatomical context. We highlight candidate cell-specific regulatory mechanisms at less characterized CAD loci, including FGD5 and MCF2L in ECs. Together, this atlas represents an important step towards fully interpreting genetic risk loci and informing new therapeutic strategies for cardiovascular disease.

Journal Article↗