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PubMed1980

Gamma ray-induced loss of expression of HLA and glyoxalase I alleles in lymphoblastoid cells.

Gamma rays from a cesium source were used to generate human lymphoblastoid cell line variants that had lost expression of all major histocompatibility complex antigens coded for by a single haplotype. The cell line was heterozygous at the glyoxalase I locus and had the HLA haplotypes HLA-A1, B8, DRw3, and HLA-A2, B5, DRw1. We selected with anti-HLA-B8 antiserum in a population of cells that had been irradiated with 300 R. The incidence of B8-loss variants was 4.1 X 10(-5) on day 5 after irradiation. Analysis of variants showed that expressions of HLA and GLO alleles trans to B8 were retained. However, expression of additional cis-linked HLA and GLO gene products was lost in 12 of 17 variants. Variants that had lost expression of (i) HLA-B8, (ii) HLA-B8, A1, (iii) HLA-B8, A1, DRw3, or (iv) HLA-B8, A1, DRw3 and the cis-linked glyoxalase I allele were obtained. Karyotype analysis was performed on eight variants that had lost expression of two or more cis-linked alleles. Three variants had two normal appearing no. 6 chromosomes, four variants had a deletion that included the region coding for HLA genes on the short arm of one no. 6 chromosome, and one variant had an inversion or translocation involving the short arm of one no. 6.

Cell Line↗
PubMed2005

BRCA1 variants in a family study of African-American and Latina women.

We sequenced the entire coding region of BRCA1 to improve our understanding of the frequency and nature of BRCA1 variants in African-American and Latina women identified from a multiethnic cohort in Los Angeles, California. The study included 109 African-American and 140 Latina sibships from families with two or more cases of breast or ovarian cancer among first-degree relatives. BRCA1 was sequenced in 278 breast or ovarian cancer cases and 229 unaffected sisters. The proportion of cases with known disease-causing mutations was low (0.72, 95% confidence interval: 0-1.7%). In total, 33 sequence variants were identified, including two protein truncation mutations, one deletion, and six silent and 24 missense variants. Two novel rare variants were identified that appeared to act as benign polymorphisms. Four rare variants may be unique to women of African descent based on existing literature, and three have been described exclusively in Latina women. The frequency of common variants was similar for cases and controls, but the frequency of common variants for African-American women significantly differed from those previously described for Caucasian women. We believe this to be the largest study of high-risk African-American and Latina women sequenced for variants in the BRCA1 gene to date.

Adult↗
PubMed1992

Alloantisera can detect some of the variants of HLA DRw13 identified by oligotyping.

Oligotyping has revealed a considerable polymorphism of HLA DRw13; so far, 5 alleles coded by DRB1 have been identified. An even greater number of haplotypes are apparent when considering the association of DRw13 with alleles coded by DRB3 and DQB1. Serology can now define some of these variants which had formerly escaped detection. We have tested by serology and by oligoprobes 66 genotyped Caucasoid cells comprising the known DR and DQ alleles. Among the 28 DRw6 cells, 10 different haplotype patterns were selected, of which 8 concern DRw13 and 2 DRw14. Four variants of DRw13 were represented: DRB1 *1301, *1302, *1303 and *1305 associated with usual and with uncommon alleles belonging to DRB3 and to DQB1. We have centered our analysis on 19 sera of the XIth Workshop defining DRw6. Two sera (639, 826) were noteworthy since they reacted with certain subtypes of DRw13 and with DRB1 *1102, *1103 only, the other DR specificities remaining negative.

Amino Acid Sequence↗
PubMed1999

Analysis of zinc fingers optimized via phage display: evaluating the utility of a recognition code.

Cys2His2 zinc finger proteins are composed of modular DNA-binding domains and provide an excellent framework for the design and selection of proteins with novel site specificity. Crystal structures of zinc finger-DNA complexes have shown that many Cys2His2 zinc fingers use a conserved docking arrangement that juxtaposes residues at key positions in the "recognition helix" with corresponding base positions in the three to four base-pair subsite. Several groups have proposed that specificity can be explained with a zinc finger-DNA recognition code that correlates specific amino acids at these key positions in the alpha-helix with specific bases in each position of the corresponding subsite. Here, we explore the utility of such a code through detailed studies of zinc finger variants selected via phage display. These proteins provide interesting systems for detailed analysis since they have affinities and specificities for their sites similar to those of naturally occurring DNA-binding proteins. Comparisons are facilitated by the fact that only key DNA-binding residues are varied in each finger while leaving all other regions of the structure unchanged. We study these proteins in detail by (1) selecting their optimal binding sites and comparing these binding sites with sites that might have been predicted from a code; (2) by examining the "evolutionary history" of these proteins during the phage display protocol to look for evidence of context-dependent effects; and (3) by reselecting finger 1 in the presence of the optimized finger 2/finger 3 domains to obtain further data on finger modularity. Our data for optimized fingers and binding sites demonstrate a clear correlation with contacts that would be predicted from a code. However, there are enough examples of context-dependent effects (not explained by any existing code) that selection is the most reliable method for maximizing the affinity and specificity of new zinc finger proteins.

Amino Acid Sequence↗
PubMed2026

Development of RS1-specific ACMG/AMP variant classification criteria with pilot variant curation.

Gene-based therapies are being developed for retinal diseases, including RS1-related X-linked retinoschisis. Therefore it is essential to determine which variants are pathogenic and which are benign when enrolling patients. The Clinical Genome Resource (ClinGen) X-Linked Inherited Retinal Diseases (XLRD) Variant Curation Expert Panel (VCEP) brings together clinician scientists, molecular biologists, and geneticists to apply their expertise and review the clinical, genetic, population, and functional evidence for variants. American College of Medical Genetics (ACMG) guidelines have been modified for RS1 to develop a highly systematic and conservative framework for evaluating variants. The curation process involves applying 28 different codes, each with 4 strength levels (very strong, strong, moderate, supporting) across different domains of phenotype, population data, computational assessment, functional impact, and segregation. With RS1-specific rules, a total of 54 pilot variants were tested. These included 47 variants in ClinVar. Of these 21 variants were re-classified: 2 likely pathogenic variants and one likely benign were changed to variants of uncertain significance and 4 previously unclassified variants were changed to pathogenic, likely pathogenic and likely benign. Other changes resolved conflicts or multiple classifications.

Humans↗
PubMed2005

The molecular basis of individual differences in phenylthiocarbamide and propylthiouracil bitterness perception.

Individual differences in perception are ubiquitous within the chemical senses: taste, smell, and chemical somesthesis . A hypothesis of this fact states that polymorphisms in human sensory receptor genes could alter perception by coding for functionally distinct receptor types . We have previously reported evidence that sequence variants in a presumptive bitter receptor gene (hTAS2R38) correlate with differences in bitterness recognition of phenylthiocarbamide (PTC) . Here, we map individual psychogenomic pathways for bitter taste by testing people with a variety of psychophysical tasks and linking their individual perceptions of the compounds PTC and propylthiouracil (PROP) to the in vitro responses of their TAS2R38 receptor variants. Functional expression studies demonstrate that five different haplotypes from the hTAS2R38 gene code for operatively distinct receptors. The responses of the three haplotypes we also tested in vivo correlate strongly with individuals' psychophysical bitter sensitivities to a family of compounds. These data provide a direct molecular link between heritable variability in bitter taste perception to functional variations of a single G protein coupled receptor that responds to compounds such as PTC and PROP that contain the N-C=S moiety. The molecular mechanisms of perceived bitterness variability have therapeutic implications, such as helping patients to consume beneficial bitter-tasting compounds-for example, pharmaceuticals and selected phytochemicals.

Animals↗
PubMed2002

Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes.

BACKGROUND: DNA variants appearing to predispose to drug-associated "acquired" long-QT syndrome (aLQTS) have been reported in congenital long-QT disease genes. However, the incidence of these genetic risk factors has not been systematically evaluated in a large set of patients with aLQTS. We have previously identified functionally important DNA variants in genes encoding K+ channel ancillary subunits in 11% of an aLQTS cohort. METHODS AND RESULTS: The coding regions of the genes encoding the pore-forming channel proteins KvLQT1, HERG, and SCN5A were screened in (1) the same aLQTS cohort (n=92) and (2) controls, drawn from patients tolerating QT-prolonging drugs (n=67) and cross sections of the Middle Tennessee (n=71) and US populations (n=90). The frequency of three common nonsynonymous coding region polymorphisms was no different between aLQTS and control subjects, as follows: 24% versus 19% for H558R (SCN5A), 3% versus 3% for R34C (SCN5A), and 14% versus 14% for K897T (HERG). Missense mutations (absent in controls) were identified in 5 of 92 patients. KvLQT1 and HERG mutations (one each) reduced K+ currents in vitro, consistent with the idea that they augment risk for aLQTS. However, three SCN5A variants did not alter I(Na), which argues that they played no role in the aLQTS phenotype. CONCLUSIONS: DNA variants in the coding regions of congenital long-QT disease genes predisposing to aLQTS can be identified in approximately 10% to 15% of affected subjects, predominantly in genes encoding ancillary subunits.

Alleles↗
PubMed1996

Phylogenetic distribution of streptococcal superantigen SSA allelic variants provides evidence for horizontal transfer of ssa within Streptococcus pyogenes.

Phylogenetic analyses recently found the gene encoding the streptococcal superantigen SSA of Streptococcus pyogenes to occur in several well-differentiated clones comprising 10 (12.5%) of 80 clonal lineages examined. To determine if distinct clonal lineages carried the same ssa coding sequence or harbored a group of allelic variants, ssa was sequenced from 23 S. pyogenes strains representing the 10 clones identified by multilocus enzyme electrophoresis. Three alleles of ssa were found in natural populations of S. pyogenes. ssa-1 and ssa-3 differed by a single synonymous substitution in codon 94; both encoded SSA-1. Each of these alleles was present in phylogenetically diverse clones that had not shared a recent common ancestor. ssa-2 was present in a single clonal lineage. It was identical to ssa-3 at codon 94 but had a nonsynonymous substitution at codon 28 that changed the second amino acid of the mature protein from serine to arginine. This substitution altered the predicted isoelectric point and affected the apparent molecular mass during sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Despite sequence variation both upstream of and within the ssa locus, all ssa-positive lineages expressed either SSA-1 or SSA-2. The observed patterns of ssa allele-clone distribution provide evidence for individual incidences of horizontal transfer and recombination of ssa among distinct group A streptococcal lineages. Although the extensive homology of SSA to the staphylococcal superantigen SEB raises the possibility of intergeneric gene transfer, a search for ssa in 68 genetically diverse clones of Staphylococcus aureus did not identify the gene. Moreover, the absence of ssa among 119 representative strains of Lancefield group B, C, or G streptococci suggests that ssa is confined to S. pyogenes.

Alleles↗
PubMed1979

Frequencies of centromeric heteromorphisms of human chromosomes 3 and 4 as detected by QFQ technique: can they be identified by RFA technique?

One hundred normal Caucasians were studied by sequential QFQ and RFA banding techniques in order to estimate the type and frequency of heteromorphisms in the centromeric regions of chromosome 3 and 4. Intensity variants were classified into 1 of 5 levels of QFQ banding. QFQ intensity heteromorphisms (greater than or equal to level 3) for chromosomes 3 and 4 were 62 and 15 percent respectively. The interrelationship between QFQ and RFA variants were also examined. When the centromere was brilliant by QFQ, it was found that it was deep red by RFA; when it was pale by QFQ, it was light red by RFA. Neverthless, a blind coded study could not pick up these color variants by RFA. QFQ banding showed variations of the centromeric regions of chromosomes 3 and 4 while RFA banding failed to demonstrate it. It was concluded that QFQ is the most useful technique in detecting the different intensity levels in the centromeric regions of chromsomes 3 and 4.

Adult↗
PubMed1998

Complete cDNA sequence, genomic structure, and chromosomal localization of the LPA receptor gene, lpA1/vzg-1/Gpcr26.

The lpA1/Gpcr26 locus encodes the first cloned and identified G-protein-coupled receptor that specifically interacts with lysophosphatidic acid. A murine full-length cDNA of size consistent with that seen on Northern blots (3.7 kb) was determined using 3' rapid amplification of cDNA ends. Analysis of genomic clones revealed that the gene is divided into five exons, with one intron inserted in the coding region for transmembrane domain VI and one exon encoding the divergent 5' sequence in another published cDNA clone variant (orphan receptor mrec1.3). This structure differs from the intronless coding region for a homologous receptor, Edg1, but is identical to another more similar orphan receptor (lpA2) that has been deposited with GenBank. Using backcross analysis, both exons 1 and 4 mapped to a proximal region of murine Chromosome 4 indistinguishable from the vacillans gene. Exon 4 also mapped to a second locus on proximal Chromosome 6 in Mus spretus, and this partial duplication was confirmed by Southern blot. The genomic structure indicates a distinct, divergent evolutionary lineage for the vzg-1/lpA1 subfamily of receptors compared to those of homologous orphan receptor genes.

Amino Acid Sequence↗
PubMed2017

Functional mapping and annotation of genetic associations with FUMA.

A main challenge in genome-wide association studies (GWAS) is to pinpoint possible causal variants. Results from GWAS typically do not directly translate into causal variants because the majority of hits are in non-coding or intergenic regions, and the presence of linkage disequilibrium leads to effects being statistically spread out across multiple variants. Post-GWAS annotation facilitates the selection of most likely causal variant(s). Multiple resources are available for post-GWAS annotation, yet these can be time consuming and do not provide integrated visual aids for data interpretation. We, therefore, develop FUMA: an integrative web-based platform using information from multiple biological resources to facilitate functional annotation of GWAS results, gene prioritization and interactive visualization. FUMA accommodates positional, expression quantitative trait loci (eQTL) and chromatin interaction mappings, and provides gene-based, pathway and tissue enrichment results. FUMA results directly aid in generating hypotheses that are testable in functional experiments aimed at proving causal relations.

Chromatin↗
PubMed2005

Variation in the alpha2B-adrenergic receptor gene (ADRA2B) and its relationship to vascular response in vivo.

The alpha2B-adrenergic receptor (ADRA2B) plays an important role in vasoconstriction and blood pressure regulation. One common variant in the ADRA2B gene (del 301--303) has been identified, and results in markedly decreased receptor desensitization in vitro but does not alter vascular sensitivity in vivo. Therefore, we fully characterized genetic variations in ADRA2B and related them to phenotype in vivo. We examined 5812 bp of contiguous sequence of ADRA2B (promoter, exonic, and 3'-untranslated region; 3'-UTR) using the polymerase chain reaction to amplify the genomic target followed by bidirectional sequencing (n=68). Haplotypes were inferred using an expectation maximization algorithm. Vasoconstriction in response to increasing doses of the highly selective alpha2-adrenergic receptor agonist, dexmedetomidine (0.01--1000 ng/min) was measured in the dorsal hand vein using a linear variable differential transformer. The dose that produced 50% (ED50) of maximum venoconstriction (Emax) was determined for each subject from the individual dose--response curves. ED50 and Emax were compared in subjects with and without variant alleles and haplotypes of interest. We identified 24 variable sites, 12 in the promoter region, five in the coding region (including two previously described as non-synonymous variants) and seven in the 3'-UTR region. Four haplotypes were inferred, representing approximately 95% of the cohort. One haplotype, characterized by two single nucleotide polymorphisms in the promoter region, and one in the 3'-UTR, occurred in seven of 38 African-Americans, and was associated with a lower Emax, 61.3% [95% confidence interval (CI) 39.5--83.0, n=7] compared to 78.1% (CI 73.8--82.5) in wild-types (n=61) (P=0.02). There was no association between the nine common variants and dexmedetomidine ED50. We have described novel variants and haplotypes of the ADRA2B gene. These do not alter sensitivity to a selective alpha2-adrenergic receptor agonist but some may decrease maximal venoconstriction in vivo.

Adolescent↗
PubMed1997

Characteristics of nucleotide substitution in the hepatitis C virus genome: constraints on sequence change in coding regions at both ends of the genome.

Comparison of complete genome sequences for different variants of hepatitis C virus (HCV) reveals several different constraints on sequence change. Synonymous changes are suppressed in coding regions at both 5' and 3' ends of the genome. No evidence was found for the existence of alternative reading frames or for a lower mutation frequency in these regions. Instead, suppression may be due to constraints imposed by RNA secondary structures identified within the core and NS5b genes. Nonsynonymous substitutions are less frequent than synonymous ones except in the hypervariable region of E2 and, to a lesser extent, in E1, NS2, and NS5b. Transitions are more frequent than transversions, particularly at the third position of codons where the bias is 16:1. In addition, nucleotide substitutions may not occur symmetrically since there is a bias toward G or C at the third position of codons, while T left and right arrow C transitions were twice as frequent as A left and right arrow G transitions. These different biases do not affect the phylogenetic analysis of HCV variants but need to be taken into account in interpreting sequence change in longitudinal studies.

Base Sequence↗
PubMed1994

An amplifiable DNA region from the Mycoplasma hyorhinis genome.

A novel amplifiable genomic region that displays variability in the number of tandem copies of a 1,368-bp DNA sequence (designated RS-2) was discovered among individual clonal derivatives within Mycoplasma hyorhinis broth-grown cell populations. Clonal isolates representing variant subpopulations from the original broth culture were of a single size variant, and although continued culture under a variety of growth conditions did not result in further amplification of RS-2, evidence for deletion events which reduced RS-2 copy number, presumably by homologous recombination, was obtained. RS-2 homologous sequences were identified in all M. hyorhinis strains tested, but only the tissue culture-derived strains GDL-1 and GDL-2 showed variability in genomic dosage. The RS-2 nucleotide sequence established that each tandem copy is flanked by direct repeats of a 20-bp sequence and suggested a possible mechanism for its original duplication as the initial phase of a genetic amplification process. The coding strand was defined by PCR amplification of a reverse transcriptase-generated cDNA, and its sequence revealed that RS-2 encodes a 456-residue internal, highly cysteine-rich domain of a larger M. hyorhinis protein whose coding sequence initiates and terminates in unique genomic sequences several hundred base pairs from RS-2 on either side of it. Changes in RS-2 copy number maintain the reading frame, and therefore the coding capacity, for this predicted size-variant protein.

Amino Acid Sequence↗
PubMed1992

The complete cDNA sequence of bovine coagulation factor V.

Lack of availability of a primary structure for bovine factor V has hindered detailed analysis of a vast majority of structure-function correlations on this molecule. To determine the primary structure of bovine factor V, we used liver mRNA as a template for the synthesis of three cDNA libraries. The sequences of seven overlapping cDNA clones infer two bovine factor V variants. Variant 1 results in a 6910-basepair (bp) cDNA including 103 bp of 5'-untranslated sequence, 6633 bp of coding sequence and 171 bp of 3'-untranslated sequence with a putative polyadenylation site. Variant 2 differs only in the size of the coding sequence (6618 bp). The open reading frame translates to factor V consisting of 2211 (or 2206) amino acids including a 28-amino acid signal peptide. Comparison of the amino acid sequences with human factor Va reveals 84% identity for the heavy and 86% for the light chains. In contrast, the B domain (connecting region) exhibits only 59% identity relative to the human molecule. The bovine B domain contains two repeats of a 14-amino acid structure that is contained only once in the human sequence. Bovine factor V lacks one of the nine amino acid repeats and one of the 17 amino acid repeats present in the human B domain. Factor V has little homology to the factor VIII molecule in the B domain. The 17-amino acid repeat missing in bovine factor V allows identification of an 18-amino acid sequence that is homologous to the B domain of human factor VIII. These 18 amino acids may either constitute the unique vestige of a divergent evolution between the B domains of factors V and VIII or reveal the convergent evolution toward a critical epitope involved in the activation of both procofactors.

Amino Acid Sequence↗
PubMed1988

Sequences of complete cDNAs encoding four variants of chicken skeletal muscle troponin T.

cDNAs containing the complete coding sequences of four isoforms of troponin T derived from 1-week-old chick skeletal muscle have been isolated and sequenced. While the 5' and 3' untranslated regions and most of the coding sequence were identical for each, dramatic differences were observed in the NH2-terminal region corresponding to amino acid residues 10-37 of rabbit skeletal troponin T. These sequence differences correspond to the alternatively spliced but not mutually exclusive exons 4 to 8 of the rat skeletal muscle troponin T gene. In addition, we observe a sequence corresponding to an extra exon or exons (between 5 and 6) present in the chicken skeletal muscle gene and not previously detected in the rat skeletal or chicken cardiac genes. This sequence of 63 nucleotides consists of an almost perfect repeat of 30 and 33 nucleotides and has previously been shown to be represented as a protein variant in chicken skeletal muscle. A difference is also present in one cDNA clone corresponding to the alternatively spliced (mutually exclusive) exons 16 and 17 of the rat gene. In the protein, this corresponds to a region implicated in the interaction of troponin T with troponin C, tropomyosin, and perhaps troponin I and F-actin.

Amino Acid Sequence↗
PubMed1988

Effects of 3' end deletions from the Vibrio harveyi luxB gene on luciferase subunit folding and enzyme assembly: generation of temperature-sensitive polypeptide folding mutants.

Ten recombinant plasmids have been constructed by deletion of specific regions from the plasmid pTB7 that carries the luxA and luxB genes, encoding the alpha and beta subunits of luciferase from Vibrio harveyi, such that luciferases with normal alpha subunits and variant beta subunits were produced in Escherichia coli cells carrying the recombinant plasmids. The original plasmid, which conferred bioluminescence (upon addition of exogenous aldehyde substrate) on E. coli carrying it, was constructed by insertion of a 4.0-kb HindIII fragment of V. harveyi DNA into the HindIII site of plasmid pBR322 [Baldwin, T.O., Berends, T., Bunch, T. A., Holzman, T. F., Rausch, S. K., Shamansky, L., Treat, M. L., & Ziegler, M. M. (1984) Biochemistry 23, 3663-3667]. Deletion mutants in the 3' region of luxB were divided into three groups: (A) those with deletions in the 3' untranslated region that left the coding sequences intact, (B) those that left the 3' untranslated sequences intact but deleted short stretches of the 3' coding region of the beta subunit, and (C) those for which the 3' deletions extended from the untranslated region into the coding sequences. Analysis of the expression of luciferase from these variant plasmids has demonstrated two points concerning the synthesis of luciferase subunits and the assembly of those subunits into active luciferase in E. coli. First, deletion of DNA sequences 3' to the translational open reading frame of the beta subunit that contain a potential stem and loop structure resulted in dramatic reduction in the level of accumulation of active luciferase in cells carrying the variant plasmids, even though the luxAB coding regions remained intact.

Amino Acid Sequence↗
PubMed2003

Distinction of sperm-binding site and reactive site for trypsin inhibition on p12 secreted from the accessory sex glands of male mice.

Six variants of P12, a Kazal-type trypsin inhibitor in the secretion of male mouse accessory sexual glands, were made using single-site mutations including R19L, Y21V, D22G, R43G, K44S, and R45T, based on one-letter-code mutation of amino acids. The other two variants, Nd10 and Cd8, were made using the deletion of 10 and 8 residues from the N- and C-terminals, respectively. Their CD profiles revealed maintenance of the P12 conformation in the seven variants, excluding Cd8, which became unfolded. Only R19L entirely lost the ability while the other variants were as strong as P12 in inhibiting the trypsin digestion of N-benzoyl-Phe-Val-Arg 7-amido-4-methylcoumarin. The immunocytochemical results demonstrated that D22G and Cd8 failed to bind to sperm, Y21V very weakly did so, and the other variants retained their sperm-binding abilities. Concomitantly, the immunocytochemical stainability of each ligand was parallel to its inhibitory effect on 125I-P12-sperm binding, and a synthetic oligopeptide corresponding to residues 18-24 of P12 was able to inhibit P12-sperm binding. The data together concluded that R19 was essential for protease inhibition and D22 and/or Y21 mainly being responsible for the binding of P12 to sperm. The steric arrangement of R19, Y21, and D22 on the tertiary structure of P12 is discussed.

Amino Acid Sequence↗