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PubMedDate not supplied

[Directed reconstruction of the influenza virus hemagglutinin gene].

A new approach to create chimeric genes by directed exchange of oligonucleotide fragments was developed. By oligonucleotide-directed mutagenesis a few deletion mutants of the influenza virus hemagglutinin (HA) gene were obtained. These variants of HA gene contain unique restriction sites in DNA regions coding for the A and B epitopes of the HA molecule. The obtained special vectors may be used for cloning DNA fragments coding for new amino acid sequences in internal sites of the HA gene.

Base Sequence↗
PubMed1990

Characterization of the normal alpha 1-antitrypsin allele Vmunich: a variant associated with a unique protein isoelectric focusing pattern.

alpha 1-Antitrypsin (alpha 1AT), the major serum inhibitor of neutrophil elastase, is a highly polymorphic protein associated with isoelectric focusing (IEF) patterns typical for each variant. alpha 1AT Vmunich, a previously unreported normal alpha 1AT variant, has a unique IEF banding pattern in which the 7 and 8 alpha 1AT protein bands focus with the normal M-type 7 and 8 bands, despite the fact that the major fraction of the Vmunich protein focuses in the "V" region of the IEF gel. To characterize the molecular basis of this variant and its unique IEF pattern, DNA sequence analysis of the coding exons of the Vmunich alpha 1AT gene was carried out using the polymerase chain reaction. The Vmunich allele differed from the common normal M1(Val213) alpha 1AT allele by a single nucleotide substitution of cytosine for adenosine, with the resultant amino acid change Asp2 GAT----Ala GCT. Inheritance of the allele was confirmed by family analysis using allele-specific amplification with the polymerase chain reaction. The Asp2----Ala mutation explains the cathodal position of the Vmunich protein on IEF, as there is a substitution of a negatively charged amino acid by a neutral one.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1982

Examination of the regulation of the actin multigene family in Dictyostelium discoideum.

The Dictyostelium actin genes constitute a seventeen-member dispersed multigene family. At least nine of the seventeen genes are expressed. Nearly all of the genes seem to code for the same protein sequence, although one gene with a variant amino acid sequence is expressed. The 5' untranslated and untranscribed sequences as well as the 3' untranscribed sequences are not conserved from gene to gene, although TATA and poly(T) sequences are found in the region of transcription initiation. The 3' untranslated sequences are conserved within some groups of genes. This allows us to suggest an evolutionary history of the actin gene duplications. We have developed a DNA mediated transformation system for Dictyostelium. We will soon be able to use this system to examine the importance of various regions around the actin genes for proper control of gene expression and to identify sequences involved in developmental regulation.

Actins↗
PubMed1995

Characterization of RET proto-oncogene 3' splicing variants and polyadenylation sites: a novel C-terminus for RET.

The RET proto-oncogene, which encodes a receptor tyrosine kinase, displays multiple alternative splicing variants. Splicing of sequences 3' of exon 19 to generate several coding and untranslated region (UTR) sequences has been previously reported. We have sequenced the full length RET coding region and characterized the transcripts and 3' UTRs generated by alternative splicing of the RET 3' terminus. These analyses were performed using both RET cDNA cloned from a pheochromocytoma library and reverse transcriptase PCR products generated using RNA from a neuroblastoma cell line (LA-N-2). Three different carboxyl termini were identified. In addition to the nine and 51 terminal amino acid forms already known, we identified a third with 43 terminal amino acids predicted to encode a novel RET protein isoform. A total of 3621 base pairs of DNA 3' of exon 19, which spans the alternatively spliced exons and RET UTRs, was sequenced. Four polyadenylation sites were identified. The observed combinations of polyadenylation sites and 3' coding sequence suggest that RET transcripts with up to 10 different 3' sequences and up to 40 different full length RET transcripts may exist.

Adrenal Gland Neoplasms↗
PubMed1993

Low levels of intraspecific variation in the mitochondrial DNA of chum salmon (Oncorhynchus keta).

A total of 798 individuals from 42 different populations of chum salmon (Oncorhynchus keta) were examined for mtDNA variation. Populations were sampled across the geographic range of the species, from mainland Japan around the Pacific Rim to the state of Washington in the United States. The entire D-loop region (approximately 1 kb) was sequenced for 16 individuals from representative populations. Subregions (approximately 200 nucleotides each) of the D-loop reported to be rapidly evolving in salmon were sequenced for another 29 individuals. Only 4 nucleotide variants were detected, and they occurred in only 4 individuals. Four coding regions of the mtDNA genome were also examined using restriction fragment analysis of products amplified via the polymerase chain reaction. Only one, the region coding for NADH dehydrogenase subunits 5 and 6, showed any variation at this level. The restriction enzyme AseI revealed a polymorphism where the frequency of haplotypes was correlated geographically. We surveyed all individuals for this polymorphism and documented a cline in frequency of the haplotypes around the Pacific Rim. There was a significant frequency difference between Japan and 3 other major geographic regions (Russia, Alaska/Yukon, and British Columbia/Washington) for the presence of the 2 haplotypes. This marker may prove useful in the identification of continent-of-origin for individual chum salmon caught in the open ocean.

Animals↗
PubMed1994

Characterization of a novel cofilin isoform that is predominantly expressed in mammalian skeletal muscle.

Cofilin is an actin-modulating protein of 20 kDa, which is widely distributed throughout muscle and non-muscle cells. By means of immunoblotting combined with two-dimensional gel electrophoresis, we found that two cofilin variants, muscle type (M-type) and non-muscle type (NM-type), exist in mammals, while a single isoform exists in chickens. During in vitro myogenesis of mouse C2 cells, expression of the M-type cofilin was upregulated. To better understand the nature of the M-type cofilin, we cloned cDNAs encoding M-type cofilin from the cDNA library of C2 myotubes and determined the entire sequence. The deduced peptide sequence contained a nuclear localization signal and a putative actin-binding sequence as reported in NM-type cofilin. The sequence showed 81% identity in the amino acid residues with the mouse NM-type cofilin sequence and, interestingly, higher homology (96% identity) with that of chicken cofilin. The mRNA encoding M-type cofilin, though it contains two variants that differ in the size of their 3'-non-coding sequences, was detected predominantly in heart, skeletal muscle, C2 myotubes, and testis by Northern blotting, while the mRNA for NM-type cofilin was seen in a variety of non-muscle tissues. The presence of the muscle type isoform of cofilin strongly suggests that cofilin is deeply involved in the regulation of actin function not only in non-muscle cells but also in muscle cells.

3T3 Cells↗
PubMed1998

U3 snoRNA genes with and without intron in the Kluyveromyces genus: yeasts can accommodate great variations of the U3 snoRNA 3'-terminal domain.

The U3 snoRNA coding sequences from the genomic DNAs of Kluyveromyces delphensis and four variants of the Kluyveromyces marxianus species were cloned by PCR amplification. Nucleotide sequence analysis of the amplification products revealed a unique U3 snoRNA gene sequence in all the strains studied, except for K. marxianus var. fragilis. The K. marxianus U3 genes were intronless, whereas an intron similar to those of the Saccharomyces cerevisiae U3 genes was found in K. delphensis. Hence, U3 genes with and without intron are found in yeasts of the Saccharomycetoideae subfamily. The secondary structure of the K. delphensis pre-U3 snoRNA and of the K. marxianus mature snoRNAs were studied experimentally. They revealed a strong conservation in yeasts of (1) the architecture of U3 snoRNA introns, (2) the 5'-terminal domain of the mature snoRNA, and (3) the protein-anchoring regions of the U3 snoRNA 3' domain. In contrast, stem-loop structures 2, 3, and 4 of the 3' domain showed great variations in size, sequence, and structure. Using a genetic test, we show that, in spite of these variations, the Kluyveromyces U3 snoRNAs are functional in S. cerevisiae. We also show that S. cerevisiae U3A snoRNAs lacking the stem-loop structure 2 or 4 are functional. Hence, U3 snoRNA function can accommodate great variations of the RNA 3'-terminal domain.

Base Sequence↗
PubMed2001

Evidence for positive selection in the capsid protein-coding region of the foot-and-mouth disease virus (FMDV) subjected to experimental passage regimens.

We present sequence data from two genomic regions of foot-and-mouth disease virus (FMDV) subjected to several experimental passage regimens. Maximum-likelihood estimates of the nonsynonymous-to-synonymous rate ratio parameter (d(N)/d(S)) suggested the action of positive selection on some antigenic sites of the FMDV capsid during some experimental passages. These antigenic sites showed an accumulation of convergent amino acid replacements during massive serial cytolytic passages and also in persistent infections of FMDV in cell culture. This accumulation was most significant at the antigenic site A (the G-H loop of capsid VP1), which includes an Arg-Gly-Asp (RGD) cellular recognition motif. Our analyses also identified a subregion of VP3, part of the fivefold axis of FMDV particles, that also appeared to be subjected to positive selection of amino acid replacements. From these results, we can conclude that under the restrictive conditions imposed either by the presence of the monoclonal antibodies, by the persistent infections, or by the competition processes established between different variants of the viral population, amino acid replacement in some capsid-coding regions can be positively selected toward an increase of those mutants with a higher capability to infect the cell.

Aphthovirus↗
PubMed2023

Exome-wide evidence of compound heterozygous effects across common phenotypes in the UK Biobank.

Exome-sequencing association studies have successfully linked rare protein-coding variation to risk of thousands of diseases. However, the relationship between rare deleterious compound heterozygous (CH) variation and their phenotypic impact has not been fully investigated. Here, we leverage advances in statistical phasing to accurately phase rare variants (MAF ~ 0.001%) in exome sequencing data from 175,587 UK Biobank (UKBB) participants, which we then systematically annotate to identify putatively deleterious CH coding variation. We show that 6.5% of individuals carry such damaging variants in the CH state, with 90% of variants occurring at MAF < 0.34%. Using a logistic mixed model framework, systematically accounting for relatedness, polygenic risk, nearby common variants, and rare variant burden, we investigate recessive effects in common complex diseases. We find six exome-wide significant () and 17 nominally significant () gene-trait associations. Among these, only four would have been identified without accounting for CH variation in the gene. We further incorporate age-at-diagnosis information from primary care electronic health records, to show that genetic phase influences lifetime risk of disease across 20 gene-trait combinations (FDR < 5%). Using a permutation approach, we find evidence for genetic phase contributing to disease susceptibility for a collection of gene-trait pairs, including FLG-asthma () and USH2A-visual impairment (). Taken together, we demonstrate the utility of phasing large-scale genetic sequencing cohorts for robust identification of the phenome-wide consequences of compound heterozygosity.

Preprint↗
PubMed1999

Sequence variants in the 5' flanking region of the leptin gene are associated with obesity in women.

Few mutations have been found in the human leptin gene and the relationship between leptin gene sequence variation and human overweight is uncertain. To determine whether sequence variation within the leptin gene and its regulatory elements contribute to extreme obesity, we screened approximately 3 kb of the 5' flanking region and the three exons in 125 unrelated extremely obese (BMI > or = 40 kg/m2) and 86 average weight women (BMI < 27 kg/m2). Within the protein coding regions only one heterozygous silent mutation was found (codon 102; AAC/AAT). Within the 5' flanking region, six frequent sequence variants were detected (q > 0.10), and the allele frequencies of three of these variants differed between obese and average weight Caucasian women (+19, chi 2 = 4.46, p = 0.035; -1823, chi 2 = 4.36, p = 0.037; -2548, chi 2 = 5.73, p = 0.017). Nine infrequent sequence variants were detected (q < 0.05) but they did not occur more often among obese women compared with those of average-weight. For extremely obese women, three polymorphisms (+19, -188, and -633) predicted the degree of obesity. Allelic variants may influence the regulation of the leptin gene and thereby influence body weight, particularly among extremely obese women. However, given the low variability in coding regions and the high variability in the 5' flanking region, discerning the functional significance of each variant is likely to be difficult.

Adolescent↗
PubMed2025

Genome topology analysis and transcriptomics of human osteoclasts reveals enhancer-promoter interactions at loci for bone traits and diseases.

Genome-wide association studies (GWAS) relevant to osteoporosis have identified hundreds of loci; however, understanding how these variants influence the phenotype is complicated because most reside in non-coding DNA sequence that serves as transcriptional enhancers and repressors. To advance knowledge on these regulatory elements in osteoclasts (OCs), we performed Micro-C analysis, which informs on the genome topology of these cells and integrated the results with transcriptome and GWAS data to further define loci linked to BMD. Using blood cells isolated from 4 healthy participants aged 31-61&#xa0;yr, we cultured OC in vitro and generated a Micro-C chromatin conformation capture dataset. We characterized chromatin loops (CLs) in OC from among more than 69 million chromatin interactions identified in the genome. Of the CL identified in OC, >16&#x2009;000 were unique compared to precursor cells. When sentinel single nucleotide polymorphisms from osteoporosis and bone-related GWAS and those in linkage disequilibrium at r 2&#x2009;>&#x2009;0.6 were mapped to CL for OC, 12&#x2009;588 of these variants were observed within chromatin contact regions. Notable in differential gene ontology enrichment analyses of the topology data for OC and precursors were pathways regulating pluripotency of stem cells, Wnt signaling, nucleotide-binding oligomerization domain (NOD)-like receptor signaling and chemokine signaling. These data, in combination with other 3D genome architecture and epigenetic data (eg, histone modifications and chromatin accessibility), will be useful in modeling to predict genome-wide, which enhancers regulate which genes in OC. This data will therefore also be informative for resolving GWAS hits. In conclusion, we have generated a high-resolution genome topology dataset for human OC and have used this to identify CLs relevant to studies of the genetics of osteoporosis. This data will serve as a powerful resource to inform future functional studies of OC biology.

BMD↗
PubMed1995

A new gene mapping resource: interspecies hybrids between Père David's deer (Elaphurus davidianus) and red deer (Cervus elaphus).

Three male F1 hybrids between Père David's deer and red deer were mated to red deer to produce 143 backcross calves. The pedigrees are a rare example of a fertile hybrid between evolutionarily divergent species. We examined the use of these families for genetic mapping of evolutionarily conserved (Type I) loci by testing for genetic linkage between five species-specific protein variants and 12 conserved DNA probes. Two probes were homologous, and the remainder syntenic, to the protein coding loci in cattle or humans. Using six restriction enzymes, each DNA probe detected one or more restriction fragments specific to Père David's deer. Linkage analyses among the species-specific variants placed the loci into four linkage groups within which linkage between adjacent loci and gene order was supported by a LOD > 3. The linkage groups were (HPX, HBB)-FSHB-ACP2, LDHA-CD5-IGF2, BMP3-(GC, ALB)-(KIT, PDGFRA) and LDLR-C3-FGF1. Southern and protein analysis of LDHA and ALB provided identical segregation data. These linkage groups were consistent with the cattle gene map and provide new information for comparing the gene maps of ruminants, humans and mice. The deer hybrids are an important new resource that can contribute to the comparative analysis of the mammalian genome.

Animals↗
PubMed1998

[Color-coded duplex ultrasound imaging of intimal fibromuscular dysplasia of the carotid artery].

Traditionally, intra-vitamin diagnosis of fibromuscular dysplasia (FMD) of brain supplying arteries is a domain of conventional selective angiography. We are aware of only two publications reporting of ultrasound displayed intimal and medial variants of carotid artery FMD, in one case each. We present a patient in whom color-coded duplex-sonography revealed a web-like carotid artery bulb stenosis meeting the specific criteria of a subtype of intimal FMD.

Brain↗
PubMed1984

Correct temperature induction and developmental regulation of a cloned heat shock gene transformed into the Drosophila germ line.

We have constructed a size variant of the Drosophila hsp28 gene by deleting 207 base pairs of the protein coding region, beginning 33 base pairs downstream of the ATG protein initiation codon. After transformation of Drosophila melanogaster rosy (ry506) flies with this altered gene, using the P transposable element system, it was found that the transformed gene was regulated correctly both after temperature elevation and during the development of the flies. Levels of the variant mRNA were as high as those of the endogenous hsp28 during all patterns of expression, and the variant mRNA appeared in all cases to be processed correctly and to be as stable as the endogenous mRNA. Nevertheless, the chromosomal locus of the transformed gene did not puff after heat shock, suggesting that normal transcription of the gene does not require puffing of the locus. The deleted hsp28 gene retained the reading frame of the endogenous one, and a protein of the expected molecular weight of 18,500 was made after heat shock at levels comparable to those of the endogenous hsp28.

Amino Acid Sequence↗
PubMed1997

Genomic structure, sequence, and mapping of human FGF8 with no evidence for its role in craniosynostosis/limb defect syndromes.

Fibroblast growth factor-8 (Fgf8) is a recently identified growth factor that stimulates the androgen-dependent growth of mouse mammary carcinoma cells. Evidence from mouse development also shows that Fgf8 may play an important role in growth and patterning of limbs, face, and the central nervous system. We describe here the human FGF8 genomic sequence and demonstrate conservation between the human and mouse sequences, including alternatively spliced exons in the mouse. Mapping of FGF8 by FISH using an FGF8-containing bacterial artificial chromosome and by genetic linkage using a SSCP variant identified in this study is also reported and refines the FGF8 map location to 10q24. Since FGF8 maps to the same chromosomal region as FGFR2, has indeed been shown to be a ligand for FGFR2, and has an expression pattern consistent with limb and craniofacial anomalies, we have screened two kindreds with Pfeiffer syndrome that were previously linked to markers from 10q24-25 and a large number of individuals with craniosynostosis and limb anomalies for mutations in the coding sequence of FGF8. While no such mutations were identified, a rare polymorphic variant, consisting of an 18-base-pair (six-amino-acid) duplication in exon 1c, is reported that apparently has no clinical effect. Our exclusionary data suggest that mutations in FGF8 would be, at best, an infrequent cause of such disorders.

Amino Acid Sequence↗
PubMed2005

PTPN22 genetic variation: evidence for multiple variants associated with rheumatoid arthritis.

The minor allele of the R620W missense single-nucleotide polymorphism (SNP) (rs2476601) in the hematopoietic-specific protein tyrosine phosphatase gene, PTPN22, has been associated with multiple autoimmune diseases, including rheumatoid arthritis (RA). These genetic data, combined with biochemical evidence that this SNP affects PTPN22 function, suggest that this phosphatase is a key regulator of autoimmunity. To determine whether other genetic variants in PTPN22 contribute to the development of RA, we sequenced the coding regions of this gene in 48 white North American patients with RA and identified 15 previously unreported SNPs, including 2 coding SNPs in the catalytic domain. We then genotyped 37 SNPs in or near PTPN22 in 475 patients with RA and 475 individually matched controls (sample set 1) and selected a subset of markers for replication in an additional 661 patients with RA and 1,322 individually matched controls (sample set 2). Analyses of these results predict 10 common (frequency >1%) PTPN22 haplotypes in white North Americans. The sole haplotype found to carry the previously identified W620 risk allele was strongly associated with disease in both sample sets, whereas another haplotype, identical at all other SNPs but carrying the R620 allele, showed no association. R620W, however, does not fully explain the association between PTPN22 and RA, since significant differences between cases and controls persisted in both sample sets after the haplotype data were stratified by R620W. Additional analyses identified two SNPs on a single common haplotype that are associated with RA independent of R620W, suggesting that R620W and at least one additional variant in the PTPN22 gene region influence RA susceptibility.

Arthritis, Rheumatoid↗
PubMed1995

Interferon-alpha 2 variants in the human genome.

Variants of human leukocyte interferon alpha 2 (IFN-alpha 2a, alpha 2b, and alpha 2c) differ from each other by changes in their coding regions at nucleotide positions 137 and 170. As a result of these nucleotide variations, the DNA sequences of the three variants can be distinguished by selective restriction enzyme analysis. Human genomic DNA obtained from over 28,000 normal healthy individuals was used as templates in the polymerase chain reaction (PCR) to amplify the human IFN-alpha 2 gene sequence. The resulting PCR products were analyzed with restriction nucleases to identify the specific IFN-alpha 2 variant sequences present in the genomic DNA of the population examined. The results show that IFN-alpha 2b was detected as the predominant species and IFN-alpha 2c as a very minor species (< 0.1%). The IFN-alpha 2a gene was not detected in this population.

Alleles↗