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PubMed2000

Rescue of mumps virus from cDNA.

A complete DNA copy of the genome of a Jeryl Lynn strain of mumps virus (15,384 nucleotides) was assembled from cDNA fragments such that an exact antigenome RNA could be generated following transcription by T7 RNA polymerase and cleavage by hepatitis delta virus ribozyme. The plasmid containing the genome sequence, together with support plasmids which express mumps virus NP, P, and L proteins under control of the T7 RNA polymerase promoter, were transfected into A549 cells previously infected with recombinant vaccinia virus (MVA-T7) that expressed T7 RNA polymerase. Rescue of infectious virus from the genome cDNA was demonstrated by amplification of mumps virus from transfected-cell cultures and by subsequent consensus sequencing of reverse transcription-PCR products generated from infected-cell RNA to verify the presence of specific nucleotide tags introduced into the genome cDNA clone. The only coding change (position 8502, A to G) in the cDNA clone relative to the consensus sequence of the Jeryl Lynn plaque isolate from which it was derived, resulting in a lysine-to-arginine substitution at amino acid 22 of the L protein, did not prevent rescue of mumps virus, even though an amino acid alignment for the L proteins of paramyxoviruses indicates that lysine is highly conserved at that position. This system may provide the basis of a safe and effective virus vector for the in vivo expression of immunologically and biologically active proteins, peptides, and RNAs.

Animals↗

PubMed2001

Frequent substitution polymorphisms in African green monkey CCR5 cluster at critical sites for infections by simian immunodeficiency virus SIVagm, implying ancient virus-host coevolution.

In contrast to humans, several primate species are believed to have harbored simian immunodeficiency viruses (SIVs) since ancient times. In particular, the geographically dispersed species of African green monkeys (AGMs) are all infected with highly diversified SIVagm viruses at high prevalences (greater than 50% of sexually mature individuals) without evident diseases, implying that the progenitor monkeys were infected prior to their dispersal. If this is correct, AGMs would be expected to have accumulated frequent resistance-conferring polymorphisms in host genes that are important for SIV replication. Accordingly, we analyzed the coding sequences of the CCR5 coreceptors from 26 AGMs (52 alleles) in distinct populations of the four species. These samples contained 29 nonsynonymous coding changes and only 15 synonymous nucleotide substitutions, implying intense functional selection. Moreover, 24 of the resulting amino acid substitutions were tightly clustered in the CCR5 amino terminus (D13N in the vervets and Y14N in the tantalus species) or in the first extracellular loop (Q93R and Q93K in all species). The Y14N substitution was extremely frequent in the 12 wild-born African tantalus, with 7 monkeys being homozygous for this substitution and 4 being heterozygous. Although two of these heterozygotes and the only wild-type homozygote were naturally infected with SIVagm, none of the Y14N homozygotes were naturally infected. A focal infectivity assay for SIVagm indicated that all five tested SIVagms efficiently use CCR5 as a coreceptor and that they also use CXCR6 (STRL33/Bonzo) and GPR15 (BOB) with lower efficiencies but not CXCR4. Interestingly, the D13N, Y14N, Q93R, and Q93K substitutions in AGM CCR5 all strongly inhibited infections by the SIVagm isolates in vitro. The Y14N substitution eliminates a tyrosine sulfation site that is important for infections and results in partial N-linked glycosylation (i.e., 60% efficiency) at this position. Nevertheless, the CCR5(Y14N) component that lacks an N-linked oligosaccharide binds the chemokine MIP-lbeta with a normal affinity and is fully active in signal transduction. Similarly, D13N and Q93R substitutions did not interfere with signal transduction. Thus, the common substitution polymorphisms in AGM CCR5 strongly inhibit SIVagm infections while substantially preserving chemokine signaling. In contrast, polymorphisms of human CCR5 are relatively infrequent, and the amino acid substitutions are randomly situated and generally without effects on coreceptor function. These results support an ancient coevolution of AGMs and SIVagm viruses and establish AGMs as a highly informative model for learning about host proteins that play critical roles in immunodeficiency virus infections.

Amino Acid Sequence↗

PubMed2004

Enterovirus capsid interactions with decay-accelerating factor mediate lytic cell infection.

The cellular receptor usage of numerous human enteroviruses can differ significantly between low-cell-culture-passaged clinical isolates and highly laboratory-passaged prototype strains. The prototype strain of coxsackievirus A21 (CVA21) displays a dual-receptor specificity as determined with a receptor complex consisting of decay-accelerating factor (DAF) and intercellular adhesion molecule 1 (ICAM-1). In this study, the cellular receptor interactions of low-cell-passage CVA21 clinical isolates with respect to their interactions with cell surface-expressed DAF and ICAM-1 were compared to those of the CVA21 prototype (Kuykendall) strain. Dual-receptor usage of DAF and ICAM-1 by CVA21 clinical isolates was confirmed by cell transfection and radiolabeled binding assays. The cellular attachment of clinical and prototype CVA21 strains to cells that coexpressed DAF and ICAM-1 was not additive compared to the viral binding to cells expressing one or other receptor. In fact, the binding data suggest there is an inhibition of CVA21 cellular attachment in environments where high-level coexpression of both DAF and ICAM-1 occurs. Antibody cross-linking of DAF rendered cells susceptible to lytic infection by the CVA21 clinical isolates. In a novel finding, three clinical isolates could, to various degrees, infect and lyse DAF-expressing cells in the absence of DAF-antibody cross-linking and ICAM-1 expression. Sequence analysis of the P1 region of clinical and prototype virus genomes identified a number of coding changes that may contribute to the observed enhanced DAF usage phenotype of the clinical CVA21 isolates. None of the amino acid changes was located in the previously postulated ICAM-1 footprint, a receptor-binding environment that was conserved on the capsid surface of all CVA21 clinical isolates. Taken together, the data suggest that community-circulating strains of CVA21 can infect target cells expressing either ICAM-1 or DAF alone and that such interactions extend tissue tropism and impact directly on viral pathogenesis.

Adult↗

PubMed2001

Rhodopsin mutations in Chinese patients with retinitis pigmentosa.

AIM: To determine the pattern of rhodopsin mutations in Chinese retinitis pigmentosa (RP) patients. METHODS: The rhodopsin gene was examined in 101 RP patients and 190 controls from Hong Kong. RESULTS: Three coding changes were identified: Pro347Leu, Ala299Ser, and 5211delC. Each protein sequence alteration was found in one patient. Ala299Ser also existed in two controls. CONCLUSION: The C-terminal nonsense mutation may cause mis-sorting of rhodopsin protein. The finding of controls with Ala299Ser suggests this is only the third missense alteration reported that does not cause RP. The expected frequency of rhodopsin mutations in RP is <7% (2/101=2.0%, 95% confidence interval: 0.2%-7.0%).

Adult↗

PubMedDate not supplied

A comparison of trends in mortality from stroke in the United States and Rochester, Minnesota.

More uniform methods of diagnosis and determination of the cause of death result in greater reliability of trends in mortality from stroke. In all categories of stroke except subarachnoid hemorrhage, the mortality rates in Rochester, Minnesota, are lower and show a more rapid decline with time than in the United States as a whole. The differential between the rates for United States white population and the Rochester population is most evident in the older age groups. This difference may be due to the effects of revisions in the International Classification of Disease and/or to the assignment of nonstroke deaths to stroke causes in the United States as a whole to a greater extent than in Rochester. Whether different patterns of medical care affect the trends in stroke mortality has not been determined. The trends in mortality from various categories of stroke in Rochester are reliable because some of the inconsistencies of diagnosis, assignment of cause of death, and coding changes have been overcome. The decline in mortality rates for Rochester corresponds well with decreasing incidence rates and lack of change in case fatality rates previously reported.

Aged↗

PubMed1992

Restricted use of fetal VH3 immunoglobulin genes by unselected B cells in the adult. Predominance of 56p1-like VH genes in common variable immunodeficiency.

The large VH3 family of human immunoglobulin genes is commonly used throughout B cell ontogeny. However, B cells of the fetus and certain autoantibody-producing clones are restricted to a recurrent subset of VH3 genes, and VH3 B cells are deficient in certain immunodeficiency diseases. In this study, we have sequenced a set of rearranged VH3 genes generated by genomic polymerase chain reaction (PCR) from normal adults and those with common variable immunodeficiency (CVI). In both groups, all cones were readily identifiable with the fetal VH3 subset, and were further distinguished by limited DH motifs and exclusive use of JH4. In CVI, the residual population of VH3 B cells were notable for predominant use of 56p1-like VH genes. All clones displayed sequence divergence (including somatic mutation) with evidence of strong selection against complementarity-determining region (CDR) coding change. A survey of other V gene families indicates that human V gene diversity may be restricted in general by germline mechanisms. These findings suggest that the expressed antibody repertoire in the human adult may be much smaller than anticipated, and selected by processes in part distinct from the paradigm of maximal antigen-binding diversity.

Antibody Diversity↗

PubMed2003

The rat STSL locus: characterization, chromosomal assignment, and genetic variations in sitosterolemic hypertensive rats.

BACKGROUND: Elevated plant sterol accumulation has been reported in the spontaneously hypertensive rat (SHR), the stroke-prone spontaneously hypertensive rat (SHRSP) and the Wistar-Kyoto (WKY) rat. Additionally, a blood pressure quantitative trait locus (QTL) has been mapped to rat chromosome 6 in a New Zealand genetically hypertensive rat strain (GH rat). ABCG5 and ABCG8 (encoding sterolin-1 and sterolin-2 respectively) have been shown to be responsible for causing sitosterolemia in humans. These genes are organized in a head-to-head configuration at the STSL locus on human chromosome 2p21. METHODS: To investigate whether mutations in Abcg5 or Abcg8 exist in SHR, SHRSP, WKY and GH rats, we initiated a systematic search for the genetic variation in coding and non-coding region of Abcg5 and Abcg8 genes in these strains. We isolated the rat cDNAs for these genes and characterized the genomic structure and tissue expression patterns, using standard molecular biology techniques and FISH for chromosomal assignments. RESULTS: Both rat Abcg5 and Abcg8 genes map to chromosome band 6q12. These genes span ~40 kb and contain 13 exons and 12 introns each, in a pattern identical to that of the STSL loci in mouse and man. Both Abcg5 and Abcg8 were expressed only in liver and intestine. Analyses of DNA from SHR, SHRSP, GH, WKY, Wistar, Wistar King A (WKA) and Brown Norway (BN) rat strains revealed a homozygous G to T substitution at nucleotide 1754, resulting in the coding change Gly583Cys in sterolin-1 only in rats that are both sitosterolemic and hypertensive (SHR, SHRSP and WKY). CONCLUSIONS: The rat STSL locus maps to chromosome 6q12. A non-synonymous mutation in Abcg5, Gly583Cys, results in sitosterolemia in rat strains that are also hypertensive (WKY, SHR and SHRSP). Those rat strains that are hypertensive, but not sitosterolemic (e.g. GH rat) do not have mutations in Abcg5 or Abcg8. This mutation allows for expression and apparent apical targeting of Abcg5 protein in the intestine. These rat strains may therefore allow us to study the pathophysiological mechanisms involved in the human disease of sitosterolemia.

Animals↗

PubMed1990

Exon 7 Ncol restriction site within CYP21B (steroid 21-hydroxylase) is a normal polymorphism.

A point mutation within exon 7 producing an amino acid coding change and a recognition site for the endonuclease Ncol has been reported in the HLA-Bw47-linked CYP21A pseudogene and some mutant CYP21B (steroid 21-hydroxylase) genes of patients with congenital adrenal hyperplasia (CAH). Whether this mutation is deleterious was not demonstrated. We analyzed DNA from various subjects for the presence of the exon 7 Ncol site: group 1, 10 normal subjects; group 2, 11 patients with salt-losing CAH; and group 3, 18 members of an Amish pedigree in which 10 expressed HLA-Bw47 not linked to CAH. Southern blots of Ncol-digested genomic DNA which were hybridized with CYP21 cDNA showed that four subjects of group 1 had a heterozygous Ncol pattern. In group 2, seven patients had the Ncol site; two of them were homozygous for the site and had deletions of both CYP21B genes. The other five were heterozygous for the Ncol site, which was linked to a CYP21B deletion and a HLA-Bw47 haplotype. In group 3, no one exhibited the exon 7 Ncol site. To map the Ncol sites to CYP21A or CYP21B in the normal subjects, DNA from the four Ncol heterozygous subjects was double digested with Ncol and Mbol and hybridized with CYP21 cDNA. Ncol-Mbol fragments unique to CYP21A were identified in all four, but the smaller CYP21B-specific fragments were not detected. Their genomic DNA in the region of exon 7 (bases +1167 to +2058) was then amplified, cloned, and sequenced.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Hyperplasia, Congenital↗

PubMed2025

Prioritization of causal genes from genome-wide association studies by Bayesian data integration across loci.

MOTIVATION: Genome-wide association studies (GWAS) have identified genetic variants, usually single-nucleotide polymorphisms (SNPs), associated with human traits, including disease and disease risk. These variants (or causal variants in linkage disequilibrium with them) usually affect the regulation or function of a nearby gene. A GWAS locus can span many genes, however, and prioritizing which gene or genes in a locus are most likely to be causal remains a challenge. Better prioritization and prediction of causal genes could reveal disease mechanisms and suggest interventions. RESULTS: We describe a new Bayesian method, termed SigNet for significance networks, that combines information both within and across loci to identify the most likely causal gene at each locus. The SigNet method builds on existing methods that focus on individual loci with evidence from gene distance and expression quantitative trait loci (eQTL) by sharing information across loci using protein-protein and gene regulatory interaction network data. In an application to cardiac electrophysiology with 226 GWAS loci, only 46 (20%) have within-locus evidence from Mendelian genes, protein-coding changes, or colocalization with eQTL signals. At the remaining 180 loci lacking functional information, SigNet selects 56 genes other than the minimum distance gene, equal to 31% of the information-poor loci and 25% of the GWAS loci overall. Assessment by pathway enrichment demonstrates improved performance by SigNet. Review of individual loci shows literature evidence for genes selected by SigNet, including PMP22 as a novel causal gene candidate.

Genome-Wide Association Study↗

PubMed2026

Codon bias variation in Staphylococcus aureus.

BACKGROUND: Staphylococcus aureus causes a multiplicity of human diseases acquired in community and healthcare settings alike around the globe. While most studies focus on coding changes to assess genome evolution and study genetic adaptation, interrogation of silent mutations in the form of synonymous codon usage bias is less well-studied. As such, understanding of patterns in codon bias at the gene and genome levels, and how codon bias impacts protein expression in S. aureus remains incomplete. METHODS: The codon bias of 2,565 protein encoding genes from NCTC 8325 was queried against all publicly available closed S. aureus genomes. Using public BioSample data, genomes were sorted by disease state, submitting institution, and collection site. Codon bias was assessed at the level of gene and genome using the codon adaptation index (CAI), calculated using 30S and 50S ribosomal genes. Gene set enrichment analysis was applied to determine associations between physiological functions, CAI gene scores, and interquartile ranges. CAI scores were also compared to an in vitro S. aureus proteomics database to correlate codon bias and protein expression. RESULTS: CAI scores varied within and between isolates at the gene and genome levels. Genes with ribosome-associated functions were most enriched among high CAI genes, and had low CAI interquartile ranges (IQR), suggesting selective pressure to maintain high expression of these genes across all S. aureus isolates. Genome sequences submitted by Aga Khan University Hospital, Nairobi, Kenya were most different from others. For the LAC USA 300 strain, CAI and protein expression were moderately positively correlated (cor = 0.534, p < 2.2e-16). CONCLUSIONS: Codon bias in S. aureus was shown to vary between gene, and to be a source of genetic variation between isolates; CAI and in vitro protein expression were positively correlated.

Staphylococcus aureus↗

PubMed2001

American Academy of Pediatrics: Falls from heights: windows, roofs, and balconies.

Falls of all kinds represent an important cause of child injury and death. In the United States, approximately 140 deaths from falls occur annually in children younger than 15 years. Three million children require emergency department care for fall-related injuries. This policy statement examines the epidemiology of falls from heights and recommends preventive strategies for pediatricians and other child health care professionals. Such strategies involve parent counseling, community programs, building code changes, legislation, and environmental modification, such as the installation of window guards and balcony railings.

Accidental Falls↗

PubMed1986

On the consistency of the MMPI in borderline personality disorder.

14 patients diagnosed as having Borderline Personality Disorder were examined on two separate occasions with the MMPI. Results strongly suggest that, as a group, borderline patients are quite consistent responders on the MMPI under test-retest conditions (1 to 58 mo.). The frequency distribution of scale elevations and code types was also examined which showed the often-noted heterogeneity of profile code types within this population. Thus, a note of caution is advised for those investigators who assume that a prototypical borderline MMPI profile exists. Specifically, considerable heterogeneity is seen among this sample of patients with respect to a two-point coding strategy, and individual codes change over time.

Adult↗

PubMed1987

Kepiński's information metabolism, Carnot's principle and information theory.

The generalized Carnot principle introduced by Brillouin provides a link between negentropy and information, but does not take into account the information stored in the brain, which is clearly excluded by the author. Further step in the generalization of Carnot's principle, which includes information turnover in the brain was accomplished by Kepiński in his theory of the metabolism of energy and information. According to Schrödinger, life processes require a supply of negentropy rather than energy stored in the food, more precisely, e.g., in glucose utilized by the brain, since energy is conserved, whereas negentropy is dissipated. The information (communication) channel transmits maximum information when the band width of the transmitted frequency is limited, and much less information when the restriction concerns the transmitted power, or energy. This can explain a considerable decrease in the information metabolism observed in depressive patients, whose life dynamics and, consequently, the amount of energy available for information metabolism is severly lowered. Thus, the fall in information metabolism is more pronounced in depression than in not too late phases of schizophrenia. As appears from Fonberg's studies the amygdaloid nucleus is responsible for the life dynamics. In different types of neuron code change is a significant parameter, which was so strongly stressed by Kepiński. Other problems discussed in the paper include: selection of information and its structural localization, localization of particular phases of information metabolism and their phylogenetic significance.

Brain↗

PubMed1988

Genetic variation among geographic isolates of Rift Valley fever virus.

The genetic variation of Rift Valley fever virus (RVFV) was estimated by sequencing a portion of the M segment RNA of 22 isolates from a variety of host species collected over 34 years in 6 African countries. The M segment RNA of the Egyptian isolate, ZH501, which has been molecularly cloned and sequenced, was used as a reference for these comparisons. Specific gene regions, responsible for antigenic determinants presumed to play a role in protection against disease, were emphasized in these investigations. Comparative sequence data revealed that most isolates were very similar to ZH501 at both the nucleic acid and deduced amino acid sequence levels. Nucleic acid sequence variation range was 0-4.5%. Amino acid sequence variation range was 0-2.4%. We identified specific amino acid coding changes which may be involved in virus neutralization and may contribute to the virulence characteristics of RVFV.

Amino Acid Sequence↗

PubMed1995

Characterization of clone 13, a naturally attenuated avirulent isolate of Rift Valley fever virus, which is altered in the small segment.

The 74HB59 strain of Rift Valley fever (RVF) virus, isolated from a human case in the Central African Republic, was shown to be composed of a heterogeneous population of viruses when plaque-purified clones were analyzed for their reactivity with monoclonal antibodies (MAbs) directed against the nucleocapsid (N) protein or the nonstructural (NSs) protein. One of these clones, C13, was of particular interest in that it proved to be avirulent in mice and hamsters, and highly immunogenic. Although C13 showed normal reactivity with a large panel of MAbs directed at the glycoproteins, it failed to react with specific MAbs or polyclonal antibodies directed at the NSs protein and with a specific MAb recognizing the N protein of the Egyptian strains. Consequently, the small RNA segment, which encodes the N and NSs proteins in an ambisense strategy, was sequenced and compared with the existing sequence of the attenuated MP-12 RVF virus strain. We found that the NSs gene contained, in addition to two conservative coding changes, a large internal deletion of 549 nucleotides that removes 69% of the open reading frame but conserves in-frame the N and C termini of the predicted translation product. In addition, the sequence revealed that the N protein of C13 contained a single amino acid change. Clone C13 replicated normally in certain cell types in vitro and in Culex pipiens mosquitoes after intrathoracic inoculation, but established abortive infections in MRC-5 human fibroblasts.

Animals↗

PubMed2001

[Host genetic epidemiology by single nucleotide polymorphism(SNP) analysis].

The completion of the whole human genome sequences is now a reality. Emphasis on the analysis of genetic variations on both an individual level and a population level is more important than ever. The identification and characterization of single nucleotide polymorphisms (SNPs) in target genes or candidate genes plays a crucial role in identification of disease genes and in expediting drug discovery/development. Identification of known SNPs can be easily accomplished by searching the ever-expanding public domain databases. However, discovery of new SNPs is best accomplished by sequencing a reasonable subset of the applicable population groups. Particular SNPs of interest will be the ones that affect coding changes and regulatory functions of genes. Once SNPs have been identified, the next step is to examine their frequency in disease models by accurate, cost-effective and high-throughput SNP genotyping methods. This presentation will cover the overview of principal techniques of SNP genotyping which have been developed so far. And also will be discussed the importance of well-defined disease model and error-free high-throughput SNP genotyping in candidate genes and genome-wide SNP screening in the near future.

Alleles↗

PubMed2001

Identification of variants of CYP3A4 and characterization of their abilities to metabolize testosterone and chlorpyrifos.

CYP3A4 is the most abundant isoform of cytochrome P450 (CYP) in adult human liver. It metabolizes numerous clinically, physiologically, and toxicologically important compounds. The expression of CYP3A4 varies 40-fold in individual human livers, and metabolism of CYP3A4 substrates varies at least 10-fold in vivo. Single nucleotide polymorphisms (SNPs) in CYP3A4 were identified by direct sequencing of genomic DNA in 72 individuals from three different ethnic groups, including Caucasians, Blacks (African-Americans and African pygmies), and Asians. A total of 28 SNPs were identified, including five which produced coding changes M445T (CYP3A4*3), R162Q (CYP3A4*15), F189S (CYP3A4*17), L293P (CYP3A4*18), and P467S (CYP3A4*19). The latter four represent new alleic variants. Racial variability was observed for the frequency of individual SNPs. CYP3A R162Q was identified only in Black populations with an allelic frequency of 4%. CYP3A4 F189S and CYP3A4 M445T were identified in Caucasians with allelic frequencies 2% and 4%, respectively. L293P and P467S were only observed in Asians at allelic frequencies of 2%. The cDNAs for the F189S, L293P, M445T, and P467S mutant alleles were constructed by site-directed mutagenesis and expressed in an Escherichia coli expression system. Testosterone and the insecticide chlorpyrifos were used to assess the catalytic activities of the most common CYP3A4 allele (CYP3A4*1) and its allelic variants. CYP3A4 F189S exhibited lower turnover numbers for testosterone and chlorpyrifos, while CYP3A4 L293P had higher turnover numbers for both substrates. The turnover numbers of the CYP3A4 M445T and P467S alleles to metabolize these compounds were not significantly different from those of wild-type CYP3A4.

Alleles↗

PubMed1990

Molecular genetics of the glucose-6-phosphate dehydrogenase (G6PD) Mediterranean variant and description of a new G6PD mutant, G6PD Andalus1361A.

Glucose-6-phosphate dehydrogenase (G6PD; E.C.1.1.1.49) deficiency is the most common human enzymopathy; more than 300 different biochemical variants of the enzyme have been described. In many parts of the world the Mediterranean type of G6PD deficiency is prevalent. However, G6PD Mediterranean has come to be regarded as a generic term applied to similar G6PD mutations thought, however, to represent a somewhat heterogeneous group. A C----T mutation at nucleotide 563 of G6PD Mediterranean has been identified by Vulliamy et al., and the same mutation has been found by De Vita et al. in G6PD Mediterranean, G6PD Sassari, and G6PD Cagliari. The latter subjects had an additional mutation, at nucleotide 1311, that did not produce a coding change. We have examined genomic DNA of five patients--four of Spanish origin and one of Jewish origin--having enzymatically documented G6PD Mediterranean. All had both the mutation at nucleotide 563 and that at nucleotide 1311. A sixth sample, resembling G6PD Mediterranean kinetically but with a slightly rapid electrophoretic mobility, was designated G6PD Andalus and was found to have a different mutation, a G----A transition at nucleotide 1361, producing an arginine-to-histidine substitution. These studies suggest that G6PD Mediterranean is, after all, relatively homogeneous.

Base Sequence↗