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PubMed1991

Two types of abnormal genes for plasminogen in families with a predisposition for thrombosis.

The gene coding for plasminogen has been compared with several abnormal genes from Japanese patients by the polymerase chain reaction and DNA sequence analysis. Two types of abnormal genes coding for plasminogen were identified in these patients. In the type I mutation, a guanosine in GCT coding for Ala-601 near the active-site histidine was replaced by an adenosine resulting in ACT coding for threonine. This mutation was also shown by the loss of a cleavage site for Fnu4HI endonuclease, a restriction enzyme that recognizes GCTGC but not ACTGC. In the type II mutation, a guanosine in GTC coding for Val-355 was replaced by a thymidine resulting in TTC coding for phenylalanine. This change was readily shown by digestion with Ava II endonuclease, a restriction enzyme that recognizes GGTCC and not GTTCC. The type I mutation has been found to be identical to a plasminogen variant identified in Japanese patients by amino acid sequence analysis and also detected by isoelectric focusing, whereas the type II mutation is a unique amino acid substitution in the connecting region between the third and fourth kringles in plasminogen. DNA sequence analysis also revealed that the abnormal genes carry several silent nucleotide substitutions located primarily within introns and 5' and 3' flanking regions.

Base Sequence↗

PubMed1991

Anti-Müllerian hormone Bruxelles: a nonsense mutation associated with the persistent Müllerian duct syndrome.

The persistent Müllerian duct syndrome (PMDS) is characterized by the persistence of Müllerian derivatives, uterus and tubes, in otherwise normally virilized males. In a previous study, we showed that this syndrome is heterogeneous, with lack of production of anti-Müllerian hormone (AMH) by testicular tissue accounting for only some, AMH-negative, cases of this disorder. We have characterized the point mutation responsible for an AMH-negative PMDS in three siblings: a guanine to thymine transversion at position 2096 in the fifth exon changes a GAA triplet, coding for glutamic acid, to a TAA stop codon. The mutation could also be recognized, using the polymerase chain reaction, on RNA produced in trace amounts by a lymphoblastic cell line. The translation product, although undetectable in testicular tissue, could be visualized in culture medium of cells transfected with the mutant gene.

Anti-Mullerian Hormone↗

PubMed1993

Identification of two missense mutations in a dihydrolipoamide dehydrogenase-deficient patient.

The molecular basis of dihydrolipoamide dehydrogenase (E3; dihydrolipoamide:NAD+ oxidoreductase, EC 1.8.1.4) deficiency in an E3-deficient patient was studied. Fibroblasts cultured from the patient contained only approximately 6% of the E3 activity of cells from a normal subject. Western and Northern blot analyses indicated that, compared to control cells, the patient's cells had a reduced amount of protein but normal amounts of E3 mRNA. Direct sequencing of E3 cDNA derived from the patient's RNA as well as each of the subclones of the cDNA revealed that the patient had two substitution mutations in the E3 coding region. One mutation changed a single nucleotide from A to G, resulting in substitution of Glu (GAA) for Lys-37 (AAA). The other point mutation was a nucleotide change from C to T, resulting in the substitution of Leu (CTG) for Pro-453 (CCG). These mutations appear to be significant in that they alter the active site and possibly the binding of FAD.

Amino Acid Sequence↗

PubMed2000

Quantification of homoplasy for nucleotide transitions and transversions and a reexamination of assumptions in weighted phylogenetic analysis.

Nucleotide transitions are frequently down-weighted relative to transversions in phylogenetic analysis. This is based on the assumption that transitions, by virtue of their greater evolutionary rate, exhibit relatively more homoplasy and are therefore less reliable phylogenetic characters. Relative amounts of homoplastic and consistent transition and transversion changes in mitochondrial protein coding genes were determined from character-state reconstructions on a highly corroborated phylogeny of mammals. We found that although homoplasy was related to evolutionary rates and was greater for transitions, the absolute number of consistent transitions greatly exceeded the number of consistent transversions. Consequently, transitions provided substantially more useful phylogenetic information than transversions. These results suggest that down-weighting transitions may be unwarranted in many cases. This conclusion was supported by the fact that a range of transition: transversion weighting schemes applied to various mitochondrial genes and genomic partitions rarely provided improvement in phylogenetic estimates relative to equal weighting, and in some cases weighting transitions more heavily than transversions was most effective.

Base Sequence↗

PubMed2000

Arrayed primer extension: solid-phase four-color DNA resequencing and mutation detection technology.

The technology and application of arrayed primer extension (APEX) is presented. We describe an integrated system with DNA chip and template preparation, multiplex primer extension on the array, fluorescence imaging, and data analysis. The method is based upon an array of oligonucleotides, immobilized via the 5' end on a glass surface. A patient DNA is amplified by PCR, digested enzymatically, and annealed to the immobilized primers, which promote sites for template-dependent DNA polymerase extension reactions using four unique fluorescently labeled dideoxy nucleotides. A mutation is detected by a change in the color code of the primer sites. The technology was applied to the analysis of 10 common beta-thalassemia mutations. Nine patient DNA samples, each of which carries a different mutation, and four wild-type DNA samples were correctly identified. The signal-to-noise ratio of this technology is, on the average, 40:1, which enables the identification of heterozygous mutations with a high confidence level. The APEX method can be applied to any DNA target for efficient analysis of mutations and polymorphisms.

DNA↗

PubMed1984

Characterization of three chicken pseudogenes for U1 RNA.

Three chicken genomic DNA clones containing the U1 RNA sequence were isolated from a chicken gene library and characterized. Two of these clones, CL64 and CL111, are overlapping clones which show several single-nucleotide changes in the U1 coding sequence, suggesting that they probably are alleles of the same sequence. The U1 sequence in the third clone, CL40, is more divergent. Flanking regions of these genes do not share any sequence homology between each other or with the previously isolated chicken genomic clone CL59. A short repeat CGGGG appears 28 times upstream of the U1 sequence in CL59. Another repeat, GCACC, is repeated 14 times upstream of the U1 region in CL40.

Animals↗

PubMed2005

West Nile virus in host-seeking mosquitoes within a residential neighborhood in Grand Forks, North Dakota.

West Nile virus (WNV) was first recovered in North Dakota near the city of Grand Forks in June 2002. During 2002, 2003, and 2004, we collected mosquitoes from Grand Forks using Mosquito Magnet traps and tested them for WNV. The seasonal abundance, species composition, and reproductive status of female mosquitoes were correlated with local environmental temperature and state surveillance data on WNV to determine the factors affecting local transmission of WNV. Over 90% of the mosquitoes collected were Aedes vexans, Ochlerotatus dorsalis, and Culex tarsalis, but WNV was detected only in Cx. tarsalis. Average summertime temperatures and relative abundance of mosquitoes were highest in 2002 but no WNV-positive mosquitoes were detected until the following summer. In 2003, nulliparous Cx. tarsalis appeared in mid-June (first summer brood), and parous Cx. tarsalis appeared in mid-July. The first WNV-positive pool occurred 21 July, and minimum daily infections rates increased thereafter until 27 August. The minimum infection rate (MIR) for Cx. tarsalis during the season was 5.7 infected mosquitoes per 1,000 tested, with the highest infection rates occurring at the end of the season as Cx. tarsalis populations started to decline. Mid-to-late August was identified as the period of highest risk for being bitten by a WNV-infected mosquito in Grand Forks during 2003. In 2004, viral activity in Grand Forks was low, due to very cool temperatures throughout the summer. To examine the genetic diversity of the 2003 WNV isolates from Grand Forks, we sequenced a 366-nucleotide region of the capsid and premembrane gene. Thirteen (46%) of the 28 WNV isolates contained at least one nucleotide substitution when compared to the homologous region of the progenitor WN NY-99 strain, and seven of these 13 substitutions coded for amino acid changes. Thus, WNV is established in North Dakota, it appears to be evolving and it is vectored primarily by Cx. tarsalis.

Aedes↗

PubMed2006

Birthweight and coronary heart disease in a cohort born 1857-1900 in Melbourne, Australia.

BACKGROUND: The widely observed association between birth size and risk of later coronary heart disease (CHD) has not been examined in an impoverished pre-20th century birth cohort. METHODS: Birth weights and maternal characteristics, for births between 1857 and 1900 in a charity hospital, were recorded from preserved ledgers. Names were linked to death certificates to determine age and cause of death. Death with CHD was coded using specific criteria, and survival analysis methods were used to relate risk of CHD to birth weight, allowing for competing causes of death and adjusting for potentially confounding maternal factors. RESULTS: Death certificates were traced for 8,584 (53%) of 16,272 registered live-births. Survival analyses were confined to 2,938 subjects (1,572 male, 1,366 female) who survived beyond age 40, since none of the 486 CHD cases was recorded earlier. CHD risk increased with time, but there was no evidence that it was related to birth weight, in men or women. CONCLUSIONS: We did not replicate findings in more recent cohorts. This may represent a true lack of association in a historical cohort who we believe remained impoverished through their early life. However, we acknowledge the strong possibility of misclassification of cause of death by the person filling in the death certificate and/or our coding criteria, and temporal change in diagnostic criteria for CHD. We cannot exclude the possibility that low birth weight babies 'programmed' in utero for later CHD were more likely to die in infancy, in this cohort with a high infant mortality rate.

Aged↗

PubMed2001

Trends in incidence of primary brain tumors in the United States, 1985-1994.

Brain tumor incidence has increased over the last 20 years in all age groups, both overall and for specific histologies. Reasons attributed to these increases include increase in lymphoma due to HIV/AIDS, introduction of computed tomography/magnetic resonance imaging, and changes in coding/classification. The purpose of this study was to describe overall and histologic-specific incidence trends in a population-based series of primary benign and malignant brain tumors. Data from the Central Brain Tumor Registry of the United States from 1985 through 1994 were used to determine incidence trends in the broad age groups 0-19, 20-64, and > or = 65 years, both overall and for selected histologies. Poisson regression was used to express trends as average annual percentage change. Overall, incidence increased modestly (annual percentage change 0.9%, 95% confidence interval, 0.4, 1.4). When lymphomas were excluded, this result was not statistically significant (annual percentage change 0.5%, 95% confidence interval, -0.1, 1.1). Specific histologies that were increasing were lymphomas in individuals aged 20 to 64 years and in males aged 65 years or older, ependymomas in the population aged 20 to 64 years, nerve sheath tumors in males, and pituitary tumors in females. Increases that were not specific to any population subgroup were seen for glioblastoma, oligodendrogliomas, and astrocytomas, excluding not otherwise specified (NOS) tumors. Corresponding decreases were noted for NOS, astrocytoma NOS, and glioma NOS. Increasing incidence trends for lymphomas were consistent with previous literature. Improvements in diagnostic technology in addition to changes in classification and coding were likely to be responsible for decreases seen in incidence of NOS subgroups and corresponding increases in glioma subgroups. In contrast, the increases identified for ependymomas, nerve sheath tumors, and pituitary tumors were less likely to be artifacts of improvements in diagnosis, and they warrant further study.

Adolescent↗

PubMed1991

Rates of DNA change and phylogeny from the DNA sequences of the alcohol dehydrogenase gene for five closely related species of Hawaiian Drosophila.

The sequence of 1.6 kb of DNA surrounding the alcohol dehydrogenase (Adh) gene from five species of the Planitibia subgroup of the Hawaiian picture-winged Drosophila, with estimated divergence times of 0.4-5.1 Myr, has been determined. The gene trees which were found by using the sequence divergence from different regions of the sequences are generally in accord with the phylogeny proposed for these species when chromosomal inversions and island of origin are used. One of the species (D. picticornis) appears to be more distant from the other species in this group than they are from a member of the Grimshawi group (D. affinidisjuncta) which is chromosomally more distant. Two of the species (D. differens and D. plantibia) show heterogeneity in the nucleotide changes in the Adh coding region, heterogeneity which is interpreted to be due to a gene conversion or recombination after hybridization between the two species. The minimal rate of nucleotide substitution of synonymous nucleotides and of nontranscribed nucleotides downstream from the coding region is estimated as 1.5 x 10(-8) and 1.1 x 10(-8) substitutions/nucleotide/year, respectively. This rate is two to three times the maximal rate estimated for mammalian synonymous substitutions.

Alcohol Dehydrogenase↗

PubMed1988

View from the Nation's Capital.

After several years of intensive debate and drafting, Congress has newly enacted legislation that will substantially change the traditional system by which drugs are distributed to physicians. While Congress acted with some specific and well-defined abuses before it, it had little empirical data that these changes would or could be effective to deal with the abuses. In the past, when Congress has enacted comprehensive legislation (changes in the Tax Code are a recent example), it has generally had to pass correcting legislation in the next session. It remains to be seen whether this Act will work without substantial corrections, particularly given the widespread disfavor it has met in the drug industry. Hopefully, it is the questionable drug practices that will be ended, rather than simply the convenient access physicians have long had both to established and newly approved drug products. An unfortunate but likely side effect of the Act is that data will be generated in the field if physicians can no longer easily receive free samples for distribution to patients without cost and for subsequent monitoring of drug safety and efficacy.

Drug Industry↗

PubMed1991

Comparison of the nucleotide sequence of the SH gene and flanking regions of mumps vaccine virus (Urabe strain) grown on different substrates and isolated from vaccinees.

The small hydrophobic (SH) protein gene and flanking regions of the Urabe Am9 vaccine strain of mumps virus were amplified by the polymerase chain reaction and sequenced directly by the dideoxynucleotide chain termination method. The 434 bp sequence was identical for the Urabe strain isolated from vaccines produced by three manufacturers and for virus isolated following post-vaccination parotitis. No changes were detected for coding, non-coding or intergenic regions between virus grown on different substrates. The Urabe virus SH coding region differed from the published sequence for strain SBL-1 by 14.4% at the nucleotide level and 24.6% at the amino acid level. The 5' non-coding SH region was strongly conserved between the two strains (2% different), whereas the other non-coding regions were not.

Amino Acid Sequence↗

PubMed1993

A comparison of the multiple alleles of xylS carried by TOL plasmids pWW53 and pDK1 and its implications for their evolutionary relationship.

Both of the independently isolated TOL plasmids pWW53 and pDK1 contain multiple regions homologous to the xylS regulatory gene of the archetypal TOL plasmid pWW0. The three homologues on pWW53 vary in the extent of their homology to xylSpWW0, xylS1pWW53 is 99% identical to xylSpWW0 and is located relative to the single copy of xylRpWW53 in exactly the same way as xylS and xylR on pWW0. The DNA sequence of xylS3pWW53 is 87% identical to the xylSpWW0 sequence within the coding region but the non-coding DNA upstream is not homologous. There is a frame-shift change at the end of the coding region which causes the C terminus of XylS3pWW53 to be extended by an additional 10 amino acids relative to XylSpWW0. xylS2pWW53 is anomalous and appears to encode a truncated pseudogene lacking the first 525 bases found in the other xylS genes. Evidence is presented to show that both xylS1pWW53 and xylS3pWW53 act as regulators of meta pathway operons. Plasmid pDK1 carries two homologues of xylS. xylS1pDK1 is functional and is a hybrid gene: its 5' end and the upstream sequences are highly homologous to both xylS1pWW53 and xylSpWW0, whereas its 3' end is identical to xylS3pWW53. The sequence of xylS2pDK1 is identical to that of the anomalous truncated xylS2pWW53. Comparison of the organization and the restriction maps of the xyl catabolic operons on pDK1 and pWW53, together with the nucleotide sequences presented here, indicates that the catabolic DNA on pDK1 has derived from a replicon on which the xyl genes are organized similarly to pWW53 and that a genetic rearrangement has taken place involving a reciprocal recombination internal to two of its xylS homologues.

Alleles↗

PubMed2003

Molecular analysis of mutS expression and mutation in natural isolates of pathogenic Escherichia coli.

Deficiencies in the MutS protein disrupt methyl-directed mismatch repair (MMR), generating a mutator phenotype typified by high mutation rates and promiscuous recombination. How such deficiencies might arise in the natural environment was determined by analysing pathogenic strains of Escherichia coli. Quantitative Western immunoblotting showed that the amount of MutS in a wild-type strain of the enterohaemorrhagic pathogen E. coli O157 : H7 decreased about 26-fold in stationary-phase cells as compared with the amount present during exponential-phase growth. The depletion of MutS in O157 : H7 is significantly greater than that observed for a laboratory-attenuated E. coli K-12 strain. In the case of stable mutators, mutS defects in strains identified among natural isolates were analysed, including two E. coli O157 : H7 strains, a diarrhoeagenic E. coli O55 : H7 strain, and a uropathogenic strain from the E. coli reference (ECOR) collection. No MutS could be detected in the four strains by Western immunoblot analyses. RNase T2 protection assays showed that the strains were either deficient in mutS transcripts or produced transcripts truncated at the 3' end. Nucleotide sequence analysis revealed extensive deletions in the mutS region of three strains, ranging from 7.5 to 17.3 kb relative to E. coli K-12 sequence, while the ECOR mutator contained a premature stop codon in addition to other nucleotide changes in the mutS coding sequence. These results provide insights into the status of the mutS gene and its product in pathogenic strains of E. coli.

Adenosine Triphosphatases↗

PubMed2005

Identification of a glyphosate-resistant mutant of rice 5-enolpyruvylshikimate 3-phosphate synthase using a directed evolution strategy.

5-enolpyruvylshikimate 3-phosphate synthase (EPSPS) is a key enzyme in the shikimate pathway and is targeted by the wide-spectrum herbicide glyphosate. Here, we describe the use of a selection system based on directed evolution to select glyphosate-resistant mutants of EPSPS. Using this system, the rice (Oryza sativa) EPSPS gene, mutagenized by Error-Prone polymerase chain reaction, was introduced into an EPSPS-deficient Escherichia coli strain, AB2829, and transformants were selected on minimal medium by functional complementation. Three mutants with high glyphosate resistance were identified in three independent glyphosate selection experiments. Each mutant contained a C(317)-->T transition within the EPSPS coding sequence, causing a change of proline-106 to leucine (P106L) in the protein sequence. Glyphosate resistance assays indicated a 3-fold increase in glyphosate resistance of E. coli expressing the P106L mutant. Affinity of the P106L mutant for glyphosate and phosphoenolpyruvate was decreased about 70-fold and 4.6-fold, respectively, compared to wild-type EPSPS. Analysis based on a kinetic model demonstrates that the P106L mutant has a high glyphosate resistance while retaining relatively high catalytic efficiency at low phosphoenolpyruvate concentrations. A mathematical model derived from the Michaelis-Menten equation was used to characterize the effect of expression level and selection conditions on kinetic (Ki and Km) variation of the mutants. This prediction suggests that the expression level is an important aspect of the selection system. Furthermore, glyphosate resistance of the P106L mutant was confirmed in transgenic tobacco (Nicotiana tabacum), demonstrating the potential for using the P106L mutant in transgenic crops.

3-Phosphoshikimate 1-Carboxyvinyltransferase↗

PubMed1990

Amino-acid composition in trichorrhexis nodosa.

Trichorrhexis nodosa is a common shaft defect affecting scalp hair. Two-hundred scalp hairs exhibiting trichorrhexis nodosa were obtained from two normal females; samples were prepared from proximal shaft, pre-nodule, nodule and post-nodule sections and analysed for their respective amino-acid compositions. Significant reductions in cystine (P less than 0.001) of the pre-nodule, nodule and post-nodule sections, which decreased by 17.2%, 19.8% and 14.3%, respectively, and an increase in the acidic amino acids (P less than 0.03) were found, compared to values obtained from proximal shaft of the same hairs. The majority of nodules occurred within the last 10% of the shaft, and the similarity in amino-acid compositions between pre-nodule, nodule and post-nodule sections suggests that 'weathering' is the major factor influencing nodule occurrence. It is postulated that nodule formation requires a specific degree of exposure to 'weathering' together with a reduction in cuticle cell coverage. It is suggested that an initial structural defect, created by a change in the DNA coding for a cuticle polypeptide fraction, could be responsible for the selective and isolated presentation of the nodule within a 'weathered' section of hair shaft.

Adolescent↗

PubMed1991

Gene sequences and comparison of the fimbrial subunits representative of Bacteroides nodosus serotypes A to I: class I and class II strains.

We have determined the nucleotide sequences of the genes encoding the fimbrial subunits representative of the known Bacteroides nodosus serogroups. All of the genes are preceded by a highly conserved region which includes the likely promoter and transcriptional regulator sites as well as the ribosome-biding site, and are followed within a short but variable distance by a sequence with the characteristics of a transcription termination or attenuation signal. Based on sequence and organization, the subunits can be divided into two major classes called I (serogroups A, B, C, E, F, G, and I) and II (serogroups D and H). All contain the same seven-amino-acid positively charged leader sequence and conserved hydrophobic amino-terminal sequence typical of type 4 fibriae. Beyond this point the class II subunits are quite different from class I and share features more in common with those from other type 4 fimbriate bacteria, such as Moraxella bovis and Pseudomonas aeruginosa. The larger class I may be further subdivided into two subsets: (i) [A, E, F)(B, I)) and (ii) (C, G). These proteins exhibit three major clusters of variation, at either end of the presumptive disulphide loop which spans the central third of the protein, and near the carboxy-terimus, with dispersed changes in between. The length of the mature subunits varies from 152-156 amino acids, and the variation includes small insertions or deletions in the variable clusters between more conserved domains. The class II subunits are 149 amino acids in length and contain two pairs of cysteine residues: one is at the end of the amino-terminal conserved region, and the other is at the end of the protein. The major variation occurs in the central region of the molecule, and again small insertions or deletions are required to align adjacent conserved domains. There is also a striking absence of silent codon changes in the 5' coding region of all of these genes, indicating that these sequences have a secondary genetic function, probably in recombinational exchange.

Amino Acid Sequence↗

PubMed1997

Two novel mutations in a Canadian family with aspartylglucosaminuria and early outcome post bone marrow transplantation.

Aspartylglucosaminuria (AGU) is a lysosomal storage disease caused by deficiency of aspartylglucosaminidase. The disease is overrepresented in the Finnish population, in which one missense mutation (Cys163Ser) is responsible for 98% of the disease alleles. The few non-Finnish cases of AGU which have been analyzed at molecular level have revealed a spectrum of different mutations. Here, we report two new missense mutations causing AGU in two Canadian siblings. The patients were compound heterozygotes with a G299-->A transition causing a Gly100-->Gln substitution and a T404-->C transition resulting in a Phe135-->Ser change in the cDNA coding for aspartylglucosaminidase. The younger patient recently underwent bone marrow transplantation.

Acetylglucosamine↗