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PubMed2004

Enteroaggregative Escherichia coli: an emerging enteric pathogen.

Enteroaggregative Escherichia coli (EAEC) represents an emerging pathogen that causes enteric and food-borne infectious diseases. Subgroups in many populations throughout the world are susceptible to EAEC infection. EAEC pathogenesis involves adherence to the intestinal mucosa; increased production and deposition of a mucus biofilm; and mucosal toxicity due to inflammation and cytokine release. Due to the heterogeneity of EAEC strains and differing host immune responses, not all EAEC infections are symptomatic. Recent data suggest that individuals with a homozygous genotype -251 AA single nucleotide polymorphism (SNP), in the IL-8 promoter region, are more susceptible to EAEC diarrhea. The HEp-2 cell adherent assay allows identification of EAEC's characteristic aggregative or "stacked brick" adherence pattern. Antimicrobial treatment of individuals who develop EAEC diarrhea should be individually based. Ciprofloxacin and rifaximin, compared to placebo, have been shown to significantly shorten the course of diarrhea in patients who developed EAEC infection. The objective of this review is to increase awareness of this important emerging pathogen and to discuss the epidemiology, pathogenesis, and host-pathogen factors associated with EAEC infection.

Adult↗
PubMed1997

A novel mitochondrial G8313A mutation associated with prominent initial gastrointestinal symptoms and progressive encephaloneuropathy.

We describe a childhood mitochondrial disorder in which the clinical symptoms began and remained confined to the gastrointestinal (GI) system during the first 4 y. Seizures heralded the onset of progressive encephalopathy at age 7. Peripheral neuropathy, retinitis pigmentosa, and neural deafness developed subsequently. Laboratory investigations disclosed elevated levels of plasma lactate, and a muscle biopsy revealed ragged red fibers lacking cytochrome c oxidase activity and diminished levels of respiratory chain enzyme complexes. Molecular genetic tests failed to show any of the previously reported pathogenic mitochondrial DNA (mtDNA) mutations. We therefore screened the whole mitochondrial genome by coupling restriction digestions with single-strand conformational polymorphism (SSCP) patterns. We identified a unique SSCP in the segment that encompassed the tRNA(Lys) gene, and direct sequencing of this segment revealed a G-->A transition at an evolutionarily conserved nucleotide at mtDNA position 8313. This G8313A transition was heteroplasmic in muscle and fibroblasts of the patient, but was absent in the white blood cells and platelets from his maternal relatives. This report illustrates how GI symptoms can be the initial manifestation in a mitochondrial disorder and suggests that mitochondrial dysfunction should be considered in differentials of unexplained chronic GI symptoms, especially when lactic acidosis or other unrelated clinical signs or symptoms are present.

Adolescent↗
PubMed1990

Chromosomal and molecular evolution in Asiatic wild asses.

Chromosomal studies of Tibetan wild ass, Equus kiang holdereri are reported for the first time. A Robertsonian polymorphism resulting in diploid numbers of 2n = 51 and 2n = 52 was identified. This polymorphism involves the same elements that participate in the polymorphic Robertsonian rearrangement producing diploid numbers of 54-56 in E. hemionus kulan and E. hemionus onager. Comparison of mitochondrial DNA restriction fragment patterns among three unrelated kiang individuals and between kiangs and a Transcaspian kulan, E. hemionus kulan, indicates an approximately 1% nucleotide sequence divergence of mitochondrial DNAs between the two taxa. The chromosomal divergence between E. hemionus and E. kiang probably originated less than 500,000 years ago. Studies of additional Asiatic wild ass taxa are indicated in order to gain further insights into the speciation and systematics of this threatened group of mammals.

Animals↗
PubMed2002

Patterns of genetic variation at a chromosome 4 locus of Drosophila melanogaster and D. simulans.

DNA sequence surveys of Drosophila melanogaster populations show a strong positive correlation between the recombination rate experienced by a locus and its level of nucleotide polymorphism. In particular, surveys of the fourth chromosome gene ci(D) show greatly reduced levels of nucleotide variation; this observation was originally interpreted in terms of selective sweeps occurring on the nonrecombining fourth chromosome. Subsequent theoretical work has, however, uncovered several other selective processes that can reduce variation. In this study, we revisit the Drosophila fourth chromosome, investigating variation in 5-6 kb of the gene ankyrin in D. melanogaster and D. simulans. Silent nucleotide site diversity is approximately 5 x 10(-4) for both species, consistent with the previous observations of low variation at ci(D). Given the observed frequency spectra at ankyrin, coalescent simulations indicate that reduced diversity in the region is unlikely to be due to a selective sweep alone. We find evidence for recombinational exchange at this locus, and both species appear to be fixed for an insertion of the transposable element HB in an intron of ankyrin.

Animals↗
PubMed2004

Interleukin-1 polymorphisms are associated with the inflammatory response in human muscle to acute resistance exercise.

Inflammation appears to play an important role in the repair and regeneration of skeletal muscle after damage. We tested the hypothesis that the severity of the inflammatory response in muscle after an acute bout of resistance exercise is associated with single nucleotide polymorphisms (SNPs) previously shown to alter interleukin-1 (IL-1) activity. Using a double-blind prospective design, sedentary young men were screened (n = 100) for enrolment (n = 24) based upon having 1 of 4 haplotype patterns composed of five polymorphic sites in the IL-1 gene cluster: IL-1A (+4845), IL-1B (+3954), IL-1B (-511), IL-1B (-3737) and IL-1RN (+2018). Subjects performed a standard bout of resistance leg exercise and vastus lateralis biopsies were obtained pre-, and at 24, and 72 h post-exercise. Inflammatory marker mRNAs (IL-1beta, IL-6 and tumor necrosis factor-alpha (TNF-alpha)) and the number of CD68(+) macrophages were quantified. Considerable variation was observed in the expression of these gene products between subjects. At 72 h post-exercise, IL-1beta had increased in a number of subjects (n = 10) and decreased (n = 4) or did not change (n = 10) in others. Inflammatory responses were significantly associated with specific haplotype patterns and were also influenced by individual SNPs. Subjects with genotypes 1.1 at IL-1B (+3954) or 2.2 at IL-1B (-3737) had approximately a 2-fold higher median induction of several markers, but no increase in macrophages, suggesting that cytokine gene expression is elevated per macrophage. The IL-1RN (+2018) SNP maximized the response specifically within these groups and was associated with increased macrophage recruitment. This is the first report that IL-1 genotype is associated with the inflammation of skeletal muscle following acute resistance exercise that may potentially affect the adaptations to chronic resistance exercise.

Adult↗
PubMed1994

Mapping of sequence-tagged sites in rice by single strand conformation polymorphism.

The conditions for efficient single-strand conformation polymorphism (SSCP) detection were examined for its application to mapping of DNA regions in the rice genome. Temperature for electrophoresis and glycerol concentrations in gel affected SSCP patterns significantly. The optimal detection conditions for SSCP also depends on the nucleotide sequences of fragments analyzed. Fragments over 300 bp show complicated patterns depending on their nucleotide sequences and were not suitable for SSCP analysis. Seventy primer pairs were designed from the sequence data available to amplify DNA regions as sequence tagged sites (STSs), and 39 of these STSs were found to generate SSCP between japonica rice (Nipponbare) and indica rice (Kasalath) in at least one of the experimental conditions. The maps of DNA fragments amplified from 186 F2-plant DNAs with 17 primer pairs were successfully determined. This direct mapping method of the amplified DNA fragments with PCR is simple and quite sensitive, and can be used to set markers in the gap regions of a genetic linkage map.

Base Sequence↗
PubMed2003

Molecular diversity of sulfate-reducing bacteria from two different continental margin habitats.

This study examined the natural diversity and distributions of sulfate-reducing bacteria along a natural carbon gradient extending down the shelf-slope transition zone of the eastern Pacific continental margin. Dissimilatory (bi)sulfite reductase gene sequences (dsrAB) were PCR amplified and cloned from five different sampling sites, each at a discrete depth, from two different margin systems, one off the Pacific coast of Mexico and another off the coast of Washington State. A total of 1,762 clones were recovered and evaluated by restriction fragment length polymorphism (RFLP) analysis. The majority of the gene sequences recovered showed site and depth restricted distributions; however, a limited number of gene sequences were widely distributed within and between the margin systems. Cluster analysis identified 175 unique RFLP patterns, and nucleotide sequences were determined for corresponding clones. Several different continental margin DsrA sequences clustered with those from formally characterized taxa belonging to the delta subdivision of the class Proteobacteria (Desulfobulbus propionicus, Desulfosarcina variabilis) and the Bacillus-Clostridium (Desulfotomaculum putei) divisions, although the majority of the recovered sequences were phylogenetically divergent relative to all of the other DsrA sequences available for comparison. This study revealed extensive new genetic diversity among sulfate-reducing bacteria in continental margin sedimentary habitats, which appears to be tightly coupled to slope depth, specifically carbon bioavailability.

Deltaproteobacteria↗
PubMed2003

Studies on the Dombrock blood group system in non-human primates.

The Dombrock blood group system consists of five distinct antigens: two antithetical antigens, Doa and Dob, and three high-frequency antigens:Gya,Hy, and Joa. Although the prevalence of Doa and Dob in different populations makes them useful as genetic markers, the scarcity of reliable antibodies to these antigens has prevented this potential from being realized. The gene (DO;ART4) encoding the Dombrock glycoprotein has been cloned and sequenced, and the molecular bases of the various Dombrock phenotypes have been determined. The purpose of this study was to perform DNA-based assays on the DO homolog in non-human primates to determine the degree of conservation in the DO gene. Murine MoAbs to Dombrock protein were developed by standard hybridoma technologies and used to test RBCs from non-human primates by hemagglutination. PCR-RFLP analysis for the six single-nucleotide polymorphisms (SNPs) that have been defined in human alleles were performed on DNA extracted from fresh or frozen blood samples from numerous non-human primates. Hemagglutination tests with six MoAbs to the Dombrock glycoprotein revealed distinct epitopes on RBCs from the non-human primates. The gorillas and orangutans had the same PCR-RFLP digestion pattern for the six SNPs studied as chimpanzees. Old world monkeys (macaques) were identical at nucleotides (nt) 323, 350, 624, and 793 with the chimpanzees, and at nt 898 the digestion pattern was the same as for the HY1 allele in humans. For the new world monkeys (tamarins and squirrel monkeys) the digestion pattern was conserved for nt 793 but different for nt 624; the other SNPs could not be determined because there was no amplification. The presence of epitopes recognized by the MoAbs and PCR-RFLP results among the non-human primates shows considerable conservation of the DO gene. The difficulties we encountered with the amplification of DNA from the non-human primates lower in the phylogenetic tree are probably due to divergence in sequence.

Journal Article↗
PubMed2005

Adaptive evolution of non-coding DNA in Drosophila.

A large fraction of eukaryotic genomes consists of DNA that is not translated into protein sequence, and little is known about its functional significance. Here I show that several classes of non-coding DNA in Drosophila are evolving considerably slower than synonymous sites, and yet show an excess of between-species divergence relative to polymorphism when compared with synonymous sites. The former is a hallmark of selective constraint, but the latter is a signature of adaptive evolution, resembling general patterns of protein evolution in Drosophila. I estimate that about 40-70% of nucleotides in intergenic regions, untranslated portions of mature mRNAs (UTRs) and most intronic DNA are evolutionarily constrained relative to synonymous sites. However, I also use an extension to the McDonald-Kreitman test to show that a substantial fraction of the nucleotide divergence in these regions was driven to fixation by positive selection (about 20% for most intronic and intergenic DNA, and 60% for UTRs). On the basis of these observations, I suggest that a large fraction of the non-translated genome is functionally important and subject to both purifying selection and adaptive evolution. These results imply that, although positive selection is clearly an important facet of protein evolution, adaptive changes to non-coding DNA might have been considerably more common in the evolution of D. melanogaster.

Adaptation, Physiological↗
PubMed2003

Haplotype structure and evidence for positive selection at the human IL13 locus.

Interleukin-13 (IL13) is believed to play an important role in the pathogenesis of atopy and allergic asthma. To better understand genetic variation at the IL13 locus, we resequenced a 5.1-kb genomic region spanning the entire locus and identified 26 single-nucleotide polymorphisms (SNPs) in 74 individuals from three major populations-Chinese, Caucasian, and African. Our survey suggests exceptionally high and significant geographic structure at the IL13 locus between African and outside Africa populations. This unusual pattern suggests that positive selection that acts in some local populations may have played a role on the IL13 locus. In support of this suggestion, we found a significant excess of high frequency-derived SNPs in the Chinese population and Caucasian population, respectively, as expected after a recent episode of positive selection. Further, the unusual haplotype structure indicates that different scenarios of the action of positive selection on the IL13 locus in different populations may exist. In the Caucasian population, the skewed haplotype distribution dominated by one common haplotype supports the hypothesis of simple directional selection. Whereas, in the Chinese population, the two-round hitchhiking hypothesis may explain the skewed haplotype structure with three dominant ones. These findings may provide insight into the likely relative roles of selection and population history in establishing present-day variation at the IL13 locus, and, motivate further studies of this locus as an important candidate in common diseases association studies.

Asian People↗
PubMed1999

Characterization of 18 new BoLA-DRB3 alleles.

The second exon of the bovine MHC class II DRB3 gene was amplified by polymerase chain reaction (PCR) from DNA samples of 568 zebu Brahman cattle (Bos indicus) from Martinique (French West Indies). Cloning of these PCR products allowed the isolation of both alleles from each animal, which were characterized by the PCR-restriction fragment length polymorphism (RFLP) technique using the restriction enzymes RsaI, BstYI and HaeIII. Four new PCR-RFLP patterns were obtained by digestion with RsaI. These patterns were named 'v', 'w', 'x' and 'y' continuing the accepted nomenclature. Sequencing of each allele allowed the identification of 18 new BoLA-DRB3 exon 2 nucleotide sequences and their deduced amino acid sequences.

Alleles↗
PubMed1999

Identification and characterisation of polymorphisms in human phosphoglucomutase (PGM1).

This study is part of our effort to map recombination hotspots in two regions (site A, 18 kb; site B, 40 kb) of the human phosphoglucomutase PGM1 gene. Twenty-two PCR amplified fragments comprising six groups, covering about 5.2 kb, were screened for single nucleotide polymorphisms (SNPs) using non-isotopic single stranded conformation polymorphism (SSCP) analysis. Fourteen fragments were variable and seven of these showed common polymorphism. Our strategy for screening for polymorphic sites in the PGM1 gene was based on the results of allelic association analysis between each new marker and the sites of the classical isozyme polymorphism (2/1 in exon 4 and +/- in exon 8). Samples from four populations (Caucasian, Chinese, Vietnamese and New Guinean) were typed for each of the seven polymorphic markers. Between two and four common alleles were found in each case, together with a few rare alleles. Co-dominant inheritance patterns were demonstrated by family studies. The molecular basis of each new marker was determined by direct sequencing of the PCR products: most were SNPs except two that were small insertions/deletions. Direct sequence analysis of a 2.1 kb segment in sixteen individuals revealed no additional nucleotide variation indicating a very high level of efficiency of the SSCP screening method used in this study. The overall nucleotide diversity (theta) for PGM1 was estimated as 0.9 x 10(-3) based on 33 segregating sites in a sequence of 5187 nt and a sample size of 614 individuals.

Alleles↗
PubMed2005

High level of functional polymorphism indicates a unique role of natural selection at human immune system loci.

Several studies have shown that immune system proteins have on average a higher rate of amino acid evolution between different species of mammals than do most other proteins. To test whether immune-system-expressed loci show a correspondingly elevated rate of within-species nonsynonymous (amino acid altering) polymorphism, we examined gene diversity (heterozygosity) at 4,911 single nucleotide polymorphism (SNP) sites at 481 protein-coding loci. At loci with nonimmune functions, gene diversity at nonsynonymous SNP sites was typically lower than that at silent SNP sites (those not altering the amino acid sequence) in the same gene, a pattern that is an evidence of purifying selection acting to eliminate slightly deleterious variants. However, this pattern was not seen at nonsynonymous SNPs causing conservative amino acid replacements in immune system proteins, indicating that the latter are subject to a reduced level of functional constraint. Similarly, immune system genes showed higher gene diversities in their 5' noncoding regions than did other proteins. These results identified certain immune system loci that are likely to be subject to balancing selection that acts to maintain polymorphism in either coding or regulatory regions.

Chromosomes, Human↗
PubMed1995

Structure of the human deoxyribonuclease I (DNase I) gene: identification of the nucleotide substitution that generates its classical genetic polymorphism.

The objectives of this study were to elucidate the structural organization of the gene for human deoxyribonuclease I (DNase I) and to identify the mutation site underlying its classical genetic polymorphism. In order to determine the organization of this gene, we utilized a combination of direct polymerase chain reaction (PCR)-amplification of human genomic DNA and isolation of the overlapping clones from a cosmid human genomic library. Restriction endonuclease mapping, Southern blotting and DNA sequencing showed that the DNase I gene was approximately 3.2 kilobases long, it comprised 9 (I-IX) exons separated by eight introns and its complete sequence was determined. The first exon contained only the non-translated sequences of mRNA. In addition to several putative regulatory elements, TATA-like and CAAT-like sequences were observed in the region upstream of the translation initiation codon. These results provide information that will help to understand the expression and regulation of DNase I. The isoelectric focusing patterns of human DNase I showed that it exhibits classical genetic polymorphism (Kishi et al. 1989, 1990). A comparison of the entire translated sequences of the DNase I gene from two pairs of individuals with common DNase I phenotypes 1 and 2 revealed only one nucleotide residue difference in exon VIII, A for phenotype 1 and G for phenotype 2, thus producing Gln and Arg amino acid substitutions respectively at position 222 from the NH2-terminus of the mature enzyme. The predicted charge changes attributable to these amino acid substitutions are entirely consistent with the isoelectric focusing profiles of these two DNase I isozymes. We conclude that this substitution is solely responsible for the classical polymorphism of DNase I protein.

Adult↗
PubMed2005

Application of MALDI-TOF mass spectrometry in screening and diagnostic research.

During the last years, mass spectrometry has revolutionised protein biochemistry and has advanced to a superior tool for the identification and detailed analysis of peptides and proteins. The high throughput allowed by some mass spectrometry platforms has enabled the important step from analysis of individual proteins to proteomics. Recently, an additional field of mass spectrometry applications has emerged - namely screening and diagnostic research. In contrast to protein identification, screening applications have to detect analyte molecules of defined molecular weights which can be calculated beforehand, for example by means of chemical structures. Here, the accuracy and sensitivity of mass spectrometry has to be combined with the requirements of high-throughput analyses, in particular speed and automation. These criteria are especially fulfilled by state of the art matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) instruments. The first high throughput screening (HTS) application proved to be genotyping of single nucleotide polymorphisms. The same principle was later applied for several quality control issues, for example for oligonucleotides, peptide or compound libraries. This development has culminated in the screening and profiling of complex biomarker patterns in clinical proteomics to detect a molecular fingerprint for specific diseases in biological samples. Thus, mass spectrometry based methods are expected to enable a very early diagnosis of diseases with minimally invasive methods of investigation. This type of high end screening application has the potential to revolutionise the early diagnosis of many diseases. Here, we give an overview of the application of mass spectrometry in the fields of screening and diagnostic research.

Biomedical Research↗
PubMed2005

A novel single nucleotide polymorphism of the neuropeptide Y (NPY) gene associated with alcohol dependence.

BACKGROUND: Neuropeptide Y (NPY) is a major endogenous regulator of anxiety-related behaviors and emotionality. Transgenic work with NPY and null-mutant mice have implicated NPY in the control of alcohol consumption, suggesting that genetic variation of the prepro-NPY gene may also contribute to the heritability of alcoholism. The aim of this study was to examine whether polymorphic variants of the NPY gene are associated with the diagnosis of alcohol dependence. METHODS: We compared allele frequencies of 5 NPY polymorphisms (-883-ins/del, -602, -399, -84, and +1128) in a Nordic population of alcohol-dependent individuals (n = 428 males; n = 149 females) and ethnically matched controls (n = 84 males; n = 93 females) for whom alcohol dependence or any diagnosis of substance disorder was excluded. Patients were further subtyped into type I (late-onset) and type II (early-onset) alcoholics. RESULTS: The -602 marker showed a significant association with alcohol dependence (p = 0.0035; OR, 2.3; 95% CI, 1.3-4.0); a trend level association was further observed for the -399 marker (p = 0.058; OR, 1.3; 95% CI, 0.99-1.7) and the +1128 marker (p = 0.053; OR, 1.8; 95% CI, 0.99-3.1). The association for the -602 marker remained and was strengthened when analyzed in type I subjects only, although this association was not seen in type II patients, and there also was a significant association in the female subjects but not in males. The -602 single nucleotide polymorphism was in strong linkage dysequilibrium (r2 = 0.7; p < 0.0001) with the +1128 single nucleotide polymorphism, which has previously been reported to be associated with a diagnosis of alcoholism. Haplotype-based association confirmed these results. CONCLUSIONS: We report a novel polymorphism at position -602 in the 5' region of the NPY gene that is significantly associated with alcohol dependence. We also describe the haplotype frequencies and linkage dysequilibrium pattern of four variations in that region.

Adolescent↗
PubMed1998

Sequence polymorphism of mitochondrial DNA control region in Japanese.

Sequence polymorphisms of the mitochondrial DNA (mtDNA) control region, hypervariable regions I and II, from 100 unrelated Japanese were determined by PCR amplification and direct sequencing. Sequences of 404 nucleotides for hypervariable region I and 379 nucleotides for region II were obtained. Variable sites (85 and 45) were revealed in region I and region II, respectively, as compared to the reference sequence, and a total of 96 different genetic patterns from both regions I and II were determined. A point mutation heteroplasmy was observed at the ratio of approximately 50:50 from one individual at the sequence position 151 showing a nucleotide transition from C to T. The probability of identity was estimated as 2.3% for region I, 3.9% for region II, and 1.1% combined for both regions. These results suggest that sequence polymorphism of mtDNA control region would be very useful in forensic practice as a marker for individual identification.

Base Sequence↗
PubMed2000

Deletion polymorphism in the coding region of the human NESP55 alternative transcript of GNAS1.

NESP55, a novel member of the chromogranins, was originally implicated as a precursor of a peptide LSAL with 5-HT1B receptor antagonist activity. In humans, NESP55 (MIM 139320) is encoded by an alternative transcript of GNAS1, the gene encoding the guanine nucleotide-binding alpha subunit of G(S). As a result of the potential relevance of NESP55 to serotoninergic neurotransmission, we screened its sequence using genomic DNA pools from autistic disorder, obsessive-compulsive disorder (OCD) probands and control subjects. Six single nucleotide polymorphisms (SNPs) were identified and the allele frequencies of those SNPs were determined. In addition, a 24-bp in-frame deletion in the coding region was found in one of the OCD probands. To further investigate its pattern of inheritance and the relevance to studied phenotypes, we genotyped 123 total subjects from autism, OCD and attention deficit hyperactivity disorder (ADHD) families. The deletion was detected only in one OCD family and followed Mendelian inheritance. All subjects with the deletion were heterozygous. However, there are no specific behavioural or physical alterations in the subjects with this deletion variant. The physiological role of NESP55 in serotoninergic neurotransmission as well as the effect of the deletion on its function should be evaluated in future studies.

Alternative Splicing↗