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PubMed1997

Quinolone-resistant Salmonella typhi in Viet Nam: molecular basis of resistance and clinical response to treatment.

Nalidixic acid-resistant Salmonella typhi (NARST) was first isolated in Viet Nam in 1993. Analysis of the quinolone resistance-determining region of gyrA in 20 NARST isolates by polymerase chain reaction and single-stranded conformational polymorphism yielded two novel patterns: pattern II corresponding to a point mutation at nucleotide 87 Asp-->Gly (n = 17), and pattern III corresponding to a point mutation at nucleotide 83 Ser-->Phe (n = 3). In trials of short-course ofloxacin therapy for uncomplicated typhoid, 117 (78%) of 150 patients were infected with multidrug-resistant S. typhi, 18 (15%) of which were NARST. The median time to fever clearance was 156 hours (range, 30-366 hours) for patients infected with NARST and 84 hours (range, 12-378 hours) for those infected with nalidixic acid-susceptible strains (P < .001). Six (33.3%) of 18 NARST infections required retreatment, whereas 1 (0.8%) of 132 infections due to susceptible strains required retreatment (relative risk = 44; 95% confidence interval = 5.6-345; P < .0001). We recommend that short courses of quinolones not be used in patients infected with NARST.

4-Quinolones↗
PubMed1994

Neutral and non-neutral evolution of Drosophila mitochondrial DNA.

To test hypotheses of neutral evolution of mitochondrial DNA (mtDNA), nucleotide sequences were determined for 1515 base pairs of the NADH dehydrogenase subunit 5 (ND5) gene in the mitochondrial DNA of 29 lines of Drosophila melanogaster and 9 lines of its sibling species Drosophila simulans. In contrast to the patterns for nuclear genes, where D. melanogaster generally exhibits much less nucleotide polymorphism, the number of segregating sites was slightly higher in a global sample of nine ND5 sequences in D. melanogaster (s = 8) than in the nine lines of D. simulans (s = 6). When compared to variation at nuclear loci, the mtDNA variation in D. melanogaster does not depart from neutral expectations. The ND5 sequences in D. simulans, however, show fewer than half the number of variable sites expected under neutrality when compared to sequences from the period locus. While this reduction in variation is not significant at the 5% level, HKA tests with published restriction data for mtDNA in D. simulans do show a significant reduction of variation suggesting a selective sweep of variation in the mtDNA in this species. Tests of neutral evolution based on the ratios of synonymous and replacement polymorphism and divergence are generally consistent with neutral expectations, although a significant excess of amino acid polymorphism within both species is localized in one region of the protein. The rate of mtDNA evolution has been faster in D. melanogaster than in D. simulans and the population structure of mtDNA is distinct in these species. The data reveal how different rates of mtDNA evolution between species and different histories of neutral and adaptive evolution within species can compromise historical inferences in population and evolutionary biology.

Amino Acid Sequence↗
PubMed2001

Strong diversifying selection on domains of the Plasmodium falciparum apical membrane antigen 1 gene.

The surface-accessible ectodomain region of the Plasmodium falciparum apical membrane antigen 1 (AMA1) is a malaria vaccine candidate. The amino acid sequence may be under selection from naturally acquired immune responses, and previous analyses with a small number of allele sequences indicate a non-neutral pattern of nucleotide variation. To investigate whether there is selection to maintain polymorphism within a population, and to identify the parts of the ectodomain under strongest selection, a sample of 51 alleles from a single endemic population was studied. Analyses using Fu and Li's D and F tests, Tajima's D test, and the McDonald-Kreitman test (with the chimpanzee parasite P. reichenowi as outgroup) show significant departure from neutrality and indicate the selective maintenance of alleles within the population. There is also evidence of a very high recombination rate throughout the sequence, as estimated by the recombination parameter, C, and by the rapid decline in linkage disequilibrium with increasing nucleotide distance. Of the three domains (I-III) encoding structures determined by disulfide bonds, the evidence of selection is strongest for Domains I and III. We predict that these domains in particular are targets of naturally acquired protective immune responses in humans.

Algorithms↗
PubMed2006

Common genetic variation in IGF1 and prostate cancer risk in the Multiethnic Cohort.

BACKGROUND: Insulin-like growth factor I (IGF-I) appears to play a role in prostate development and carcinogenesis. We investigated whether genetic variation at the IGF1 locus is associated with prostate cancer risk. METHODS: We sequenced IGF1 exons in germline DNA from 95 men with advanced prostate cancer to identify missense variants. IGF1 linkage disequilibrium patterns and common haplotypes were characterized by genotyping 64 single-nucleotide polymorphisms (SNPs) spanning 156 kilobases in 349 control subjects. Associations between IGF1 haplotypes and genotypes were investigated among 2320 patients with prostate cancer and 2290 control subjects from the Multiethnic Cohort. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by unconditional logistic regression to determine the association between prostate cancer and IGF1 haplotypes and genotypes. We used permutation testing to correct for multiple hypothesis testing. All statistical tests were two-sided. RESULTS: No IGF1 missense variants were observed. We identified four blocks of strong linkage disequilibrium and selected a subset of 29 tagging SNPs that could accurately predict both the common IGF1 haplotypes and the remaining SNPs. Haplotype analysis revealed nominally statistically significant associations with prostate cancer risk in each of the four haplotype blocks: haplotype 1B (OR = 1.21, 95% CI = 1.04 to 1.40), haplotype 2C (OR = 1.24, 95% CI = 1.06 to 1.44), haplotype 3C (OR = 1.25, 95% CI = 1.03 to 1.50), and haplotype 4D (OR = 1.19, 95% CI = 1.02 to 1.39). Two SNPs--rs7978742 (Ptrend = .002) and rs7965399 (Ptrend = .002)--were perfectly correlated (correlation coefficient = 1.0) with one another and also associated with prostate cancer risk. These two SNPs were strong proxies for haplotypes 1B, 2C, 3C, and 4D and could account for the haplotype findings. Permutation testing revealed that a similarly strong result would be observed by chance only 5.6% of the time. CONCLUSION: Inherited variation in IGF1 may play a role in the risk of prostate cancer.

Black or African American↗
PubMed2001

Genetic variation in 16S-23S rDNA internal transcribed spacer regions and the possible use of this genetic variation for molecular diagnosis of Bacteroides species.

The structural variation in 16S-23S rDNA internal transcribed spacer regions (ITS) among Bacteroides species was assessed by PCR amplification and sequencing analysis, and its possible use for molecular diagnosis of these species was evaluated. Ninety strains of the genus Bacteroides, including the species B. distasonis, B. eggerthii, B. fragilis, B. ovatus, B. thetaiotaomicron, B. uniformis and B. vulgatus, produced one to three ITS amplification products with sizes ranging from 615 to 810 bp. Some Bacteroides strains could be differentiated at species level on the basis of ITS amplification patterns and restriction fragment length polymorphism (RFLP) analysis using a four-nucleotide-recognizing enzyme, Msp I. The results of sequence analysis of ITS amplification products revealed genes for Ile-tRNA and Ala-tRNA in all strains tested. The nucleotide sequence, except for that in tRNA-coding regions, was highly variable and characteristic for each species, but a common sequence among B. fragilis, B. thetaiotaomicron and B. ovatus was observed. A digoxigenin-labeled oligonucleotide probe (named FOT1), which was designed from this conserved sequence, specifically hybridized to the ITS amplification products from B. fragilis, B. thetaiotaomicron and B. ovatus. These results suggest that the ITS region is a useful target for the development of rapid and accurate techniques for identification of Bacteroides species.

Bacteroides↗
PubMed2001

Blocks of limited haplotype diversity revealed by high-resolution scanning of human chromosome 21.

Global patterns of human DNA sequence variation (haplotypes) defined by common single nucleotide polymorphisms (SNPs) have important implications for identifying disease associations and human traits. We have used high-density oligonucleotide arrays, in combination with somatic cell genetics, to identify a large fraction of all common human chromosome 21 SNPs and to directly observe the haplotype structure defined by these SNPs. This structure reveals blocks of limited haplotype diversity in which more than 80% of a global human sample can typically be characterized by only three common haplotypes.

Algorithms↗
PubMed2006

Detection of novel Y SNPs provides further insights into Y chromosomal variation in Pakistan.

Biallelic polymorphisms on the Y chromosome have been extensively used to study the history, evolution, and migration patterns of world populations. In this study we screened 8.5 kb of Y chromosomal DNA for single nucleotide polymorphisms (SNPs) in a panel of 95 male individuals belonging to different haplogroups. Five novel Y-SNPs (PK1-5) were identified, four in the Pakistani sample and one in an African sample. The ancestral state of each SNP was determined in two chimpanzee samples and a variety of Pakistani ethnic groups. In addition to these novel Y-SNPs 77 additional markers on the Y chromosome were analyzed to place the SNPs on the phylogenetic tree of Y chromosomal lineages and to further investigate extant human Y chromosomal variation within Pakistan. BATWING analysis gave an estimate of between 2,500 and 7,300 YBP for population expansion in Pakistan which coincides with the period of the Indus Valley civilizations.

Alleles↗
PubMed1986

Pig mitochondrial DNA: polymorphism, restriction map orientation, and sequence data.

Restriction endonuclease cleavage patterns of mitochondrial DNA (mtDNA) in pigs were analyzed using 18 enzymes which recognize six nucleotides and 1 four-nucleotide-recognizing enzyme. Pigs including Taiwan native breeds and miniature strains maintained in Japan were examined in this study; four commercial breeds of pigs and Japanese wild boars have been investigated earlier [Watanabe, T., et al. (1985). Biochem. Genet. 23:105]. mtDNA polymorphisms were observed in the cleavage patterns of five restriction enzymes, Bg1II, EcoRV, ScaI, StuI, and TaqI. The results support the previous hypothesis that pigs must be derived from two different maternal origins, European and Asian wild boars, and that a breed, Large White, arises from both European and Asian pigs. Two HindIII cleavage fragments were cloned into the HindIII site of M13mp10 and were partially sequenced by the dideoxynucleotide-chain termination method. Furthermore, DraI and StuI cleavage sites were newly determined on the restriction endonuclease map. On the basis of these results, the restriction endonuclease cleavage map of pig mtDNA was rewritten. Comparing sequence data of pig mtDNA at 237 positions with those of cow, human, mouse, and rat mtDNA, the sequence difference, silent and replacement changes, and transitions and transversions among mammalian species were estimated. The relationships among them are discussed.

Animals↗
PubMed2006

No association between TPH2 gene polymorphisms and ADHD in a UK sample.

Tryptophan Hydroxylase 2 (TPH2) is the rate-limiting enzyme in the biosynthesis of serotonin which is exclusively expressed in the brain. Recent molecular studies reported significant association between markers mapped to TPH2 and psychiatric conditions including ADHD. We have examined four single nucleotide polymorphisms (SNPs) two of which (rs1843809, rs1386493) were reported to associate with ADHD in an Irish ADHD sample. Transmission disequilibrium analysis revealed no significant association between any of these markers and ADHD. Dividing by the sex of the transmitting parent has also failed to replicate the previously reported paternal over-transmission of the associated alleles to ADHD probands. A larger sample size will be required to clarify if TPH2 alleles are or are not associated with ADHD.

Adolescent↗
PubMed2006

Imprinted status of pleomorphic adenoma gene-like I and paternal expression gene 10 genes in pigs.

Genomic imprinting is theorized to exist in all placental mammals and some marsupials. Imprinted genes play important roles in the regulation of fetal growth, development, and postnatal behavior, but the study of imprinted genes has been limited in livestock. In this study, the polymorphism-based approach was used to detect the expression patterns of the porcine pleomorphic adenoma gene-like I (PLAGL1) and paternal expression gene 10 (PEG10) genes. Single nucleotide polymorphisms in the exons were detected between the Meishan and Large White breeds in the PLAGL1 and PEG10 genes. The polymorphisms were used to determine the monoallelic or biallelic expression with reverse transcription-PCR-RFLP in 44 tissues from 4 heterozygous pigs (based on SNP). Imprinting analysis indicated that the PLAGL1 and PEG10 genes were both paternally expressed in all tissues tested (heart, liver, spleen, lung, kidney, stomach, small intestine, skeletal muscle, fat, uterus, and ovary). Our study showed that the method of identifying polymorphic transcripts with reverse transcription-PCR-RFLP may be beneficial for detecting the imprinting status of some candidate imprinted genes.

Animals↗
PubMed2003

Nucleotide variation of the Est-6 gene region in natural populations of Drosophila melanogaster.

We have investigated nucleotide polymorphism in the Est-6 gene region in four samples of Drosophila melanogaster derived from natural populations of East Africa (Zimbabwe), Europe (Spain), North America (California), and South America (Venezuela). There are two divergent sequence types in the North and South American samples, which are not perfectly (North America) or not at all (South America) associated with the Est-6 allozyme variation. Less pronounced or no sequence dimorphism occurs in the European and African samples, respectively. The level of nucleotide diversity is highest in the African sample, lower (and similar to each other) in the samples from Europe and North America, and lowest in the sample from South America. The extent of linkage disequilibrium is low in Africa (1.23% significant associations), but much higher in non-African populations (22.59, 21.45, and 37.68% in Europe, North America, and South America, respectively). Tests of neutrality with recombination are significant in non-African samples but not significant in the African sample. We propose that demographic history (bottleneck and admixture of genetically different populations) is the major factor shaping the nucleotide patterns in the Est-6 gene region. However, positive selection modifies the pattern: balanced selection creates elevated levels of nucleotide variation around functionally important (target) polymorphic sites (RsaI-/RsaI+ in the promoter region and F/S in the coding region) in both African and non-African samples; and directional selection, acting during the geographic expansion phase of D. melanogaster, creates an excess of very similar sequences (RsaI- and S allelic lineages, in the promoter and coding regions, respectively) in the non-African samples.

Animals↗
PubMed2005

Identification of novel SLC3A1 gene mutations in Spanish cystinuria families and association with clinical phenotypes.

Cystinuria is an inherited metabolic disease characterized by an abnormal urinary excretion of cystine and dibasic amino acids, leading to kidney stone formation. Incidence of cystinuria in the Mediterranean Spanish population is one of the highest in the world. In view of the low prevalence of previously reported mutations in the SLC3A1 gene, analyses to identify novel variants were carried out on 20 cystinuria families. Additionally, we investigated the possible association between these molecular variants and clinical phenotypes. Genomic DNA from 48 cystinuria patients, 44 healthy relatives and 81 unrelated controls from the East Mediterranean coast of Spain was screened by conformation sensitive gel electrophoresis. Abnormal patterns were confirmed by nucleotide sequence determination and by further restriction fragment-length polymorphism. We only found 11 genetic variants within the SLC3A1 gene: five known polymorphisms (114C > A, 231T > A, 1136 + 3delT, 1332 + 7T > C and 1338G > A), four point mutations (M467T, R452W, I105R and Y461X), one single base pair deletion (1767delA) and one 2-bp insertion (1670insAT). Two of these genetic variants (I105R and 1670insAT) were described for the first time. All mutations but one were detected in families classified as Type I cystinuria due to the transmission pattern of the disease. Association analyses revealed that 231T > A (M467T), 1136 + 3delT and 1332 + 7T > C genetic variants were statistically related with urinary amino acid excretion in cystinuria patients. Although some molecular variants within the SLC3A1 gene were associated with clinical traits in cystinuria patients, the low detection rate of mutations in this gene strongly suggests that variation of the SLC3A1 is not the major genetic factor contributing to cystinuria in this Mediterranean population.

Adolescent↗
PubMed1998

Role of mutation in the gyrA and parC genes of nalidixic-acid-resistant salmonella serotypes isolated from animals in the United Kingdom.

To answer the question as to whether isolates of salmonella from animals with decreased susceptibility to quinolones possess the same mechanism of resistance as isolates from humans, the polymerase chain reaction (PCR) was used to amplify a 347 base pair fragment equivalent to codons 39-159 covering the quinolone resistance determining region (QRDR) of the gyrA gene of Salmonella typhimurium NCTC 74, and 196 veterinary isolates of 26 serotypes of salmonella (109 from turkeys, 29 from chickens, the remainder from cattle, parrots, pigs, dogs, a pigeon, an exotic bird, a duck, a partridge, a sheep, a horse and environmental samples including litter, a nest and water). All PCR products were electrophoresed for single-stranded conformational polymorphism (SSCP). The DNA sequence of all eight novel SSCP patterns was determined. Nucleotide substitutions were identified in the gyrA gene of all except two isolates; all substitutions conferred a substitution at serine 83 or aspartate 87, as has previously been shown for isolates from humans. No mutations conferring an amino acid substitution in parC (the gene encoding the secondary target for quinolones) were revealed in the 48 isolates requiring 0.5-1 mg/L ciprofloxacin for inhibition, or the isolates for which no mutation in gyrA was revealed. The accumulation of enrofloxacin and ciprofloxacin was determined for 30 representative isolates (of which five were multiply drug resistant). Five isolates accumulated one-quarter to one-half the concentration achieved by the corresponding wild-type serotype. For two of these five isolates no mutation in gyrA was revealed, and one lacked OmpF.

Animals↗
PubMed2001

Insights from linked single nucleotide polymorphisms: what we can learn from linkage disequilibrium.

New methods for analyzing sequence polymorphism data have uncovered some striking patterns of linkage disequilibrium in both humans and fruitflies. These methods have revealed examples where the observed amount of linkage disequilibrium is either much more or much less than expected, and have led to advances in our understanding of the forces that affect naturally occurring genetic variation. With the recent explosion of sequence polymorphism data, the prospects for further progress from these methods are quite promising.

Alleles↗
PubMed2004

A single nucleotide polymorphism in glycogen synthase kinase 3-beta promoter gene influences onset of illness in patients affected by bipolar disorder.

Genetic studies in medicine exploited age of onset as a criterion to delineate subgroups of illness. Bipolar patients stratified with this criterion were shown to share clinical characteristics and patterns of inheritance of illness. The molecular mechanisms driving the biological clock in the suprachiasmatic nucleus of the hypothalamus may play a role in mood disorders. A single nucleotide polymorphism (SNP) (-50 T/C) falling into the effective promoter region (nt -171 to +29) of the gene coding for glycogen synthase kinase 3-beta (GSK3-beta) has been identified. GSK3-beta codes for an enzyme which is a target for the action of lithium and which is also known to regulate circadian rhythms in Drosophila. We studied the effect of this polymorphism on the age at onset of bipolar disorder type I. A homogeneous sample of 185 Italian patients affected by bipolar disorder was genotyped. Age at onset was retrospectively ascertained with best estimation procedures. No association was detected between GSK3-beta -50 T/C SNP and the presence of bipolar illness. Homozygotes for the wild variant (T/T) showed an earlier age at onset than carriers of the mutant allele (F=5.53, d.f.=2,182, P=0.0047). Results warrant interest for the variants of genes pertaining to the molecular clock as possible endophenotypes of bipolar disorder, but caution ought to be taken in interpreting these preliminary results and future replication studies must be awaited.

Adolescent↗
PubMed2007

A new multimarker test for family-based association studies.

We propose a new multimarker test for family-based studies in candidate genes. We use simulations under different genetic models to assess the performance of competing testing strategies, characterized in this study as combinations of the following important factors: genes, statistical tests, tag single nucleotide polymorphisms (SNP) methods, number of tag SNPs and family designs. An ANOVA model is employed to provide descriptive summaries of the effects on power of the above-mentioned factors. We find that tag SNP methods, gene characteristics and family designs have minimal impact on the best testing strategy. The familywise error rate (FWER) controlling multiple comparison procedure and the new multimarker test offer the highest power followed by the asymptotic global haplotype test. Both the FWER and the multimarker test are invariant to family designs and gain power as we increase the number of tag SNPs. However, the performance of the global haplotype test is slightly degraded when analyzing larger numbers of tag SNPs. Within the framework of our study, the best strategy for family-based studies in candidate genes that emerged from our analysis is to use the FWER or the multimarker test and select 6-10 tag SNPs using any of the tag SNP methods considered. We confirm the conclusions of our study with an application to Alzheimer's disease data.

Alzheimer Disease↗
PubMed1991

Detection of mutations in insulin-receptor gene in NIDDM patients by analysis of single-stranded conformation polymorphisms.

We used the recently described technique of single-stranded conformation-polymorphism (SSCP) analysis to examine the insulin-receptor locus. First, the ability of the method to detect known mutations and polymorphisms in the insulin-receptor coding sequence was assessed. Regions of the insulin-receptor sequence containing 16 different nucleotide changes, 9 in patient genomic DNA and 7 as cloned cDNA in plasmids, were analyzed. All 9 patient genomic DNA mutants and 5 of 7 plasmid mutants exhibited variant SSCP patterns. To investigate the potential of the technique for screening many patients, the 5 exons that encode the tyrosine kinase domain of the insulin receptor were examined in 30 unrelated white subjects with non-insulin-dependent diabetes mellitus (NIDDM). Exons 17-21 were amplified from genomic DNA with polymerase chain reaction and subjected to SSCP analysis. Exons 19, 20, and 21 revealed no bands of aberrant migration, suggesting a high degree of conservation of these sequences. One diabetic subject had an SSCP variant in exon 18. Direct sequencing of this subject's genomic DNA revealed a heterozygous missense mutation (Lys1068----Glu1068). Five different SSCP patterns were detected in exon 17. Based on direct sequencing, these patterns were explained by combinations of three different nucleotide substitutions, two of which were common silent polymorphisms. One subject had a heterozygous missense mutation Val985---- Met985. Allele-specific oligonucleotide hybridization confirmed the presence of these mutations in the appropriate diabetic subjects and also detected the Val985 mutation in heterozygous form in 1 of 13 nondiabetic white subjects. SSCP analysis is a sensitive rapid method for screening for mutations in the insulin-receptor gene.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed2005

Haplotype analysis of a 100 kb region spanning TNF-LTA identifies a polymorphism in the LTA promoter region that is associated with atopic asthma susceptibility in Japan.

BACKGROUND: The tumour necrosis factor (TNF) gene family, which includes TNF, LTA, and LTB, is located consecutively on human chromosome 6p21 region, which has been linked to asthma by several genome-wide screens. (LTA, lymphotoxin-alpha; LTB, lymphotoxin-beta). OBJECTIVE: The aim of the present study was to determine whether genes on 6q21 are related to development of atopic asthma. Methods We screened for mutations in the coding and promoter regions of genes in the TNF-LTA region, including BAT1, NFKBIL1, LTA, TNF, LTB, AIF, and BAT2, and conducted a transmission disequilibrium test of 41 polymorphisms in 137 families identified through pro-bands with childhood-onset atopic asthma. (BAT1, HLA-B-associated transcript 1; NFKBIL1, nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor-like 1; AIF, allograft inflammatory factor 1). RESULTS: Haplotypes of the LTA/TNF linkage disequilibrium block were associated significantly with asthma (global P=0.0097). Transmission patterns of the common haplotypes to asthmatic offspring were predicted by a single-nucleotide polymorphism in the LTA promoter region. The G allele of the LTA-753G/A polymorphism was transmitted preferentially to asthma-affected individuals (P=0.001). Luciferase reporter assays with constructs containing the 5' and 3' flanking regions of the LTA gene showed 30-50% lower transcriptional activity when the -753A allele was present than that of other haplotypes. CONCLUSION: Our results suggest that LTA is one of the genes that contributes to susceptibility to atopic asthma, and that the association of the TNF/LTA haplotypes to asthma may be defined by the polymorphism in the LTA promoter region in the Japanese population.

Adolescent↗