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PubMed1999

Genomic organization of the human galpha14 and Galphaq genes and mutation analysis in chorea-acanthocytosis (CHAC).

Chorea-acanthocytosis (CHAC) (OMIM 200150) is a rare neurological syndrome characterized by neurodegeneration in combination with morphologically abnormal red cells (acanthocytosis). A partial yeast artificial chromosome contig of the CHAC critical region on chromosome 9q21 has been constructed, and 21 expressed sequence tags have been mapped. We have subsequently cloned Galpha14, a member of the G-protein alpha-subunit multigene family, and have identified Galphaq in the contig. The genomic structure of both genes has been established after construction of a bacterial artificial chromosome contig that showed Galphaq and Galpha14 to be in a head-to-tail arrangement (Cen-Galphaq-Galpha14-qter). Northern analysis found Galphaq to be ubiquitously expressed and Galpha14 to display a more restricted pattern of expression. Mutation analysis of the coding regions and splice sites for Galphaq and Galpha14 in 10 affected individuals from different families identified no changes likely to cause disease; however, two distinct single nucleotide polymorphisms in the coding region of Galpha14 have been identified. This study has excluded two plausible candidate genes from involvement in CHAC and has provided a solid platform for a positional cloning initiative.

Acanthocytes↗
PubMed1985

Phylogenetic analysis of polymorphic DNA sequences at the Adh locus in Drosophila melanogaster and its sibling species.

Recent sequencing of over 2300 nucleotides containing the alcohol dehydrogenase (Adh) locus in each of 11 Drosophila melanogaster lines makes it possible to estimate the approximate age of the electrophoretic "fast-slow" polymorphism. Our estimates, based on various possible patterns of evolution, range from 610,000 to 3,500,000 years, with 1,000,000 years as a reasonable point estimate. Furthermore, comparison of these sequences with those of the homologous region of D. simulans and D. mauritiana allows us to infer the pattern of evolutionary change of the D. melanogaster sequences. The integrity of the Adh-f electrophoretic alleles as a single lineage is supported by both unweighted pair-group method (UPGMA) and parsimony analyses. However, considerable divergence among the Adh-s lines seems to have preceded the origin of the Adh-f allele. Comparisons of the sequences of D. melanogaster genes with those of D. simulans and D. mauritiana genes suggest that the split between the latter two species occurred more recently than the divergence of some of the present-day Adh-s genes in D. melanogaster. The phylogenetic analyses of the D. melanogaster sequences show that the fast-slow distinction is not perfect, and suggest that intragenic recombination or gene conversion occurred in the evolution of this locus. We extended conventional phylogenetic analyses by using a statistical technique for detecting and characterizing recombination events. We show that the pattern of differentiation of DNA sequences in D. melanogaster is roughly compatible with the neutral theory of molecular evolution.

Alcohol Dehydrogenase↗
PubMed2002

Changes in hypervariable region 1 in patients with chronic hepatitis C of genotype 1b with biochemical response to interferon.

BACKGROUND/AIMS: The outcome of interferon (IFN) therapy of hepatitis C virus (HCV) infection can be classified as a complete viral response (CR), biochemical response (BR), or no response (NR). Why alanine aminotransferase (ALT) activity decreases in patients with BR despite viral persistence is unknown. METHODS: Of 158 patients infected with HCV genotype 1b, all 20 patients with BR and 20 of the 114 patients with NR, matched for viral load to the BR group, were studied. We sequenced nucleotides in the hypervariable region (HVR) of serum HCV RNA, and analyzed quasispecies of this region by the polymerase chain reaction and single-strand conformation polymorphism (PCR-SSCP). RESULTS: In HVR 1, SSCP patterns differed after therapy; the major clone before therapy disappeared with therapy in eight of the 20 BR patients, but in none of the 20 NR patients (P=0.0033; Fisher's exact test). PCR products of HVR 1 from six patients were cloned before and after therapy, and 40 clones from each patient were sequenced each time. Results of cloning and sequencing were generally consistent with those of SSCP. For the six patients, a major clone could be identified both before and after therapy. In two patients with BR, there were many changes in the amino acid sequence of the major clone after IFN; in one patient with NR, mutations were not found. CONCLUSION: Changes in the major viral clone with IFN treatment may be related to the decrease in ALT activity in some patients, in spite of the continued presence of HCV RNA.

Journal Article↗
PubMed2002

The mosaic structure of variation in the laboratory mouse genome.

Most inbred laboratory mouse strains are known to have originated from a mixed but limited founder population in a few laboratories. However, the effect of this breeding history on patterns of genetic variation among these strains and the implications for their use are not well understood. Here we present an analysis of the fine structure of variation in the mouse genome, using single nucleotide polymorphisms (SNPs). When the recently assembled genome sequence from the C57BL/6J strain is aligned with sample sequence from other strains, we observe long segments of either extremely high (approximately 40 SNPs per 10 kb) or extremely low (approximately 0.5 SNPs per 10 kb) polymorphism rates. In all strain-to-strain comparisons examined, only one-third of the genome falls into long regions (averaging >1 Mb) of a high SNP rate, consistent with estimated divergence rates between Mus musculus domesticus and either M. m. musculus or M. m. castaneus. These data suggest that the genomes of these inbred strains are mosaics with the vast majority of segments derived from domesticus and musculus sources. These observations have important implications for the design and interpretation of positional cloning experiments.

Albinism↗
PubMed1996

Nonneutral mitochondrial DNA variation in humans and chimpanzees.

We sequenced the NADH dehydrogenase subunit 3 (ND3) gene from a sample of 61 humans, five common chimpanzees, and one gorilla to test whether patterns of mitochondrial DNA (mtDNA) variation are consistent with a neutral model of molecular evolution. Within humans and within chimpanzees, the ratio of replacement to silent nucleotide substitutions was higher than observed in comparisons between species, contrary to neutral expectations. To test the generality of this result, we reanalyzed published human RFLP data from the entire mitochondrial genome. Gains of restriction sites relative to a known human mtDNA sequence were used to infer unambiguous nucleotide substitutions. We also compared the complete mtDNA sequences of three humans. Both the RFLP data and the sequence data reveal a higher ratio of replacement to silent nucleotide substitutions within humans than is seen between species. This pattern is observed at most or all human mitochondrial genes and is inconsistent with a strictly neutral model. These data suggest that many mitochondrial protein polymorphisms are slightly deleterious, consistent with studies of human mitochondrial diseases.

Amino Acid Sequence↗
PubMed2000

A long-term study on seasonal changes of gametic disequilibrium between allozymes and inversions in Drosophila subobscura.

Seasonal variation (spring, early summer, late summer, and autumn) of gametic disequilibrium between gene arrangements (OST and O3+4) of the O chromosome and Lap, Pept-1, and Acph allozyme loci, located inside these inversions, has been recorded in a natural population of Drosophila subobscura during seven years over a 15-year period. The length of the study allowed us to investigate the temporal variation of the allozyme-inversion associations by statistical methods of time series analysis. Cyclic seasonal changes of allozyme-inversion associations for both Lap and Pept-1 are detected in the natural population. In both cases, the patterns of seasonal change are due to the seasonal change of frequency of Lap and Pept-1 allozymes occurring exclusively within the OST gene arrangement. In contrast, the allozyme frequencies at these loci within the O3+4 gene arrangement are stable along seasons. The patterns of temporal variation of allozyme-inversion associations for Lap and Pept-1 in the natural population are contrasted with those previously published that correspond to gene arrangements of the O chromosome and nucleotide polymorphism at the rp49 region located inside these inversions, suggesting that natural selection is operating on these allozyme-inversion associations.

Acid Phosphatase↗
PubMed2006

Nucleotide oligomerization domain 2 (Nod2) is not involved in the pattern recognition of Candida albicans.

Nucleotide-binding oligomerization domain 2 (Nod2) pathways are known to interact with Toll-like receptor 2 (TLR2) and TLR4, which are pattern recognition receptors for Candida albicans. We observed that the prevalence of Nod2 polymorphisms was not increased in patients with Candida infections. Candida-induced cytokine production in individuals with Nod2 polymorphisms was unaffected. We conclude that Nod2 is unlikely to play an important role in the recognition of Candida albicans.

Adaptor Proteins, Signal Transducing↗
PubMed1992

An amino acid polymorphism within the RGD binding domain of platelet membrane glycoprotein IIIa is responsible for the formation of the Pena/Penb alloantigen system.

The human Pena/Penb alloantigen system represents a naturally occurring polymorphism of human platelet membrane glycoprotein (GP) IIIa, and has previously been implicated in the onset of two important clinical syndromes, neonatal alloimmune thrombocytopenic purpura and posttransfusion purpura. To investigate the molecular basis of the polymorphism underlying the Pen alloantigen system, we used the polymerase chain reaction to amplify platelet-derived GPIIIa mRNA transcripts. DNA sequence analysis of amplified GPIIIa cDNAs from nucleotides 161 to 1341 (encompassing amino acid residues 22-414) revealed a G526<==>A526 polymorphism that segregated precisely with Pen phenotype in twelve other individuals examined. This nucleotide substitution results in an Arg (CGA) to Gln (CAA) polymorphism at amino acid 143 of GPIIIa. Interestingly, this polymorphic residue is located within the putative RGD binding site (residues 109-171) of GPIIIa. Platelet aggregation patterns of a Penb/b individual, however, were nearly normal in response to all physiological agonists tested, indicating that this polymorphism does not grossly affect integrin function. Short synthetic peptides encompassing residue 143 were unable to mimic either the Pena or Penb antigenic determinants, suggesting that the Pen epitopes are dependent upon proper folding of the polypeptide chain. Finally, we constructed allele-specific recombinant forms of GPIIIa that differed only at amino acid residues 143. Whereas anti-Pena alloantibodies were able to recognize the Arg143 recombinant form of GPIIIa, anti-Penb antibodies were not. Conversely, anti-Penb alloantibodies were reactive only with the Gln143 isoform of the GPIIIa molecule. It thus appears that amino acid 143 of GPIIIa is not only associated with Pen phenotype, but specifically controls the formation and expression of the Pen alloantigenic determinants.

Amino Acid Sequence↗
PubMed2006

Alternative promoter use and splice variation in the human histamine H1 receptor gene.

Upstream gene structure and mRNA expression of the human histamine H1 receptor gene was investigated in cells relevant to the pathogenesis of asthma, (primary cultured human airway smooth muscle (HASM) cells, primary cultured human bronchial epithelial cells and bronchial epithelial cell line [BEAS2B]), and other tissues known to express histamine H1 receptors (placenta and brain). Splice variation of the 5' terminal exons gave three separate locations for novel promoters upstream of the detected transcription start sites. Further splice variants in the 5' untranslated region were also observed. Transient transfections of promoter/luciferase constructs showed these regions directed expression in HASM cells and BEAS2B cells. Polymorphism screening of the major regulatory regions identified a number of novel single-nucleotide polymorphisms. Expression of splice variants was confirmed by real-time PCR assays. Results showed one 5' terminal exon splice variant, comprising exons B/K, expressed preferentially in all tissues. Interestingly, the other 5' terminal exon splice variants showed tissue-specific patterns of expression, with variant F/K expressed negligibly (0.1%) in HASM cells, but accounting for 19.3% and 8.3% of total expression in BEAS2B cells and differentiated human bronchial epithelial cells, respectively. Splice variant A/K was second most highly expressed in differentiated human bronchial epithelial cells (23%), whereas its expression in BEAS2B and HASM cells was 1.7% and 4.4%, respectively. These data suggest the use of alternative promoters directing human H1 receptor gene expression, both within and between cell types.

3' Untranslated Regions↗
PubMed1989

RFLP-defined HLA-DP polymorphism in four ethnic groups.

Patterns of BglII, MspI, and TaqI DP alpha and DP beta hybridizing restriction fragment length polymorphisms are compared with primed lymphocyte typing--determined specificities in 28 10th International Histocompatibility Workshop core cell lines. Correlation of specific RFLP patterns with most recognized DP types is confirmed, although the RFLPs do not distinguish DPw3 from DPw6. Analysis of DP-region nucleotide sequence data shows that the observed RFLPs are those expected to hybridize to the DP alpha and beta probes and are thus not due to cross-hybridization to other genes. The distribution of RFLPs in Chinese, Micronesian, South Indian, and white Australian populations is described. The most frequent DP specificity in Chinese is DPw5. In the other populations DPw4 is the most common specificity, although DPw5 is also relatively common in Micronesians. Four new DP alpha RFLP patterns and three new DP beta patterns are described. There are also numerous unusual combinations of DP alpha and DP beta alleles particularly in the South Indian population.

Australia↗
PubMed2004

Association of the hCLCA1 gene with childhood and adult asthma.

Asthma is caused by bronchial inflammation. This inflammation involves mucus overproduction and hypersecretion. Recently, a mouse model of asthma showed that gob-5 is involved in the pathogenesis of asthma. The gob-5 gene is involved in mucus secretion and its expression is upregulated upon antigen attack in sensitized mice. The observation suggests that human homologue of gob-5, hCLCA1 (human calcium-dependent chloride channel-1), may be involved in human disease. We screened for single-nucleotide polymorphisms (SNPs) in hCLCA1 in the Japanese population. We identified eight SNPs, and performed association studies using 384 child patients with asthma, 480 adult patients with asthma, and 672 controls. In haplotype analysis, we found a different haplotype distribution pattern between controls and childhood asthma (P<0.0001) and between controls and adult asthma (P=0.0031). We identified a high-risk haplotype (CATCAAGT haplotype; P=0.0014) and a low-risk haplotype (TGCCAAGT haplotype; P=0.00010) in cases of childhood asthma. In diplotype analysis, patients who had the CATCAAGT haplotype showed a higher risk for childhood asthma than those who did not (P=0.0011). Individuals who had the TGCCAAGT haplotype showed a lower risk for childhood asthma than those who did not (P<0.0001). Our data suggested that variation of the hCLCA1 gene affects patients' susceptibility for asthma.

Adolescent↗
PubMed2005

Sequence context analysis in the mouse genome: single nucleotide polymorphisms and CpG island sequences.

A genome-wide view of sequence mutability in mice is still limited, although biologists usually assume the same scenario for mice as for humans. In this study, we examined the sequence context in the local environment of 482,528 mouse single nucleotide polymorphisms (SNPs). We found that CpG-containing short sequences, in general, had more representation in the local sequences of SNPs compared to the genome sequences. The extent of this overrepresentation was stronger in mice than in humans, which is inconsistent with previous observations of the weaker neighboring-nucleotide biases on mouse SNPs. To exclude the CpG effect, we compared the distribution patterns of short sequences among the six categories of SNPs. The results revealed an even stronger pattern in the CpG-containing group for C/G substitution compared to for A/G or C/T substitutions. We next performed the first genome-wide sequence context analysis of SNPs in the mouse CpG islands. SNPs occurring at CpG sites were 3.14-fold less prevalent than expected, suggesting the suppression of methylation-dependent deamination in the CpG islands. The extent of this suppression was less in mice than in humans. Finally, compared with humans, the observations of a greater deficit of CpG dinucleotides, a stronger overrepresentation of CpG-containing n-mers surrounding the polymorphic sites, and a higher SNP/genome ratio of CpG dinucleotides in the mouse genome support the "loss of CpG islands" model in the mouse lineage.

Animals↗
PubMed2004

[Sequence polymorphisms of the mitochondrial DNA control region in 100 Chengdu Hans in China].

OBJECTIVE: To study the genetic polymorphisms of the mitochondrial DNA (mtDNA) control region in Chengdu Han population. METHODS: Sequence polymorphisms of the mtDNA control region, hypervariable regions I and II from 100 unrelated Chinese Hans were determined by PCR and direct sequencing. RESULTS: Sequences of 404 nucleotides for hypervariable region I and 379 nucleotides for region II were obtained. Ninety-two and fifty variable sites were revealed in region I and region II respectively as compared to the reference sequence, and a total of 97 different genetic patterns from both the regions I and II were determined. The probability of identity was estimated at 1.84% for region I, 1.94% for region II, and 1.18% for both the regions. CONCLUSION: 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↗
PubMed2006

Spectrum of pathogenic mutations and associated polymorphisms in a cohort of 44 unrelated patients with long QT syndrome.

Long QT syndrome (LQTS) is a rare and clinically heterogeneous inherited disorder characterized by a long QT interval on the electrocardiogram, increased risk of syncope and sudden death caused by arrhythmias. This syndrome is mostly caused by mutations in genes encoding various cardiac ion channels. The clinical heterogeneity is usually attributed to variable penetrance. One of the reasons for this variability in expression could be the coexistence of common single nucleotide polymorphisms (SNPs) on LQTS-causing genes and/or unknown genes. Some synonymous and nonsynonymous exonic SNPs identified in LQTS-causing genes may have an effect on the cardiac repolarization process and modulate the clinical expression of a latent LQTS pathogenic mutation. We report the molecular pattern of 44 unrelated patients with LQTS using denaturing high-performance liquid chromatography analysis of the KCNQ1, KCNH2, SCN5A, KCNE1 and KCNE2 genes. Forty-five disease-causing mutations (including 24 novel ones) were identified in this cohort. Most of our patients (84%) showed complex molecular pattern with one mutation (and even two for four patients) associated with several SNPs located in several LQTS genes.

Adolescent↗
PubMed1998

Development of a PCR-restriction fragment length polymorphism assay using the nucleotide sequence of the Helicobacter hepaticus urease structural genes ureAB.

Infection with Helicobacter hepaticus causes chronic active hepatitis in certain strains of mice and is associated with hepatocellular carcinoma in A/JCr mice. Like the gastric helicobacters, H. pylori and H. mustelae, H. hepaticus possesses a high level of urease activity. However, the H. hepaticus urease structural gene sequences have not been previously determined, and the role of the urease enzyme in colonization and in pathogenesis is not known. PCR was used to amplify a portion of the urease structural genes from H. hepaticus genomic DNA. Amplified DNA fragments were cloned, and the nucleotide sequence was determined. The deduced amino acid sequence of the partial H. hepaticus ureA gene product was found to exhibit 60% identity and 75% similarity to the predicted H. pylori UreA. The deduced amino acid sequence of a partial H. hepaticus ureB gene product exhibited 75% identity and 87% similarity to the predicted H. pylori UreB. Diversity among H. hepaticus isolates was evaluated by means of a restriction fragment length polymorphism (RFLP) assay. The 1.6-kb fragments within the ureAB open reading frames, amplified from 11 independent isolates, were digested with the restriction endonuclease HhaI. Three distinct RFLP patterns were observed. Identical RFLP profiles were noted in sequential isolates of one strain of H. hepaticus during an 18 month in vivo colonization study, suggesting that the urease genes of H. hepaticus are stable. The urease genes among H. hepaticus strains were also well conserved, showing 98.8 to 99% nucleotide sequence identity among three isolates analyzed. These findings indicate that H. hepaticus has urease structural genes which are homologous to those of the gastric Helicobacter species and that these gene sequences can be used in a PCR and RFLP assay for diagnosis of this important murine pathogen.

Amino Acid Sequence↗
PubMed1995

HLA class I variation in Australian aborigines: characterization of allele B*1521.

Traditional methods of serological typing have largely used antisera of Caucasoid origin, which can overlook HLA heterogeneity in non-Caucasoid populations. Therefore, we have used molecular techniques to evaluate potential polymorphism in HLA class I molecules of Aborigines from the central desert and northern coast of Australia. The DNA sequence of common Aboriginal HLA-A and B antigens were compared with serological reaction patterns which suggested new polymorphisms. Although serological data indicated that long and short variants of A34 may exist, regardless of the serological pattern, all individuals carried the A*3401 allele. Therefore, the variation in A34 reaction pattern observed serologically was not attributable to primary sequence variation in the HLA A*3401 allele. Similarly, there was no detectable polymorphism in the sequences of selected HLA-B alleles, even though some of these alleles showed unusual serological reaction patterns. However, a new allele of B15 (B*1521) was detected in two individuals carrying this serotype. The cells from both of these individuals showed ambiguous reaction patterns with monospecific B62 and B75 sera. cDNA sequencing of the HLA B15 gene from these cells revealed a B15 allele that differed from B*1502 by a single nucleotide change. This change occurred at position 272, resulting in a C to G substitution at residue 67 in the consensus B15 cDNA sequence. Hence, the Australian Aborigines as an ethnic group show very little primary sequence polymorphism within the class I loci, consistent with the results obtained from previous serological studies.

Amino Acid Sequence↗
PubMed2006

Sequence diversity of the mucABD locus in Pseudomonas aeruginosa isolates from patients with cystic fibrosis.

The mucA gene of the muc operon, which is instrumental in the control of the biosynthesis of the exopolysaccharide alginate, is a hotspot of mutation in Pseudomonas aeruginosa, a micro-organism that chronically colonizes the airways of individuals with cystic fibrosis (CF). The mucA, mucB and mucD genes were sequenced in nine environmental isolates from aquatic habitats, and in 37 P. aeruginosa strains isolated from 10 patients with CF, at onset or at a late stage of chronic airway colonization, in order to elucidate whether there was any association between mutation and background genotype. The 61 identified single nucleotide polymorphisms (SNPs) segregated into 18 mucABD genotypes. Acquired and de novo stop mucA mutations were present in 14 isolates (38 %) of five mucABD genotypes. DeltaG430 was the most frequent and recurrent mucA mutation detected in four genotypes. The classification of strains by mucABD genotype was generally concordant with that by genome-wide SpeI fragment pattern or multilocus SNP genotypes. The exceptions point to intragenic mosaicism and interclonal recombination as major forces for intraclonal evolution at the mucABD locus.

Adolescent↗
PubMed1997

The amounts of nucleotide variation within and between allelic classes and the reconstruction of the common ancestral sequence in a population.

The amounts of nucleotide variation within and between allelic classes were studied. The expectation and variance of the number of segregating sites and the expectation of the average number of pairwise differences among a sample of DNA sequences were obtained by using the theory of gene genealogy with no recombination. When the ancestral allelic class is unknown, it was found that the amount of variation within an allelic class increases with its frequency in the sample, while the amount of variation between two allelic classes is the largest when the two allelic classes exist equally. On the other hand, if we know the ancestral allelic class, as the frequency of the mutant allelic class increases, the amounts of variation within the mutant allelic class and between two allelic classes increase and the amount of variation within the ancestral allelic class decreases. As an example, we analyzed the polymorphism in the ND5 gene of Drosophila melanogaster and constructed the common ancestral sequence with high confidence, suggesting that the pattern of polymorphism within species gives useful information to know the ancestral sequence of the species.

Alleles↗