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PubMed2000

Sequence variation at two eosinophil-associated ribonuclease loci in humans.

Host defense against invading pathogens is of great importance to the survival of higher organisms. We have been studying the evolution of mammalian eosinophil-associated ribonucleases (EARs), which are members of the ribonuclease A superfamily with known antipathogen activities. Earlier studies showed that positive selection promoted rapid diversification of paralogous EAR genes in both primates and rodents. Intraspecifically, however, it is unknown whether these genes also have divergent alleles. The recent discovery that the gene repertoire of the EAR family is much larger in rodents than in primates has led us to consider the possibility that primates maintain a large number of polymorphic alleles to compensate for a smaller gene repertoire. Here we present sequences of 2417 nucleotides at the two EAR loci, the eosinophil-derived neurotoxin (EDN, RNase 2) and eosinophil cationic protein (ECP, RNase 3), from >50 human individuals. Our data demonstrate that the nucleotide diversities (0.06-0.11%) at these loci are typical for human nuclear genes, thus permitting us to reject this polymorphism hypothesis. No significant departure from neutrality is noted and no signs of overdominant selection are observed. Similar patterns were observed in a preliminary study of chimpanzees. In summary, our results suggest that the antipathogen functions of the primate EARs are conserved after they are established and that these proteins are not currently undergoing rapid diversification in response to challenge from invading microorganisms.

Alleles↗
PubMed2004

A polymorphic tandem repeat potentially useful for typing in the chromosome of Yersinia enterocolitica.

The hexanucleotide CCAGCA was found repeated 15 times in tandem on the 5' side of the virginiamycin acetyl transferase gene of Yersinia enterocolitica strain Y56. The corresponding region was analysed by PCR from 54 clinical strains belonging to the same biotype and serotype, and others from this laboratory collection belonging to different biotypes and serotypes. Each strain produced a single amplification product whose size was variable among strains, revealing that the locus was polymorphic. Nucleotide sequence determination of selected PCR products showed that the polymorphism was due to the precise expansion or reduction in the number of hexanucleotide repeats. Analysis of this locus in a few strains showing the same PFGE pattern showed that it was also polymorphic. These results suggest that this method could be valuable to increase the discriminatory power of current Y. enterocolitica typing schemes.

Amino Acid Sequence↗
PubMed1996

Topical gentamicin-induced hearing loss: a mitochondrial ribosomal RNA study of genetic susceptibility.

Mitochondrial ribosomal RNA mutation has been shown to predispose affected individuals to aminoglycoside-induced hearing loss (AIHL). An A-to-G nucleotide substitution at the 1555 position within the 12S ribosomal RNA gene has been identified with a maternally inherited pattern in affected Asian pedigrees. The aim of this study was to identify the frequency of this DNA polymorphism in subjects who appear to show hypersensitivity to topical (middle ear) application of aminoglycoside. In this pilot study, 10 subjects with AIHL were recruited. Eight underwent vestibular ablative therapy with middle ear instillation of gentamicin for disabling vertigo, and two were treated with topical antibiotic drops for otitis media in the presence of a tympanic perforation. DNA samples were extracted, and polymerase chain reaction (PCR) technique was used for gene amplification and purification, searching for 1555 A-to-G substitution in the 12S ribosomal RNA gene. None of the subjects demonstrated this specific mutation.

Adult↗
PubMed2003

A conservative test of genetic drift in the endosymbiotic bacterium Buchnera: slightly deleterious mutations in the chaperonin groEL.

The obligate endosymbiotic bacterium Buchnera aphidicola shows elevated rates of sequence evolution compared to free-living relatives, particularly at nonsynonymous sites. Because Buchnera experiences population bottlenecks during transmission to the offspring of its aphid host, it is hypothesized that genetic drift and the accumulation of slightly deleterious mutations can explain this rate increase. Recent studies of intraspecific variation in Buchnera reveal patterns consistent with this hypothesis. In this study, we examine inter- and intraspecific nucleotide variation in groEL, a highly conserved chaperonin gene that is constitutively overexpressed in Buchnera. Maximum-likelihood estimates of nonsynonymous substitution rates across Buchnera species are strikingly low at groEL compared to other loci. Despite this evidence for strong purifying selection on groEL, our intraspecific analysis of this gene documents reduced synonymous polymorphism, elevated nonsynonymous polymorphism, and an excess of rare alleles relative to the neutral expectation, as found in recent studies of other Buchnera loci. Comparisons with Escherichia coli generally show patterns predicted by their differences in N(e). The sum of these observations is not expected under relaxed or balancing selection, selective sweeps, or increased mutation rate. Rather, they further support the hypothesis that drift is an important force driving accelerated protein evolution in this obligate mutualist.

Buchnera↗
PubMed2006

Frequency of LRRK2 mutations in early- and late-onset Parkinson disease.

OBJECTIVE: To evaluate the frequency of leucine-rich repeat kinase gene (LRRK2) mutations and single nucleotide polymorphisms (SNPs) in early-onset Parkinson disease (EOPD) and late-onset Parkinson disease (LOPD). METHODS: We genotyped five previously reported LRRK2 mutations (G2019S, L1114L, I1122V, R1441C, and Y1699C) and 17 coding SNPs for haplotype analysis in 504 cases with PD and 314 controls enrolled in the Genetic Epidemiology of PD Study. Cases and controls were recruited without knowledge of family history of PD and cases were oversampled in the < or =50 age at onset (AAO) category. RESULTS: The LRRK2 G2019S mutation was present in 28 cases with PD (5.6%) and two controls (0.6%) (chi(2) = 13.25; p < 0.01; odds ratio 9.18, 95% CI: 2.17 to 38.8). The mutations L1114L, I1122V, R1441C, and Y1699C were not identified. The frequency of the LRRK2 G2019S mutation was 4.9% in 245 cases with AAO < or =50 years vs 6.2% in 259 cases with AAO >50 (p = 0.56). All cases with PD with the G2019S mutation shared the same disease-associated haplotype. The frequency of the LRRK2 G2019S mutation was higher in the subset of 181 cases reporting four Jewish grandparents (9.9%) than in other cases (3.1%) (p < 0.01). Age-specific penetrance to age 80 was 24% and was similar in Jewish and non-Jewish cases. CONCLUSIONS: The G2019S mutation is a risk factor in both early- and late-onset Parkinson disease and confirms the previous report of a greater frequency of the G2019S mutation in Jewish than in non-Jewish cases with Parkinson disease.

Adult↗
PubMed1994

Familial hypercholesterolaemia caused by a non-sense mutation in codon 329 of the LDL receptor gene.

Analysis of single-strand conformation polymorphisms (SSCP) was employed to screen familial hypercholesterolaemia (FH) subjects for point mutations in exon 7 of the low density lipoprotein receptor (LDLR) gene. An abnormal band pattern was found in one out of 100 unrelated FH subjects. The underlying mutation was found by DNA sequencing to be due to heterozygosity (C/T) at nucleotide 1048. Nucleotide 1048 is the first nucleotide of codon 329, and is located within the domain that has a high degree of homology with the precursor for epidermal growth factor. The C-->T transition, referred to as FH-Fossum, changes codon 329 from CGAArg to TGAStop. The mutation is expected to cause a class 1 receptor defect.

Codon↗
PubMed1995

The diversity of T-cell receptor repertoire of peripheral CD4+ lymphocytes in LEC mutant rats.

A novel mutant strain of rats, LEC, exhibits an arrest of T-cell maturation from CD4+CD8+ to CD4+CD8- but not the CD4-CD8+ cells in the thymus. Nevertheless, CD4+T cells arise in lymph nodes of LEC rats, implying extrathymic T-cell maturation. We analyzed the variable (V) and junctional region diversity of T-cell receptor (TCR) beta- chains in this population, since several reports have provided evidence that extrathymically matured T cells exhibit a biased expression of the TCR repertoire. CD4+ T cells in LEC rat lymph nodes exhibited a polymorphic V beta gene expression pattern. However, biased V beta gene expression was not identified in peripheral CD4+ T cells of LEC rats when compared with V beta gene expression in their thymocytes. Furthermore, junctional regions of TCR beta chains exhibited a vast diversity created by non-germline- encoded nucleotide (N nucleotide) additions. These results indicate that peripheral CD4+ T cells in LEC rats possess a vast diversity in the TCR repertoire as do thymocytes of the same rat, suggesting that they derive from the thymus.

Amino Acid Sequence↗
PubMed2006

Construction of a single nucleotide polymorphism linkage map for the silkworm, Bombyx mori, based on bacterial artificial chromosome end sequences.

We have developed a linkage map for the silkworm Bombyx mori based on single nucleotide polymorphisms (SNPs) between strains p50T and C108T initially found on regions corresponding to the end sequences of bacterial artificial chromosome (BAC) clones. Using 190 segregants from a backcross of a p50T female x an F1 (p50T x C108T) male, we analyzed segregation patterns of 534 SNPs between p50T and C108T, detected among 3840 PCR amplicons, each associated with a p50T BAC end sequence. This enabled us to construct a linkage map composed of 534 SNP markers spanning 1305 cM in total length distributed over the expected 28 linkage groups. Of the 534 BACs whose ends harbored the SNPs used to construct the linkage map, 89 were associated with 107 different ESTs. Since each of the SNP markers is directly linked to a specific genomic BAC clone and to whole-genome sequence data, and some of them are also linked to EST data, the SNP linkage map will be a powerful tool for investigating silkworm genome properties, mutation mapping, and map-based cloning of genes of industrial and agricultural interest.

Animals↗
PubMed1995

Aberrant patterns of immunoglobulin levels in Wiskott-Aldrich syndrome.

We have investigated IgM deficiency in Wiskott-Aldrich syndrome patients. From the assessment of T and B cell functions in pokeweed mitogen-induced immunoglobulin (Ig) production, IgM deficiency was chiefly thought to result from B cell dysfunction. The percentages of surface IgM-bearing cells were decreased in peripheral blood mononuclear cells (PBMCs) and the number of IgM-secreting cells was also decreased. Lymphoblast cell lines (LCLs) from the patients have produced IgG and IgA, but never IgM. Moreover the expression of the C mu transcript from the patients' PBMCs and their LCLs were decreased, whereas the C gamma gene was well expressed. No germ-line polymorphism existed between the patients and the controls in the C mu region, and no mutation was detected in the mu s C-terminal and the M exon by nucleotide sequencing. These suggest that the Ig heavy chain (IGHC) isotype switch may be abnormally accelerated in the patients' B cells. While the methylation patterns of the human Ig enhancer gene region were the same between the patient and the control, the methylation patterns of the I gamma 1 region showed less methylation in the patient than in the control, which may cause low IgM expression and high expression levels of other classes located downstream of the IGHC gene.

Adolescent↗
PubMed2006

Human clock, PER1 and PER2 polymorphisms: lack of association with cocaine dependence susceptibility and cocaine-induced paranoia.

Considerable research points to the importance of genetic mechanisms in psychostimulant addiction. Behavioral sensitization, a well-documented response to repeated stimulant exposure, may be mechanistically important in clinical features of the disorder, including escalating patterns of drug use, craving and drug-induced paranoia. Basic studies in both Drosophila melanogaster and mice have suggested the importance of circadian rhythm genes in locomotor sensitization and reward. The primary objective of the current study was to assess the potential involvement of three human orthologs (CLOCK, PER1 and PER2) in clinical phenotypes of the disorder. Allelic associations of three single nucleotide polymorphisms (SNPs) were assessed for both cocaine dependence and cocaine-induced paranoia in 186 cases and 273 controls. Potential population stratification biases were controlled for by means of within-population comparisons, and by structured association methods (using all populations). No differences in allele frequencies were found for any of the three single nucleotide polymorphisms studied between cocaine dependent and control subjects or between paranoid and nonparanoid cocaine users. These results do not support the involvement of genetic variation in these three circadian gene SNPs for influencing risks for either of these cocaine phenotypes.

Animals↗
PubMed2003

Analysis of the transcobalamin II 776C>G (259P>R) single nucleotide polymorphism by denaturing HPLC in healthy elderly: associations with cobalamin, homocysteine and holo-transcobalamin II.

A relatively new method for the detection of single nucleotide polymorphisms is the use of denaturing high-performance liquid chromatography (DHPLC). DHPLC was used to analyse the transcobalamin II 776C>G polymorphism in DNA from 159 healthy elderly. Furthermore, cobalamin, folate, homocysteine and holo-transcobalamin II (holo-TC II) were measured. The allele frequency of the G-allele was 17% with n = 55 harbouring the CC genotype, n = 77 being heterozygous and n = 27 showing the GG genotype. Holo-TC II concentrations were significantly decreased in patients harbouring the GG genotype. There was no effect on cobalamin, methylmalonyl-CoA, folate or homocysteine concentrations. A new G>A variant at nucleotide position 810 in the TC II gene was detected by an altered peak pattern in the DHPLC and further elucidated by direct sequencing. The TC II G810A variant is a silent mutation without replacement of the corresponding amino acid (alanine) at position 270 in the TC II protein and was only found as a heterozygous genotype in a single patient. The new variant would have been undetected by other methods used for single nucleotide polymorphism detection, e.g., restriction fragment length polymorphism analysis. The results suggest that the common TC II 776C>G polymorphism has no major influence on vitamin B12 metabolism.

Aged↗
PubMed2006

Evidence for recombination in Mycobacterium tuberculosis.

Due to its mostly isolated living environment, Mycobacterium tuberculosis is generally believed to be highly clonal, and thus recombination between different strains must be rare and is not critical for the survival of the species. To investigate the roles recombination could have possibly played in the evolution of M. tuberculosis, an analysis was conducted on previously determined genotypes of 36 synonymous single nucleotide polymorphisms (SNPs) in 3,320 M. tuberculosis isolates. The results confirmed the predominant clonal structure of the M. tuberculosis population. However, recombination between different strains was also suggested. To further resolve the issue, 175 intergenic SNPs and 234 synonymous SNPs were genotyped in 37 selected representative strains. A clear mosaic polymorphic pattern ahead of the MT0105 locus encoding a PPE (Pro-Pro-Glu) protein was obtained, which is most likely a result of recombination hot spot. Given that PPE proteins are thought to be critical in host-pathogen interactions, we hypothesize that recombination has been influential in the history of M. tuberculosis and possibly a major contributor to the diversity observed ahead of the MT0105 locus.

Antigens, Bacterial↗
PubMed2004

A novel deletion mutation in the arginine vasopressin receptor 2 gene and skewed X chromosome inactivation in a female patient with congenital nephrogenic diabetes insipidus.

X-linked nephrogenic diabetes insipidus (NDI) is a rare inherited disorder caused by mutations in the arginine vasopressin receptor 2 (V2R) gene. The clinical phenotype is fully expressed in hemizygous male patients and is usually asymptomatic in heterozygous females. In the present study, a 51-yr-old Japanese female with congenital NDI and her family members were examined. The patient developed severe hypernatremia accompanied by hypoosmotic polyuria after gynecological surgery, and was unable to concentrate urinary osmolality in response to exogenous vasopressin. Direct sequencing analysis of the propositus and her two affected sons revealed a two-nucleotide deletion change at codon 30 (g.452-453delAC) in the V2R gene, resulting in a frameshift and premature termination in translation at codon 190. The X chromosome inactivation pattern was investigated in the propositus using methylation analysis of the polymorphic CAG repeat in the androgen receptor gene, and the value for relative X chromosome inactivation of one allele was 70.2%. In conclusion, we identified a novel V2R gene mutation in a female patient and her sons with congenital NDI, and her phenotype may be caused by skewed X chromosome inactivation.

Chromosomes, Human, X↗
PubMedDate not supplied

Plasmodium falciparum: limited genetic diversity of MSP-2 in isolates circulating in Brazilian endemic areas.

The genetic polymorphism of the surface merozoite protein 2 (MSP-2) was evaluated in Plasmodium falciparum isolates from individuals with uncomplicated malaria living in a Brazilian endemic area of Peixoto de Azevedo. The frequency of MSP-2 alleles and the survival of genetically different populations clones in 104 isolates were verified by Southern blot and SSCP-PCR. Single and mixed infections were observed in similar frequencies and the rate of detection of FC27 and 3D7 allelic families was equivalent. Eight alleles were identified and among them, the sequence polymorphism was mainly attributed to variations in the repetitive region. Interestingly, in three alleles nucleotide polymorphism was identical to that detected in a previous study, conducted in 1992, in a near Brazilian endemic area. This finding demonstrated the genetic similarity between two isolate groups, besides the certain temporal stability in the allelic patterns. The implications of these data for studies on the genetic diversity are also discussed.

Alleles↗
PubMed2005

Array-based binary analysis for bacterial typing.

An allele-specific oligonucleotide microarray was developed for rapid typing of pathogens based on analysis of genomic variations. Using a panel of Escherichia coli strains as a model system, selected loci were sequenced to uncover differences, such as single- or multiple-nucleotide polymorphisms as well as insertion/deletions (indels). While typical genomic profiling experiments employ specific sequences targeted to genomic DNA unique to a single strain or virulent gene, the present array is designed to type bacteria based on a patterned signature response across multiple loci. In the signature concept, all strains are interrogated by hybridizing their amplified DNA to an array containing multiple probe sequences. Allele-specific oligonucleotide probe sequences targeting each of these variable regions were synthesized and included in a custom fiber-optic array. For each locus, a set of specific probe sequences is selected, such that hybridization gives a binary signal/no signal response to each of the probes. Using this strategy for multiple loci, many pathogens or microorganisms could be classified using a limited number of probes. Because of the advantages of the fiber-optic array platform over other array formats, including sensitivity and speed, the platform described in this paper is capable of supporting a high-throughput diagnostic strategy.

Bacterial Typing Techniques↗
PubMed2001

Physical and transcriptional map of the hereditary inclusion body myopathy locus on chromosome 9p12-p13.

Hereditary inclusion body myopathy (HIBM) is a group of neuromuscular disorders characterised by adult-onset, slowly progressive distal and proximal muscle weakness and typical muscle pathology. Previously, we have mapped the gene responsible for a recessive form of HIBM to chromosome 9p1 and narrowed the interval to one single YAC clone of 1 Mb in size. As a further step towards the identification of the HIBM gene, we have constructed a detailed physical and transcriptional map of this region. A high resolution BAC contig that includes the HIBM critical region, flanked by marker 327GT4 and D9S1859, was constructed. This contig allowed the precise localisation of 25 genes and ESTs to the proximal region of chromosome 9. The expression pattern of those mapped genes and ESTs was established by Northern blot analysis. In the process of refining the HIBM interval, 13 new polymorphic markers were identified, of which 11 are CA-repeats, and two are single nucleotide polymorphisms. Certainly, this map provides an important integration of physical and transcriptional information corresponding to chromosome 9p12-p13, which is expected to facilitate the cloning and identification not only of the HIBM gene, but also other disease genes which map to this region.

Chromosomes, Artificial, Bacterial↗
PubMed1994

New polymorphism on platelet glycoprotein IIIa gene recognized by endonuclease Msp I: implications for PlA typing by allele-specific restriction analysis.

BACKGROUND: Five human platelet alloantigen systems have been shown to result from single base pair substitutions in encoding regions of platelet glycoprotein genes IIIa, Ib, IIb, and Ia. For each of the diallelic systems, at least one restriction enzyme is known to cut only one of the two haplotypes. In the PlA system, restriction endonucleases Nci I and Msp I both recognize the PlA2 allele. STUDY DESIGN AND METHODS: A causal observation of an unexpected Msp I restriction pattern of a PlA2/PlA2 individual was made. Samples from 261 blood donors were then typed for antigens of the PlA system by restriction fragment length polymorphism analysis using the Nci I and Msp I restriction enzymes. RESULTS: Applying both enzymes, concordant restriction patterns were found in 258 of 261 blood donors. Three donors had a base pair mutation on the PlA2 allele, which creates an additional restriction site for Msp I 20 base pairs downstream from the PlA polymorphic site. Nucleotide sequence analysis revealed a CT217-->CG217G base exchange resulting in a Leu40-->Arg40 polymorphism of glycoprotein IIIa. CONCLUSION: Presuming that the mutation is not a singular phenomenon and also occurs with the PlA1 haplotype, it could lead to false interpretations of restriction analysis with Msp I. To exclude that possibility, Nci I is preferred for restriction fragment length polymorphism typing in the PlA system.

Antigens, Human Platelet↗
PubMed1997

Comparison of SSCP analysis and CFLP analysis for mutation detection in the human iduronate 2-sulfatase gene.

Scanning methodologies are used for the identification of DNA fragments that differ from the normal nucleotide sequence. Fragments that produce abnormal band patterns are sequenced for characterization of the exact mutation. Factors considered in choosing a scanning methodology include reproducibility, sensitivity, and time. In the present study, we compared single-stranded conformational polymorphism (SSCP) and Cleavase fragment length polymorphism (CFLP) methodologies for mutation scanning of exon VIII in the iduronate 2-sulfatase (IDS) gene. Mutations of the IDS gene result in an X-linked lysosomal storage disease, Hunter syndrome. These six known mutations analyzed by the two methods included a one base pair deletion, a one base pair insertion, and four point mutations. SSCP analysis detected all of the mutations and CFLP analysis detected three of the six mutations. We concluded that SSCP analysis was preferable to CFLP analysis for scanning exon VIII in the IDS gene for mutations.

Base Sequence↗