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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↗
PubMed1992

Nucleotide sequence polymorphism in a hotspot mutation region of the p53 gene.

By screening for mutations in the p53 coding sequence by means of single-strand conformation polymorphism (SSCP) in a series of breast tumors we detected a novel polymorphism. This change in the SSCP pattern was detected in 6.2% of the tumor DNAs analysed and implied an A to G substitution at the last base of codon 213, thus representing a neutral change. First suspecting a somatic mutation we confirmed its presence in matched sets of DNAs from normal tissues. Extending our study to a series of 60 ovarian carcinomas and 70 healthy blood donors we noticed that this polymorphism represented only 3% and 2.6% respectively. We wondered if the difference in frequency in the breast cancer population might not be related to familial breast cancer and analysed 26 DNAs from patients showing predisposition to the disease. Two patients presented this polymorphism and one corresponding kindred was analysed, revealing a mendelian mode of transmission but no correlation with the cancer phenotype.

Base Sequence↗
PubMed1987

Allelic forms of the alpha- and beta-chain genes encoding DQw1-positive heterodimers.

On chromosome 6, in the HLA region, the DQ subregion is located immediately centromeric to the DR subregion. Even though only three serological specificities to date have been officially recognized (DQw1, DQw2, and DQw3), it seems likely that the phenotypical polymorphism expressed by DQ molecules is much more complex. There are reasons to believe that fixed alpha-beta combinations exist, each of them associated with a different DR allele. DQw1 is a determinant present on DQ molecules that are found associated with DR1-, DR2-, and DRw6-positive haplotypes. By restriction fragment length polymorphism analysis, we recognized three allelic DQ-alpha and three allelic DQ-beta patterns associated with DQw1. In addition, one of these alpha/beta pairs associated with DR1, two with DR2, and a fourth with DRw6. We have obtained evidence using nucleotide sequencing that there are as many allelic forms of DQ-alpha and DQ-beta genes as there are different molecular DQ-alpha and DQ-beta patterns. The DQ-alpha and DQ-beta chains of DQw1-positive molecules each are encoded by at least three distinctly different allelic genes, and particular alpha/beta gene combinations are associated with the same DR alleles as their corresponding molecular alpha/beta pairs.

Alleles↗
PubMed2002

Patterns of diversity and recombination along chromosome 1 of maize (Zea mays ssp. mays L.).

We investigate the interplay between genetic diversity and recombination in maize (Zea mays ssp. mays). Genetic diversity was measured in three types of markers: single-nucleotide polymorphisms, indels, and microsatellites. All three were examined in a sample of previously published DNA sequences from 21 loci on maize chromosome 1. Small indels (1-5 bp) were numerous and far more common than large indels. Furthermore, large indels (>100 bp) were infrequent in the population sample, suggesting they are slightly deleterious. The 21 loci also contained 47 microsatellites, of which 33 were polymorphic. Diversity in SNPs, indels, and microsatellites was compared to two measures of recombination: C (=4Nc) estimated from DNA sequence data and R based on a quantitative recombination nodule map of maize synaptonemal complex 1. SNP diversity was correlated with C (r = 0.65; P = 0.007) but not with R (r = -0.10; P = 0.69). Given the lack of correlation between R and SNP diversity, the correlation between SNP diversity and C may be driven by demography. In contrast to SNP diversity, microsatellite diversity was correlated with R (r = 0.45; P = 0.004) but not C (r = -0.025; P = 0.55). The correlation could arise if recombination is mutagenic for microsatellites, or it may be consistent with background selection that is apparent only in this class of rapidly evolving markers.

Chromosome Mapping↗
PubMed1997

Analysis of amino-acid and nucleotide variants in the spinocerebellar ataxia type 1 (SCA1) gene in schizophrenic patients.

Several loci-containing genes that might harbour mutations predisposing to schizophrenia have recently been identified. The locus on chromosome 6p has been detected by several groups and appears to predispose to schizophrenia in 15%-30% of the pedigrees in one of these studies. The chromosome 6p locus for schizophrenia spans about 30 cM, between markers D6S296 and D6S276. The current transcription map of the 6p22-24 region includes three expressed sequence tags and six genes, one of which is the spinocerebellar ataxia type 1 (SCA1) gene. Patients with SCA1 have the CAG repeat sequence, which encodes a polyglutamine stretch in the ataxin-1 protein, expanded beyond the normal range. More recently, linkage disequilibrium between schizophrenia and the SCA1 CAG repeat has been reported. SCA1 is a good candidate gene for the schizophrenia-susceptibility locus on chromosome 6p as indicated by its expression pattern. We have studied the coding region of the SCA1 gene (exons 8 and 9) in samples from schizophrenia patients and have identified two amino-acid variants (S186C and P754S) and three nucleotide polymorphisms (1409A/G, 1865T/C and 2150A/G). One of the amino-acid changes (S186C) was present in two schizophrenic brothers from one family and in a schizophrenic patient and a non-affected subject of a second family but it was not detected in 100 unrelated subjects from the general population. S186C and other variants may be of relevance to the complex genetic factors involved in schizophrenia phenotypes.

Alleles↗
PubMed2002

Sequence of a new DR12 allele with two silent mutations that affect PCR-SSP typing.

A new HLA-DR12 allele has been identified in a European Caucasoid bone marrow donor. The DRB1*12012 allele differs from DRB1*12011 by two silent substitutions at codons 72 and 78, two polymorphic positions used for DNA subtyping of the DR12 serotype. The co-occurence of the two nucleotide changes is unique to the DR12 group and results in a new PCR-SSP typing pattern. The complete HLA type of the donor is A24, A68; B55, B61; Cw*01, Cw*0304; DRB1*12012, DRB1*1402; DRB3*0101, DRB3*0202; DQB1*0301. HLA-DRB1*12012 is a rare allele as it occurs in < 0.2% of DR12 donors.

Alleles↗
PubMed2002

Evolution of a perfect simple sequence repeat locus in the context of its flanking sequence.

Microsatellites, which have rapidly become the preferred markers in population genetics, reliably assign individual chinook salmon to the winter, fall, late-fall, or spring chinook runs in the Sacramento River in California's Central Valley (Banks et al. 2000. Can. J. Fish. Aquat. Sci. 57:915-927). A substantial proportion of this discriminatory power comes from Ots-2, a simple CA repeat, which is expected to evolve rapidly under the stepwise mutation model. We have sequenced a 300-bp region around this locus and typed 668 microsatellite-flanking sequence haplotypes to explore further the basis of this microsatellite divergence. Three sites of nucleotide polymorphism in the Ots-2 flanking sequence define five haplotypes that are shared by the Californian and Canadian populations. The Ots-2 microsatellite alleles are nonrandomly distributed among these five haplotypes in a pattern of gametic disequilibrium that is also shared among populations. Divergence between the winter run and other Central Valley stocks appears to be caused by a combination of surprisingly static evolution at Ots-2 within a context of more rapidly changing haplotype frequencies.

Alleles↗
PubMed2005

Roles of methylenetetrahydrofolate reductase C677T polymorphism in repeated pregnancy loss.

Congenital thrombophilia in repeated pregnancy lost (RPL) has been noted for years. Methylenetetrahydrofolate reductase (MTHFR) gene is an interesting gene, mentioned for its possible roles in RPL. There is considerable controversy regarding the clinical role of MTHFR C677T polymorphism as a risk factor of RPL. Here, a summative analysis is performed on the recent previous reports on the MTHFR C677T and its correlation to RPL. The metanalysis was performed to assess the correlation between the pattern of MTHFR C677T polymorphism and RPL. From available eight case-control studies, 752 patients and 625 controls are evaluated. The overall frequencies of 4G allele for the patients and controls are 31.5 and 33.5, respectively. According to this study, 53.1% of subjects with T allele have RLP while 55.3% of subjects without T allele have RLP. From overall risk estimation, the subjects with T alleles have 0.96 times lower risk to RLP. According to this analysis, the pattern of MTHFR C677T polymorphism might not represent a useful marker of increased risk for RPL. In addition, there was no association between pattern of MTHFR C677T polymorphism and ethnicity of the patients in this study.

Abortion, Habitual↗
PubMed1998

Differentiation of BCG-induced lymphadenitis from tuberculosis in lymph node biopsy specimens by molecular analyses of pncA and oxyR.

Without culture, differentiation of bacille Calmette-Guérin-induced lymphadenitis (BCG-LA) from tuberculosis (TB) is sometimes difficult by histology, but is important because of different treatment schemes. The purpose of this study was to investigate the feasibility of differentiating BCG-LA from TB in lymph nodes (LNs) by molecular analyses of two recently identified genes, pncA and oxyR. In both genes, a single tuberculosis difference exists between Mycobacterium bovis and M. tuberculosis. M tuberculosis complex (MTC) DNA was first detected in nine of ten formalin-fixed, paraffin-embedded LNs from patients aged under 20 years with suspected mycobacterial infections, using polymerase chain reaction (PCR) for IS6110, an insertion sequence specific for MTC species. PCR, together with direct DNA sequencing and PCR-restriction fragment length polymorphism (RFLP) assay, was then performed to identify polymorphic nucleotide in pncA and oxyR, respectively. For comparison, 37 adult cases of tuberculous lymphadenitis were also analysed by PCR-single strand conformation polymorphism (SSCP) assay for pncA and by PCR-RFLP for oxyR. The results revealed that five of the nine IS6110-positive child cases had a G residue at nucleotide 169 in pncA, and also had a three-band pattern after digesting the amplified oxyR segment with AluI, suggesting BCG-LA. The remaining four child cases, as well as all adult cases with detectable IS6110, showed no motility shift in pncA PCR-SSCP and had the same one-band pattern as M. tuberculosis in oxyR PCR-RFLP, suggesting TB lymphadenitis. The data from molecular analyses showed a good correlation with the vaccination history and clinicopathological findings, except for one case. This study indicates that molecular assay of either oxyR or pncA could be a rapid and useful tool to distinguish BCG-LA from TB.

Adolescent↗
PubMed2004

Genomic imprinting of H19 in naturally reproduced and cloned cattle.

Animals produced from assisted reproductive technologies suffer from developmental abnormalities and early fetal death at a higher frequency than that observed in those produced by natural breeding. These symptoms are reminiscent of imprinting disruptions in the human and mouse, suggesting the possibility of perturbations in the expression of imprinted genes such as biallelic expression or silencing. H19 is one of the imprinted genes first identified in mice and humans, but its sequence and imprinting status have not been determined in cattle. In the present study, we obtained the majority of the bovine H19 gene sequence (approximately 2311 base pairs), identified a single nucleotide polymorphism (SNP) in exon 5 and determined the frequencies of different alleles containing the SNP. Our analysis demonstrated that, in cattle produced by natural breeding, H19 was indeed imprinted as shown by either predominant or exclusive expression of the maternal allele. We also analyzed the imprinting pattern of H19 in organs of four animals produced by somatic cell nuclear transfer that died shortly after birth or had developed abnormalities that necessitated immediate killing at birth. Three out of four cloned animals showed biallelic expression of H19, supporting our hypothesis that imprinting disruption is present in cloned animals that suffered from developmental abnormalities at birth. Examination of the expression of H19 in the offspring of a cloned animal produced by artificial insemination showed that the imprinting pattern in this animal was indistinguishable from those of control animals, suggesting that either imprinting disruptions in cloned animals are corrected through natural reproduction or that they are not present in healthy cloned animals capable of undergoing natural reproduction.

Alleles↗
PubMed2004

Nucleotide and amino acid polymorphisms at drug resistance sites in non-B-subtype variants of human immunodeficiency virus type 1.

We have compared nucleotide substitutions and polymorphisms at codons known to confer drug resistance in subtype B strains of human immunodeficiency virus type 1 (HIV-1) with similar substitutions in viruses of other subtypes. Genotypic analysis was performed on viruses from untreated individuals. Nucleotide and amino acid diversity at resistance sites was compared with a consensus subtype B reference virus. Among patients with non-subtype B infections, polymorphisms relative to subtype B were observed at codon 10 in protease (PR). These included silent substitutions (CTC-->CTT, CTA, TTA) and an amino acid mutation, L10I. Subtype A viruses possessed a V179I substitution in reverse transcriptase (RT). Subtype G viruses were identified by silent substitutions at codon 181 in RT (TAT-->TAC). Similarly, subtype A/G viruses were identified by a substitution at position 67 in RT (GAC-->GAT). Subtype C was distinguished by silent substitutions at codons 106 (GTA-->GTG) and 219 (AAA-->AAG) in RT and codon 48 (GGG-->GGA) in PR. Variations relative to subtype B were seen at RT position 215 (ACC-->ACT) for subtypes A and A/E. These substitutions and polymorphisms reflect different patterns of codon usage among viruses of different subtypes. However, the existence of different subtypes may only rarely affect patterns of drug resistance-associated mutations.

Amino Acid Substitution↗
PubMed2001

Effect of polymorphism in the human glutathione S-transferase A1 promoter on hepatic GSTA1 and GSTA2 expression.

The patterns of expression of glutathione S-transferases A1 and A2 in human liver (hGSTA1 and hGSTA2, respectively) are highly variable, notably in the ratio of hGSTA1/hGSTA2. We investigated if this variation had a genetic basis by sequencing the proximal promoters (-721 to -1 nucleotides) of hGSTA1 and hGSTA2, using 55 samples of human liver that exemplified the variability of hGSTA1 and hGSTA2 expression. Variants were found in the hGSTA1 gene: -631T or G, -567T, -69C, -52G, designated as hGSTA1*A; and -631G, -567G, -69T, -52A, designated as hGSTA1*B. Genotyping for the substitution -69C > T by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP), showed that the polymorphism was widespread in Caucasians, African-Americans and Hispanics, and that it appeared to conform to allelic variation. Constructs consisting of the proximal promoters of hGSTA1*A, hGSTA1*B or hGSTA2, with luciferase as a reporter gene, showed differential expression when transfected into HepG2 cells: hGSTA1*A approximately hGSTA2 > hGSTA1*B. Similarly, mean levels of hGSTA1 protein expression in liver cytosols decreased significantly according to genotype: hGSTA1*A > hGSTA1-heterozygous > hGSTA1*B. Conversely, mean hGSTA2 expression increased according to the same order of hGSTA1 genotype. Consequently, the ratio of GSTA1/GSTA2 was highly hGSTA1 allele-specific. Because the polymorphism in hGSTA1 correlates with hGSTA1 and hGSTA2 expression in liver, and hGSTA1-1 and hGSTA2-2 exhibit differential catalysis of the detoxification of carcinogen metabolites and chemotherapeutics, the polymorphism is expected to be of significance for individual risk of cancer or individual response to chemotherapeutic agents.

Base Sequence↗
PubMed2006

Low Y chromosome variation in Saudi-Arabian hamadryas baboons (Papio hamadryas hamadryas).

It is important to characterise the amount of variation on the mammalian Y chromosome in order to assess its potential for use in evolutionary studies. We report very low levels of polymorphism on the Y chromosome of Saudi-Arabian hamadryas baboons, Papio hamadryas hamadryas. We found no segregating sites on the Y, despite sequence analysis of 3 kb noncontiguous intron sequence in 16 males with divergent autosomal microsatellite genotypes, and a further analysis of 1.1 kb intron sequence in 97 males from four populations by SSCP. In addition, we tested seven human-derived Y-linked microsatellites in baboons. Only four of these loci were male-specific and only one was polymorphic in our 97 male sample set. Polymorphism on the Y chromosome of Arabian hamadryas appears to be low compared to other primate species for which data are available (eg humans, chimpanzees and bonobos). Low effective population size (Ne) of paternal genes due to polygyny and female-biased adult sex ratio is a potential reason for low Y chromosome variation in this species. However, low Ne for the Y should be counterbalanced to some extent by the species' atypical pattern of male philopatry and female-biased dispersal. Allelic richness averaged over seven loci was not significantly different between an African and an Arabian population, suggesting that loss of variation during the colonisation of Arabia does not explain low Y variation. Finally, in the absence of nucleotide polymorphism, it is unclear to what extent selection could be responsible for low Y variation in this species.

Animals↗
PubMed2001

A D(V)-like phenotype is obliterated by A226P in the partial D DBS.

BACKGROUND: In D category V types, the RHD exon 5 or parts thereof are replaced by the corresponding RHCE DNA segments. In D category V types I and II, the amino acid at position 226 is alanine, which is typical of the prevalent RHD allele and is observed in all RHCE alleles encoding the antigen e. A proline at position 226 in RHCE encodes the antigen E. STUDY DESIGN AND METHODS: A blood sample of ccDEe phenotype was referred as suspected D category VI. The RHD nucleotide sequence and the D epitope pattern were determined. RESULTS: A new partial D, DBS, encoded by an RHD-RHcE(5)-RHD hybrid allele, was found. Although it differed from D(Va) type II by an A226P substitution only, it lacked epitopes epD4, epD12, epD17, epD18, and epD22 that were present in D(Va). The 5' breakpoint region was located between the deletion in RHD intron 4 and the first polymorphic nucleotide of DBS exon 5. CONCLUSION: The phenotypes of RHD alleles with gene conversions limited to exon 5 depended critically on the amino acid at position 226. If alanine was present at this position, gene conversions involving E233Q led to a D(Va)-like phenotype. If proline was present, many additional epitopes were lost, and the phenotype became reminiscent of DFR. The 5' breakpoint region is shared by 10 alleles and may represent the most active "hot spot" for gene conversions known in RH.

Adult↗
PubMed2002

Molecular characterization of three new avian infectious bronchitis virus (IBV) strains isolated in Quebec.

Three unrecognized field isolates of Infectious Bronchitis Virus (IBV) were recovered from commercial broiler chickens vaccinated with live Mass viral strain (H120). These isolates were identified by immunofluorescence using monoclonal antibodies produced against reference serotypes: Mass, Conn, and Ark. RT-PCRs were performed on viral RNAs to amplify S1 gene using a specific set of primers S1OLIGO3' and S1OLIGO5'. Restriction polymorphism (RFLP) of PCR products was determined by the use of HaeIII restriction enzyme. As expected, patterns of PCR products were different from common pattern of strains assigned to Mass serotype M41, Beaudette, H120, and Florida. Molecular analysis showed a nucleotide insertion in hypervariable region one (HVR-1) of S1 gene of only Quebec isolates (Qu16, Qu_mv and Q_37zm). However, New Brunswick IBV isolate (NB_cp) did not display these insertions. Major amino acid changes involved insertion of two stretches (aa118-119: Arg-Ser and aa141-145: Sys-Ser-Asn-Ala-Ser-Cys) located at N-terrminal and C-terminal regions of HVR-2. It is speculated that cysteine residue located upstream and downstream of Cys-Ser-Asn-Ala-Ser-Cys segment might be involved in the formation of loop structure and disulfide bond that could trigger important epitope changes. Insertion of new NXT and NXS (X not equal to P) glycosylation motifs scattered along S1 region and insertion of cysteine residues in HVR are contributing to the antigenic shifting of Quebec isolates. Fragment insertions were thought to be induced by inter-serotype recombination between vaccine strain (H120) that belongs to Mass serotype and another strain belonging to Ark serotype. Phylogenetic tree based on amino acid sequences showed that Quebec isolates formed a new phylogenetic cluster.

Amino Acid Sequence↗
PubMed1994

Molecular analysis of the von Hippel-Lindau disease tumor suppressor gene in human lung cancer cell lines.

The deletion of the short arm of chromosome 3 is frequently observed in lung cancer. To determine whether the von Hippel-Lindau (VHL) disease tumor suppressor gene located at 3p25 is responsible for oncogenesis in lung cancer, we searched the known open reading frame using the single-strand conformation polymorphism (SSCP) technique for mutations in the VHL gene in 72 cancer cell lines including small cell (SCLC) and non-small cell (NSCLC) lung cancers, carcinoids, and mesotheliomas. SSCP analysis showed that four cell lines have altered SSCP patterns within the coding region and one in an intron of the VHL gene. SCLC line NCI-H1672 had a somatic mutation, G to A at nucleotide (nt) 530, leading to amino acid substitution (glycine to aspartic acid) compared to normal DNA from the same patient. Mesothelioma line NCI-H28 had T to A mutation at nt 479 leading to leucine to histidine amino acid change. We found one frequent polymorphism A (0.72) or G (0.28) at nt 19 resulting in either serine or glycine at this position, changes also found in normal peripheral blood cell DNA, often in a heterozygous state. In addition, we found single rare polymorphisms which did not alter the coding region including: C to G at nt 396, G to T at nt 843, and C to T change in an intron. These results suggest that the VHL gene is only rarely mutated in thoracic malignancies.

Base Sequence↗
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↗