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PubMed2006

C2028T polymorphism in exon 12 and dinucleotide repeat polymorphism in intron 13 of the HIF-1alpha gene define HIF-1alpha protein expression in non-small cell lung cancer.

OBJECTIVES: In this study, we investigated whether polymorphisms of the HIF-1alpha gene may account for the patterns of HIF-1alpha protein expression in non-small cell lung carcinomas (NSCLC) and the expression of HIF-1alpha down-stream proteins. METHODS: Specific HIF-1alpha polymorphisms were assessed in a series of patients with NSCLC: (a) the C to T transition at nucleotide 1744 (position 2028 according to sequence with accession number , which gives rise to Pro/Ser variation at codon 582), (b) the G to A nucleotide substitution at point 1790 (position 2046 according to sequence with accession number , which gives rise to Ala/Thr variation at codon 588), and (c) the dinucleotide GT repeat polymorphism in intron 13. Immunohistochemistry for HIF-1alpha and down-stream proteins (VEGF, LDH-5, GLUT-1) was also performed in tumor material. RESULTS: A strong association of the P582S polymorphism and of GT repeat polymorphism higher than 14/14 with increased HIF-1alpha expression was noted. HIF-1alpha polymorphism did not relate to the expression of the HIF-1alpha downstream proteins analysed, but significant association of HIF-1alpha expression with LDH-5 was confirmed (p=0.008). CONCLUSIONS: HIF-1alpha polymorphisms may have an important impact on HIF-protein stability and, eventually, function.

Aged↗
PubMed1997

Germline mutation of the RET proto-oncogene in children with total intestinal aganglionosis.

To clarify the pathogenesis of total intestinal aganglionosis, an extremely severe from of neural crest-derived cell migration disorder of the gut, the authors studied possible germline mutations of the RET proto-oncogene (10q11.2) in five pedigrees at high risk for congenital aganglionosis. All five patients analyzed were boys, and one had a family history of Hirschsprung's disease. Genomic DNA was extracted from lymphoblastoid cell lines established from patients and their relatives. Polymerase chain reaction (PCR) products, which were amplified using specific primers (RET; exon 1 approximately 20), were electrophoresed to analyze the single-strand conformational polymorphism (SSCP) patterns. DNA sequences were determined in pedigrees showing abnormal SSCP bands. Among the five patients, three germline mutations were found in the receptor tyrosine kinase domain (exon 15; codons 884, 897, and 904). Amino acid substitutions of the Ret protein were predicted based on the mutated nucleotide changes. Phenotypic variations of congenital aganglionosis may depend on the RET mutation pattern and other genetic or environmental determinants. In our series of patients, male sexuality and germline mutation of the RET tyrosine kinase domain were the most likely factors contributing to this form of Hirschsprung's disease.

Child↗
PubMed2002

Molecular characterization of a salt-tolerant bacterial community in the rice rhizosphere.

The diversity of salt-tolerant bacteria present in the rhizosphere of Oryza sativa was investigated. Fourteen bacterial strains, isolated after enrichment in nitrogen-free, semi-solid medium and showing tolerance to 3% NaCl, were analyzed by restriction patterns produced by amplified DNA coding for 16S rDNA (ARDRA) with enzymes Sau3AI, AluI and RsaI which showed that they were represented by 4 ARDRA types. Biodiversity among the 14 strains was also analyzed by the random amplified polymorphic DNA (RAPD) technique with a 10-mer primer. Partial nucleotide sequence of 16S rDNA assigned these clusters to Serratia marcescens, Pseudomonas aeruginosa, Alcaligenes xylosoxidans and Ochrobactrum anthropi. Notably, all four bacterial species are potential human pathogens that infect immunocompromised patients.

Alcaligenes↗
PubMed1998

Genetic evidence for a higher female migration rate in humans.

Mitochondrial DNA and the Y chromosome have been used extensively in the study of modern human origins and other phylogenetic questions, but not in the context of their sex-specific modes of transmission. mtDNA is transmitted exclusively by females, whereas the Y chromosome is passed only among males. As a result, differences in the reproductive output or migration rate of males and females will influence the geographic patterns and relative level of genetic diversity on the Y chromosome, autosomes and mtDNA (ref. 1). We have found that Y chromosome variants tend to be more localized geographically than those of mtDNA and the autosomes. The fraction of variation within human populations for Y chromosome single nucleotide polymorphisms (SNPs) is 35.5%, versus 80-85% for the autosomes and mtDNA (refs 6-8). A higher female than male migration rate (via patrilocality, the tendency for a wife to move into her husband's natal household) explains most of this discrepancy, because diverse Y chromosomes would enter a population at a lower rate than mtDNA or the autosomes. Polygyny may also contribute, but the reduction of variation within populations that we measure for the Y chromosome, relative to the autosomes and mitochondrial DNA, is of such magnitude that differences in the effective population sizes of the sexes alone are insufficient to produce the observation.

DNA, Mitochondrial↗
PubMed1992

Two distinct mechanisms alter p53 in breast cancer: mutation and nuclear exclusion.

Twenty-seven cases of inflammatory breast cancer were screened for the presence of the p53 protein by immunocytochemical methods using a monoclonal antibody directed against the p53 protein. Three groups were detected: 8 cases (30%) had high levels of p53 in the nucleus of the cancer cells; 9 cases (33%) had a complete lack of detectable staining; 10 cases (37%) showed a pattern of cytoplasmic staining with nuclear sparing. Nucleotide sequence analysis of p53 cDNAs derived from the samples with cytoplasmic staining revealed only wild-type p53 alleles in 6 out of 7 cases. An eighth case was determined to be wild type by a single-strand conformation polymorphism. In contrast, the samples containing nuclear p53 contained a variety of missense mutations and a nonsense mutation. The p53 cDNAs from 3 of the tumors that lacked detectable p53 staining were analyzed, and all 3 had wild-type nucleotide sequences. Interestingly, a case of normal lactating breast tissue also showed intense cytoplasmic staining for p53 with nuclear sparing. These data suggest that some breast cancers that contain the wild-type form of p53 protein may inactivate its tumor-suppressing activity by sequestering this protein in the cytoplasm, away from its site of action in the cell nucleus. The detection of cytoplasmic p53 in normal lactating breast tissue could suggest that this is the mechanism employed in specific physiological situations to permit transient cell proliferation. This observation could explain how some breast cancer tissues inactivate p53 function without mutation.

Amino Acid Sequence↗
PubMed2006

Contrasting histories of G6PD molecular evolution and malarial resistance in humans and chimpanzees.

Although mutations in the glucose-6-phosphate dehydrogenase (G6PD) gene result in several blood-related diseases in humans, they also confer resistance to malarial infection. This association between G6PD and malaria was supported by population genetic analyses of the G6PD locus, which indicated that these mutations may have recently risen in frequency in certain geographic regions as a result of positive selection. Here we characterize nucleotide sequence variation in a 5.2-kb region of the G6PD locus in a population sample of 56 chimpanzees, as well as among 7 other nonhuman primates, to compare with that in humans in determining whether other primates that are impacted by malaria also exhibit patterns of G6PD polymorphism or divergence consistent with positive selection. We find that chimpanzees have several amino acid variants but that the overall pattern at G6PD in chimpanzees, as well as in Old and New World primates in general, can be explained by recent purifying selection as well as strong functional constraint dating back to at least 30-40 MYA. These comparative analyses suggest that the recent signature of positive selection at G6PD in humans is unique.

Animals↗
PubMed1996

Zea ribosomal repeat evolution and substitution patterns.

Zea and Tripsacum nuclear ribosomal internal transcribed spacer (ITS) sequences were used to evaluate patterns of concerted evolution, rates of substitutions, patterns of methylation-induced deamination, and structural constraints of the ITS. ITS pseudogenes were identified by their phylogenetic position, differences in nucleotide composition, extensive deamination at ancestral methylation sites, and substitutions resulting in low-stability secondary RNA structures. Selection was important in shaping the kinds of polymorphisms and substitutions observed in the ITS. ITS substitution rates were significantly different among the Zea taxa. Deamination of cytosines at methylation sites was a potent mutation source, but selection appeared to maintain high methylation site density throughout the ribosomal repeat except for the gene promoter. Nucleotide divergence statistics identified selectively constrained regions at the 5' ends of the ITS1 and ITS2.

DNA, Plant↗
PubMed1996

Hereditary spherocytosis with band 3 deficiency. Association with a nonsense mutation of the band 3 gene (allele Lyon), and aggravation by a low-expression allele occurring in trans (allele Genas).

We describe an 18-year-old with moderate hereditary spherocytosis. The condition was associated with a 35% decrease in band 3. The underlying mutation was Arg to stop at codon 150 (CGA-->TGA) and was designated R150X, which defined allele Lyon of the EPB3 gene. The inheritance pattern was dominant. However, the mother, who also carried the allele Lyon, had a milder clinical presentation and only a 16% decrease of band 3. We suggested that the father had transmitted a modifying mutation that remained silent in the heterozygous state. Nucleotide sequencing after single strand conformation polymorphism analysis of the band 3 cDNA and promoter region revealed a G-->A substitution at position 89 from the cap site in the 5'-untranslated region, designated 89G-->A, which defined allele Genas. A ribonuclease protection assay showed that (1) the allele Genas (father) resulted in a 33% decrease in the amount of band 3 mRNA, (2) the reduction caused by the allele Lyon (mother) was 42%, and (3) the compound heterozygous state for both alleles (proband) resulted in a 58% decrease. These results suggest that some mildly deleterious alleles of the EPB3 gene are compensated for by the normal allele in the heterozygous state. They are shown through the aggravation of the clinical picture, based on more obvious molecular alterations when they occur in trans to an allele causing a manifest reduction of band 3 membrane protein concentration.

Alleles↗
PubMed2006

Strand bias in complementary single-nucleotide polymorphisms of transcribed human sequences: evidence for functional effects of synonymous polymorphisms.

BACKGROUND: Complementary single-nucleotide polymorphisms (SNPs) may not be distributed equally between two DNA strands if the strands are functionally distinct, such as in transcribed genes. In introns, an excess of A<-->G over the complementary C<-->T substitutions had previously been found and attributed to transcription-coupled repair (TCR), demonstrating the valuable functional clues that can be obtained by studying such asymmetry. Here we studied asymmetry of human synonymous SNPs (sSNPs) in the fourfold degenerate (FFD) sites as compared to intronic SNPs (iSNPs). RESULTS: The identities of the ancestral bases and the direction of mutations were inferred from human-chimpanzee genomic alignment. After correction for background nucleotide composition, excess of A-->G over the complementary T-->C polymorphisms, which was observed previously and can be explained by TCR, was confirmed in FFD SNPs and iSNPs. However, when SNPs were separately examined according to whether they mapped to a CpG dinucleotide or not, an excess of C-->T over G-->A polymorphisms was found in non-CpG site FFD SNPs but was absent from iSNPs and CpG site FFD SNPs. CONCLUSION: The genome-wide discrepancy of human FFD SNPs provides novel evidence for widespread selective pressure due to functional effects of sSNPs. The similar asymmetry pattern of FFD SNPs and iSNPs that map to a CpG can be explained by transcription-coupled mechanisms, including TCR and transcription-coupled mutation. Because of the hypermutability of CpG sites, more CpG site FFD SNPs are relatively younger and have confronted less selection effect than non-CpG FFD SNPs, which can explain the asymmetric discrepancy of CpG site FFD SNPs vs. non-CpG site FFD SNPs.

Algorithms↗
PubMed1996

Sequenase sequence profiles used for HLA-DPB1 sequencing-based typing.

Sequencing-based HLA typing (SBT) is a PCR based high resolution HLA typing method in which polymorphic regions of the gene are sequenced and directly used for typing. Currently, for class II SBT, alleles are identified by comparison of the exon 2 sequence with their corresponding allele sequence library. Routine SBT requires reliable identification of heterozygosity, and automated assignment of the alleles. In sequencing strategies different enzymes can be used for primer extension. The most characteristic difference between sequences obtained by two protocols using Sequenaseregistered, or Taq-cycle sequencing, respectively, is a difference in incorporation of nucleotides in the primer extension leading to different sequence profiles. In Taq-cycling sequencing variable nucleotide incorporation results in irregular, but reproducible peak patterns, whereas Sequenase incorporates nucleotides in nearly equal amounts, resulting in more even peak patterns. In a previously published multi-center study we evaluated HLA-DPB1 SBT using Taq-cycle sequencing, and showed that typing can reliably be performed, considering the specific sequence profiles. In this study the applicability of Sequenase for HLA-DPB1 SBT was tested. A panel of samples were typed by SBT at five test sites which participate in the Sequencing Based Typing component of the 12th International Histocompatibility Workshop. The panel represents the existing polymorphism at all known polymorphic positions of exon 2, both in homozygous and heterozygous combinations. The assignment of homozygosity and heterozygosity was validated by Multi-Sequence Analysis, performing cluster analysis of chromatographic data of all sequences at each position. Sequence characteristics were examined and considered for appropriate assignment. Data reveals that Sequenase sequencing can also reliably be used for HLA-DPB1 typing.

Bacteriophage T7↗
PubMed2004

Analysis of gyrA mutations in quinolone-resistant and -susceptible Campylobacter jejuni isolates from retail poultry and human clinical isolates by non-radioactive single-strand conformation polymorphism analysis and DNA sequencing.

AIMS: The aims of this study were to characterize the molecular variations in the quinolone resistance-determining region (QRDR) of gyrA among quinolone-resistant and -susceptible Campylobacter jejuni isolates originating from foods of animal origin and human infections and to evaluate the suitability of the single-strand conformation polymorphism (SSCP) method as a screening method for molecular characterization of fluoroquinolone resistance. METHODS AND RESULTS: Alterations in QRDR of gyrA from 182 C. jejuni isolates were determined by nonradioisotopic SSCP analysis and direct sequencing. A total of 13 types of nucleic acid sequence combinations within the QRDR of the gyrA gene resulted in 11 different SSCP patterns. All nalidixic acid resistant strains possessed nucleotide substitution at either codon Thr-86 or Asp-90. Silent mutations were detected additionally. Thr-86 to Ile mutation was detected in all 139 ciprofloxacin resistant strains, which showed cross-resistance to nalidixic acid. CONCLUSIONS: The SSCP method is suitable for a molecular screening of quinolone resistant C. jejuni isolates and in combination with DNA sequencing suitable to detect genetic variations of the QRDR of gyrA. SIGNIFICANCE AND IMPACT OF STUDY: This study provides data of the genetic variations of the QRDR of gyrA from C. jejuni isolates of foods and human beings.

Animals↗
PubMed2005

A comparison in association and linkage genome-wide scans for alcoholism susceptibility genes using single-nucleotide polymorphisms.

We conducted genome-wide linkage scans using both microsatellite and single-nucleotide polymorphism (SNP) markers. Regions showing the strongest evidence of linkage to alcoholism susceptibility genes were identified. Haplotype analyses using a sliding-window approach for SNPs in these regions were performed. In addition, we performed a genome-wide association scan using SNP data. SNPs in these regions with evidence of association (P <or= 0.0001) were identified. We found that the general patterns for nonparametric linkage (NPL) scores from SNP and microsatellite genome scans are fairly consistent; however, the peaks of the NPL scores are mostly higher in the SNP-based scan than those using microsatellite markers, which might be located at different regions. Furthermore, SNPs identified from linkage screens were not so strongly associated with alcoholism (the most significant SNP had a p-value of 0.030) as those identified from association genomic screening (the most significant SNP had a p-value of 2.0 x 10(-8)).

Alcoholism↗
PubMed2001

Phage-related DNA polymorphism in dairy and probiotic Lactobacillus.

Various DNA-based methods are presently being applied for identification of industrial bacterial cultures including dairy starter and probiotic strains of Lactobacillus. The success of strain-specific identification depends on the power of the DNA-based methods to reveal intraspecies DNA polymorphism. This study reveals that all eleven arbitrarily chosen Lactobacillus rhamnosus starter, laboratory and probiotic strains contain Lb. rhamnosus phage Lc-Nu related nucleotide sequences. One of these highly homologous regions in the genome of phage Lc-Nu was the 2.4kb HindIII fragment, which has been sequenced. Nucleotide sequence analysis suggested that one side of the 2.4kb HindIII fragment encodes a phage Lc-Nu helicase and accordingly represents an early gene region of phage Lc-Nu genome. Five forward and five reverse primers were derived from the nucleotide sequence of the 2.4kb HindIII fragment of phage Lc-Nu DNA for PCR-based identification of the eleven Lb. rhamnosus strains included in this study. Six different types of PCR product patterns were obtained. Among the patterns three were unique to particular Lb. rhamnosus strains. The results suggest that phage-related DNA sequences are, surprisingly, distributed widely among the Lb. rhamnosus strains, and that these sequences could also be a source of DNA polymorphism to apply for DNA-based identification of bacterial strains. Phage Lc-Nu related DNA homology was also found in the chromosome of Lb. casei, the species closely related to Lb. rhamnosus.

Bacteriophages↗
PubMed1986

DNA finger printing by oligonucleotide probes specific for simple repeats.

Interspersed simple repetitive DNA is a convenient genetic marker for analysis of restriction fragment length polymorphisms (RFLPs) because of the numbers and the frequencies of its alleles. Oligonucleotide probes specific for variations of the GATCA simple repeats have been designed and hybridized to a panel of human DNAs digested with various restriction enzymes. Numerous RFLPs were demonstrated in AluI and MboI digested DNA with "pure" GATA oligonucleotides as probes. The optimal length of the probe for RFLP analysis was 20 bases taking into account fragment lengths (1.5-7 kilobases = kb), signal to background ratio, and number of clearly evaluable RFLPs. By using different restriction enzymes individual-specific hybridization patterns ("DNA fingerprints") can be established. Hypervariable simple repeat fragments are stably inherited in a Mendelian fashion. Advantages of this method are discussed.

DNA↗
PubMed2004

A survey of genetic and epigenetic variation affecting human gene expression.

The identification of human sequence polymorphisms that regulate gene expression is key to understanding human genetic diseases. We report a survey of human genes that demonstrate allelic differences in gene expression, reflecting the presence of putative allele-specific cis-acting factors of either genetic or epigenetic nature. The expression of allelic transcripts in heterozygous samples is assessed directly by relative quantitation of intragenic marker alleles in messenger or heteronuclear RNA derived from cells or tissues. This survey used 193 single-nucleotide polymorphisms (SNPs) from 129 genes expressed in lymphoblastoid cell lines, to identify 23 genes (18%) with common allele-specific transcripts whose expression deviated from the expected equimolar ratio. A subset of these deviations, or "allelic imbalances," can be observed in multiple samples derived from reference CEPH ("Centre d'Etude du Polymorphisme Humain") pedigrees and demonstrate a spectrum of patterns of transmission, including cosegregation of allelic skewing across generations compatible with Mendelian inheritance as well as random monoallelic expression for three genes (IL1A, HTR2A, and FGB). Additional studies for BTN3A2 provide evidence of SNPs and haplotypes in complete linkage disequilibrium with high- and low-expressing transcripts. The pipeline described herein offers tools for efficient identification and characterization of allelic expression allowing identification of regulatory sequence variants as well as epigenetic variation affecting human gene expression.

Allelic Imbalance↗
PubMed2001

Molecular variation in plant cell populations evolving in vitro in different physiological contexts.

Previous work has shown the fixation of context-specific random amplified polymorphic DNA (RAPD) patterns in tomato cell cultures grown for 2 years in different hormonal contexts. In this work, RAPD sequences were characterised and RAPD-derived molecular markers used for a further study of variation between and within auto- and auxo-trophic tomato cultures grown in different hormonal equilibria. Results were then compared with those obtained using microsatellite markers located in noncoding regions of differentiation- and hormone-related genes and with those obtained with the external transcribed spacer (ETS) from tomato rDNA. Hybridisation of RAPDs on a tomato genomic DNA bank, or on total DNA after enzymatic digestion, suggested that the markers were repetitive in nature. Sequence analysis. however, showed that the homology between different fragments was due mainly to the presence of homo-AT nucleotide stretches. Moreover, a series of computational methods, such as an information-theory algorithm coupled with AG estimates, suggested that the RAPD fragments isolated in our experiments are noncoding. The amplification of SSR-containing RAPD-derived markers, and of other SSRs located in noncoding regions of tomato functional genes, consistently showed polymorphism between auxo- and auto-trophic somaclones (the latter being either habituated or transgenic for Agrobacterium tumefaciens oncogenes) but not within these same clones. Differences were also found between auxotrophic clones and the differentiated tissue. These findings were confirmed by restriction fragment length polymorphism (RFLP) analysis with the REII repetitive element of the ETS from tomato rDNA, which was isolated during this study. The results obtained suggest a possible role for physiological context in the selection of RAPD patterns during the evolution of tomato cells with different endogenous hormonal equilibria. The results are discussed in terms of a possible role for variation in noncoding regions of hormone-related genes in the adaptation to different physiological contexts.

Algorithms↗
PubMedDate not supplied

Single nucleotide polymorphisms of the heat shock protein 90 gene in varicocele-associated infertility.

PURPOSE: Varicoceles are associated with impaired testicular function and male infertility, but the molecular mechanisms by which fertility is affected have not been satisfactorily explained. Spermatogenesis might be affected by increased scrotal temperature, such as that caused by varicocele. HSP90 is a molecular chaperone expressed in germ cells and is related to spermatogenesis, motility, and both heat and oxidative stress. Possible correlations between coding single region nucleotide polymorphisms (cSNPs) in the HSP90 gene in patients with varicocele associated with infertility were analyzed, and polymorphisms in these exons were characterized through DNA sequencing. MATERIALS AND METHODS: PCR-SSCP and DNA sequencing were used to search for mutations in 18 infertile patients with varicocele, 11 patients with idiopathic infertility and 12 fertile men. DNA was extracted from leucocytes for PCR amplification and SSCP analysis. DNA from samples with an altered band pattern in the SSCP was then sequenced to search for polymorphisms. RESULTS: Three silent polymorphisms that do not lead to amino acid substitutions were identified. CONCLUSION: Mutations in the HSP90 gene do not appear to be a common cause of male factor infertility. The low incidence of gene variation, or SNPs, in infertile men demonstrates that this gene is highly conserved and thus confirms its key role in spermatogenesis and response to heat stress.

HSP90 Heat-Shock Proteins↗
PubMed2026

Fine-Scale Landscape Genomics Show Asymmetric Patterns of Gene Flow for the Invasive Mosquito Aedes albopictus.

Mosquito-borne viruses like dengue, Zika, and chikungunya pose increasing health risks in the United States due to the expanding range of Aedes albopictus, a highly invasive mosquito species that now has a global distribution. Aedes albopictus thrive in artificial containers associated with anthropogenic land use, allowing populations to reach high numbers in urban and suburban environments. While the global spread of Ae. albopictus has been well characterized, the effects of heterogeneous urban landscapes on dispersal and gene flow at fine spatial scales remain unclear. This study analyzed the genetic connectivity of Aedes albopictus populations collected in Wake County, North Carolina in 2018. We used single nucleotide polymorphisms (SNP) data from double-digest restriction-enzyme associated DNA sequencing (ddRADseq) and examined genetic connectivity through principal component analysis (PCA) and genetic network analysis. We then evaluated migration and source-sink dynamics using a Bayesian approach for SNP data (BA3-SNP). We found little evidence of genetic clustering or isolated populations of Ae. albopictus in Wake County, suggesting high gene flow between sites. Migration analysis demonstrated asymmetric gene flow from rural to urban regions within Wake County, with greater gene flow occurring between and within urban regions. These findings suggest that the pattern of gene flow of Ae. albopictus populations within local metropolitan areas may involve urban city centers serving as genetic sinks and surrounding suburban and rural regions serving as sources. This study highlights how heterogeneous landscapes shape mosquito population connectivity and migration at fine spatial scales, which is critical for informing vector control and public health intervention strategies.

Aedes albopictus↗