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PubMed2004

HapBlock: haplotype block partitioning and tag SNP selection software using a set of dynamic programming algorithms.

UNLABELLED: Recent studies have revealed that linkage disequilibrium (LD) patterns vary across the human genome with some regions of high LD interspersed with regions of low LD. Such LD patterns make it possible to select a set of single nucleotide polymorphism (SNPs; tag SNPs) for genome-wide association studies. We have developed a suite of computer programs to analyze the block-like LD patterns and to select the corresponding tag SNPs. Compared to other programs for haplotype block partitioning and tag SNP selection, our program has several notable features. First, the dynamic programming algorithms implemented are guaranteed to find the block partition with minimum number of tag SNPs for the given criteria of blocks and tag SNPs. Second, both haplotype data and genotype data from unrelated individuals and/or from general pedigrees can be analyzed. Third, several existing measures/criteria for haplotype block partitioning and tag SNP selection have been implemented in the program. Finally, the programs provide flexibility to include specific SNPs (e.g. non-synonymous SNPs) as tag SNPs. AVAILABILITY: The HapBlock program and its supplemental documents can be downloaded from the website http://www.cmb.usc.edu/~msms/HapBlock.

Algorithms↗
PubMed2002

No abnormalities of reg1 alpha and reg1 beta gene associated with diabetes mellitus.

In order to investigate whether there would be any association between abnormalities of either reg1 alpha or reg1 beta gene and diabetes mellitus in man, these two genes were analyzed in 42 patients with type 1 diabetes mellitus, 12 with fibrocalculous pancreatopathy, 37 with type 2 diabetes mellitus, and 22 normal controls, by PCR-SSCP analysis and nucleotide sequencing technique. Polymorphism in the reg1 alpha gene resulted in three mobility patterns in the PCR-SSCP analysis, due to nucleotide constituents at position -10 before exon 1 being either C/C, T/C or T/T. These three mobility patterns were observed in every group of subjects. The analysis of reg1 beta gene showed nucleotide substitutions in exon 4 in one patient, exon 5 in another patient with type 1 diabetes, and in exon 4 and intron 5 in one patient with fibrocalculous pancreatopathy. The nucleotide substitutions in exon 4 in the patient with type 1 diabetes and that with fibrocalculous pancreatopathy occurred at codons 103 and 84 while that in exon 5 in the patient with type 1 diabetes occurred at codon 141, changing the codons from CAT to CAC, GTG to GCG, and ACT to AAT and resulting in H103H silent, V84A and T141N missense mutations, respectively. In conclusion, using PCR-SSCP and nucleotide sequence analyses, we did not find any association between abnormalities of either reg1 alpha or reg1 beta gene with any type of diabetes studied.

Adult↗
PubMed1995

Variations in the core region of hepatitis C virus genomes in patients with chronic hepatitis.

In each infected patient, the population of hepatitis C virus is composed of quasispecies that differ in their nucleotide sequences. Among regions in hepatitis C virus genomes, nucleotide sequences of the hypervariable region have been shown to change quickly during the course of infection. It is not known, however, whether these variations exist in the core region that has recently been suggested to contain human lymphocyte antigen class 1 restricted sites for cytotoxic T cell recognition. To clarify this, RNA was extracted from the plasma of four patients with chronic hepatitis C. After cDNA synthesis, DNA fragments that contain the core region were amplified by the polymerase chain reaction and the diversity of the core region was analyzed by the single strand conformation polymorphism analysis. Using this method, single or multiple DNA bands were observed in each patient, and representative bands showed different nucleotide sequences. Comparison of single strand conformation polymorphism patterns revealed that the population of quasispecies changed during the course of chronic infection. These changes were more remarkable in patients with high serum alanine aminotransferase levels than those with low serum alanine aminotransferase levels. Thus, sequential variations exist in the core region of hepatitis C virus in same individuals, and the population of quasispecies as determined by the sequence of the core region changes during the course of infection, which might be related to cytopathic effects of hepatitis C virus.

Alanine Transaminase↗
PubMed2004

The canine HMGA1.

Due to the emerging advantages of numerous canine diseases as a genetic model for their human orthologs, the dog could join the mouse as the species of choice to unravel genetic mechanisms, e.g. of cancer predisposition, development and progression. However, precondition for such studies is the characterisation of the corresponding canine genes. Human and murine HMGA1 non-histone proteins participate in a wide variety of cellular processes including regulation of inducible gene transcription, integration of retroviruses into chromosomes, and the induction of neoplastic transformation and promotion of metastatic progression of cancer cells. Chromosomal aberrations affecting the human HMGA1 gene at 6p21 were described in several tumours like pulmonary chondroid hamartomas, uterine leiomyomas, follicular thyroid adenomas and others. Over-expression of the proteins of HMGA1 is characteristic for various malignant tumours suggesting a relation between high titer of the protein and the neoplastic phenotype. In this study, we characterised the molecular structure of the canine HMGA1 cDNA, its splice variants and predicted proteins HMGA1a and HMGA1b. Furthermore, we compared the coding sequence(s) (CDS) of both splice variants for 12 different breeds, screened them for single nucleotide polymorphisms (SNPs) and characterised a basic expression pattern.

Alternative Splicing↗
PubMed1996

Unexpected beta2-microglobulin sequence diversity in individual rainbow trout.

For mammals beta2-microglobulin (beta2m), the light chain of major histocompatibility complex (MHC) class I molecules, is invariant (or highly conserved) and is encoded by a single gene unlinked to the MHC. We find that beta2m of a salmonid fish, the rainbow trout (Oncorhynchus mykiss), does not conform to the mammalian paradigm. Ten of 12 randomly selected beta2m cDNA clones from an individual fish have different nucleotide sequences. A complex restriction fragment length polymorphism pattern is observed with rainbow trout, suggesting multiple beta2m genes in the genome, in excess of the two genes expected from the ancestral salmonid tetraploidy. Additional duplication and diversification of the beta2m genes might have occurred subsequently. Variation in the beta2m cDNA sequences is mainly at sites that do not perturb the structure of the mature beta2m protein, showing that the observed diversity of the trout beta2m genes is not primarily a result of pathogen selection.

Amino Acid Sequence↗
PubMed2004

Polymorphisms in xenobiotic metabolism genes and autism.

Autism is a neurodevelopmental syndrome defined by deficits in social reciprocity and communication and by unusual repetitive behaviors. Although there is an underlying genetic predisposition, the etiology of autism is currently unknown. A recent increase in prevalence suggests that genetically determined vulnerability to environmental exposure might contribute to the causation of autism. We performed family-based association studies of polymorphisms in metal-regulatory transcription factor 1(MTF1), a multispecific organic anion transporter (ABCC1), proton-coupled divalent metal ion transporters (SLC11A3 and SLC11A2), paraoxonase 1 (PON1), and glutathione S-transferase (GSTP1) genes in 196 autistic disorder families. There was deviation from the expected pattern of transmission for polymorphisms in MTF1 (Single nucleotide polymorphism database reference identification number, dbSNP rs3790625, P = .02) and divalent metal ion transporter SLC11A3 (dbSNP rs2304704, P = .07) genes. Although these results might represent chance finding, further investigations of genetic variations of metal metabolism in autism are warranted.

Autistic Disorder↗
PubMed2001

Biochip technologies in cancer research.

Development of high-throughput 'biochip' technologies has dramatically enhanced our ability to study biology and explore the molecular basis of disease. Biochips enable massively parallel molecular analyses to be carried out in a miniaturized format with a very high throughput. This review will highlight applications of the various biochip technologies in cancer research, including analysis of 1) disease predisposition by using single-nucleotide polymorphism (SNP) microarrays, 2) global gene expression patterns by cDNA microarrays, 3) concentrations, functional activities or interactions of proteins with proteomic biochips, and 4) cell types or tissues as well as clinical endpoints associated with molecular targets by using tissue microarrays. One can predict that individual cancer risks can, in the future, be estimated accurately by a microarray profile of multiple SNPs in critical genes. Diagnostics of cancer will be facilitated by biochip readout of activity levels of thousands of genes and proteins. Biochip diagnostics coupled with informatics solutions will form the basis of individualized treatment decisions for cancer patients.

Computational Biology↗
PubMed2001

Introduction: transmission/disequilibrium test/association group. .

A range of study designs, using unrelated or family controls, were used to investigate the pattern of association with disease of single nucleotide polymorphisms (SNPs) within candidate gene 1 (simulated data). Strong evidence of disease association at the functional locus was detected using all study designs, and in the "general" but not the "isolated" population the functional polymorphism displayed considerably higher association than surrounding SNPs. There was much variation in the strength of association of SNPs with disease, up to 70% of which was explained by SNP allele frequency and distance from the functional polymorphism. Some common polymorphisms very close to the functional locus however showed no association with disease. Analysis of short haplotypes of SNPs reduced but did not totally remove this feature.

Genetic Markers↗
PubMed2004

[Biomarker in gynecologic malignancies].

We selected ovarian cancer as being the most representative of the gynecologic malignancies since it has the largest number of tumor markers now in clinical use. First, variety of serum tumor markers were developed and regularly used to detect the existence of ovarian cancer and its stage. These markers of monoclonal antibodies could detect three different classes of cell surface antigen. CA 125, CA 130, CA 602 are antibodies raised against the core protein of the proteoglycan molecule, whereas CA 19-9, CA 50, KMO-1 and CA 72-4, STN, CA 546 are antibodies against a different portion of the glycosaminoglycan chain from the core protein. These markers, when combined with another group of tumor markers for discriminating the variety of pathological types of ovarian cancer, might have the potential to provide a better predictive value. Second, biomarkers for the detection of early-stage ovarian cancer are urgently needed and developed also in gynecologic tumors. These include a ovarian cancer-specific proteomic patterns generated by mass spectroscopy and single nucleotide polymorphism (SNP) digital analysis combined with assessment of allelic imbalance. Third, for monitoring the effect of treatment with cytostatic drugs, various types of biomarkers could be used as surrogate markers for the treatment depending on the mechanism of the effects of the drug used. For treatment with Bryostatin, a strong protein kinase C (PKC) stimulator, PKC activity promises to be an effective marker. For the trials with bevacizumab, anti-VEGF antibody, VEGF and its associated bFGF, CD-31, and thrombospondin-1 (TSP-1), are leading candidates for monitoring markers.

Antigens, Tumor-Associated, Carbohydrate↗
PubMed2002

Cyclin D1 gene polymorphism is associated with an increased risk of urinary bladder cancer.

Cyclin D1 is believed to play an important role in the genesis and/or progression of transitional cell cancer (TCC) of the urinary bladder. Cyclin D1 gene (CCND1) mRNA is alternatively spliced to produce two transcripts, and the splicing pattern may be modulated by a G to A single nucleotide polymorphism within the splice donor site of exon 4. This study was conducted to explore the association between the polymorphism and the susceptibility to and disease status of TCC of the bladder in 222 cases and 317 native Japanese controls. The relationship between the CCND1 polymorphism and the mRNA splicing pattern in TCC cells was evaluated by semi-quantitative reverse-transcription PCR. The CCND1 A allele was more frequently observed in the TCC group than the control group (P = 0.032) with a significant difference in the genotype frequency between the two groups (P = 0.029). The AA genotype was associated with a significantly higher risk of TCC compared with the AG+GG genotypes (adjusted odds ratio (aOR) = 1.76, 95% confidence interval (CI) = 1.09-2.84, P = 0.022). This association was observed more significantly in nonsmoking cases (aOR = 2.53; 95% CI = 1.28-4.51, P = 0.008). Looking at tumor grade, the presence of the A allele was associated with higher grade (= grade 3) tumors with a gene dosage effect (aOR = 1.77, CI = 1.16-2.69, P = 0.008). In tumor stage, although not significant, the AA + AG genotypes tended to be more frequently observed in cases with T1-4 tumors than those with Ta tumors (aOR = 1.94, 95% CI = 0.98-3.82, P = 0.057). The genotype seemed to influence the two alternatively spliced forms of the CCND1 mRNA because the ratio of the CCND1 transcript-b/transcript-a was significantly higher in cases with the AA genotype compared with those with the AG + GG genotypes. These data suggest that the CCND1 variant A allele may be associated with an increased risk of TCC of the bladder, especially in men without a history of smoking, and it may also have an effect on its disease status.

Age Factors↗
PubMed2006

Evidence for a large-scale population structure of Arabidopsis thaliana from genome-wide single nucleotide polymorphism markers.

Population-based methods for the genetic mapping of adaptive traits and the analysis of natural selection require that the population structure and demographic history of a species are taken into account. We characterized geographic patterns of genetic variation in the model plant Arabidopsis thaliana by genotyping 115 genome-wide single nucleotide polymorphism (SNP) markers in 351 accessions from the whole species range using a matrix-assisted laser desorption/ionization time-of-flight assay, and by sequencing of nine unlinked short genomic regions in a subset of 64 accessions. The observed frequency distribution of SNPs is not consistent with a constant-size neutral model of sequence polymorphism due to an excess of rare polymorphisms. There is evidence for a significant population structure as indicated by differences in genetic diversity between geographic regions. Accessions from Central Asia have a low level of polymorphism and an increased level of genome-wide linkage disequilibrium (LD) relative to accessions from the Iberian Peninsula and Central Europe. Cluster analysis with the structure program grouped Eurasian accessions into K = 6 clusters. Accessions from the Iberian Peninsula and from Central Asia constitute distinct populations, whereas Central and Eastern European accessions represent admixed populations in which genomes were reshuffled by historical recombination events. These patterns likely result from a rapid postglacial recolonization of Eurasia from glacial refugial populations. Our analyses suggest that mapping populations for association or LD mapping should be chosen from regional rather than a species-wide sample or identified genetically as sets of individuals with similar average genetic distances.

Arabidopsis↗
PubMed1997

Differentiation of Mycobacterium paratuberculosis isolates by rDNA-spacer analysis and random amplified polymorphic DNA patterns.

The ability to distinguish between isolates of Mycobacterium paratuberculosis isolates was studied using two molecular techniques. Nucleotide sequence analysis of the rDNA-spacer and random amplified polymorphic DNA (RAPD) analysis using decamer primers with GC contents of 60 to 70% were evaluated on 16 isolates of M. paratuberculosis from cattle. The rDNA spacer analysis did not discriminate between isolates as it revealed an identical sequence for all 16 strains tested but it showed one common difference to the sequence previously described for M. paratuberculosis J2A. In the RAPD analysis, 14 of the 60 decamer primers used resulted in distinct amplification products for most of the isolates. For seven of the primers the size of the amplification products varied among strains thus allowing the specific identification of eight of the 16 isolates; of the remaining eight isolates five could each be differentiated from 14 other isolates, two from 13, and one from 12 isolates. Therefore, these data illustrate the possibility of using RAPD-analysis with certain primers for the differentiation of individual M. paratuberculosis isolates.

Animals↗
PubMed2005

SEAN: SNP prediction and display program utilizing EST sequence clusters.

SEAN is an application that predicts single nucleotide polymorphisms (SNPs) using multiple sequence alignments produced from expressed sequence tag (EST) clusters. The algorithm uses rules of sequence identity and SNP abundance to determine the quality of the prediction. A Java viewer is provided to display the EST alignments and predicted SNPs.

Algorithms↗
PubMed2005

Development of an automation system for single nucleotide polymorphisms genotyping using bio-strand, a new three-dimensional microarray.

Previously, we developed a novel three-dimensional microarray system called Bio-Strand, which may be used in various applications including single nucleotide polymorphisms genotyping. In Bio-Strand, samples for detection are immobilized on a one-dimensional thread, which is wound around a cylinder-shaped core to form a three-dimensional thread-and-core structure. The thread-and-core structure is then inserted into a plastic pipette tip, where hybridization and detection are performed. In this study, we have developed an automation system, NIAGALA Bio-Station SDx, which enables automated hybridization and detection during the genotyping procedure using Bio-Strand. Using this system, we have performed the single nucleotide polymorphism (SNP) genotyping of CYP2C, one of the important human cytochrome P450 genes and the results were completely consistent with the genotyping results determined by the TaqMan method.

Algorithms↗
PubMed2006

OGG1 polymorphisms and breast cancer risk.

The role of oxidative stress in breast cancer risk is still unclear. OGG1 encodes an 8-oxoguanine DNA glycosylase/AP lyase that catalyzes the removal of 8-oxodeoxyguanosine from DNA. 8-Oxodeoxyguanosine, the most abundant lesion generated by oxidative stress, is highly mutagenic. Environmental sources of oxidative stress, such as alcohol consumption, cigarette smoking, high body mass index (BMI), and low fruits and vegetables intake, may modify the association of genetic polymorphisms with breast cancer risk. We investigated the association between three genetic polymorphisms in OGG1 (Ser(326)Cys, 7143A/G, and 11657A/G) and breast cancer risk among 1,058 cases and 1,102 controls participating in the Long Island Breast Cancer Study Project. No associations were observed between individual OGG1 polymorphisms, haplotypes, or diplotypes and breast cancer. The association between having at least one variant allele and breast cancer risk was stronger among moderate alcohol drinkers for Ser(326)Cys [odds ratio (OR), 1.82; 95% confidence interval (95% CI), 1.06-3.10] relative to nondrinkers with the wild-type genotype and among those with higher BMI for 7143A/G (OR, 1.47; 95% CI, 1.10-1.96) and for 11657A/G (OR, 1.41; 95% CI, 1.05-1.88), relative to women with BMI < 25 kg/m(2) and the wild-type genotype. However, the patterns were not seen for all three single nucleotide polymorphisms (SNP) nor were there any clear allele dose associations; only one interaction was statistically significant, assuming a multiplicative model (11657A/G, P(interaction) = 0.04). In summary, although we found some differences between the three OGG1 SNPs and breast cancer risk among moderate alcohol drinkers and women with higher BMI, replication of these results is needed to rule out spurious findings. In addition, data on functionality of these polymorphisms are crucial to understand if these modest differences are important.

Alcohol Drinking↗
PubMed2005

Nucleotide polymorphism and linkage disequilibrium in wild populations of the partial selfer Caenorhabditis elegans.

An understanding of the relative contributions of different evolutionary forces on an organism's genome requires an accurate description of the patterns of genetic variation within and between natural populations. To this end, I report a survey of nucleotide polymorphism in six loci from 118 strains of the nematode Caenorhabditis elegans. These strains derive from wild populations of several regions within France, Germany, and new localities in Scotland, in addition to stock center isolates. Overall levels of silent-site diversity are low within and between populations of this self-fertile species, averaging 0.2% in European samples and 0.3% worldwide. Population structure is present despite a lack of association of sequences with geography, and migration appears to occur at all geographic scales. Linkage disequilibrium is extensive in the C. elegans genome, extending even between chromosomes. Nevertheless, recombination is clearly present in the pattern of polymorphisms, indicating that outcrossing is an infrequent, but important, feature in this species ancestry. The range of outcrossing rates consistent with the data is inferred from linkage disequilibrium, using "scattered" samples representing the collecting phase of the coalescent process in a subdivided population. I propose that genetic variation in this species is shaped largely by population subdivision due to self-fertilization coupled with long- and short-range migration between subpopulations.

Animals↗
PubMed2005

Rhizobial 16S rRNA and dnaK genes: mosaicism and the uncertain phylogenetic placement of Rhizobium galegae.

The phylogenetic relatedness among 12 agriculturally important species in the order Rhizobiales was estimated by comparative 16S rRNA and dnaK sequence analyses. Two groups of related species were identified by neighbor-joining and maximum-parsimony analysis. One group consisted of Mesorhizobium loti and Mesorhizobium ciceri, and the other group consisted of Agrobacterium rhizogenes, Rhizobium tropici, Rhizobium etli, and Rhizobium leguminosarum. Although bootstrap support for the placement of the remaining six species varied, A. tumefaciens, Agrobacterium rubi, and Agrobacterium vitis were consistently associated in the same subcluster. The three other species included Rhizobium galegae, Sinorhizobium meliloti, and Brucella ovis. Among these, the placement of R. galegae was the least consistent, in that it was placed flanking the A. rhizogenes-Rhizobium cluster in the dnaK nucleotide sequence trees, while it was placed with the other three Agrobacterium species in the 16S rRNA and the DnaK amino acid trees. In an effort to explain the inconsistent placement of R. galegae, we examined polymorphic site distribution patterns among the various species. Localized runs of nucleotide sequence similarity were evident between R. galegae and certain other species, suggesting that the R. galegae genes are chimeric. These results provide a tenable explanation for the weak statistical support often associated with the phylogenetic placement of R. galegae, and they also illustrate a potential pitfall in the use of partial sequences for species identification.

Alleles↗
PubMed2004

CLUSTAG: hierarchical clustering and graph methods for selecting tag SNPs.

UNLABELLED: Cluster and set-cover algorithms are developed to obtain a set of tag single nucleotide polymorphisms (SNPs) that can represent all the known SNPs in a chromosomal region, subject to the constraint that all SNPs must have a squared correlation R2>C with at least one tag SNP, where C is specified by the user. AVAILABILITY: http://hkumath.hku.hk/web/link/CLUSTAG/CLUSTAG.html CONTACT: mng@maths.hku.hk.

Algorithms↗