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PubMed2006

Levels of linkage disequilibrium in a wild bird population.

Population-based mapping approaches are attractive for tracing the genetic background to phenotypic traits in wild species, given that it is often difficult to gather extensive and well-defined pedigrees needed for quantitative trait locus analysis. However, the feasibility of association or hitch-hiking mapping is dependent on the degree of linkage disequilibrium (LD) in the population, on which there is yet limited information for wild species. Here we use single nucleotide polymorphism (SNP) markers from 23 genes in a recently established linkage map of the Z chromosome of the collared flycatcher, to study the extent of LD in a natural bird population. In most but not all cases we find SNPs within the same intron (less than 500 bp) to be in perfect LD. However, LD then decays to background level at a distance 1cM or 400-500 kb. Although LD seems more extensive than in other species, if the observed pattern is representative for other regions of the genome and turns out to be a general feature of natural bird populations, dense marker maps might be needed for genome scans aimed at identifying association between marker and trait loci.

Animals↗
PubMed2004

A new method for detecting single nucleotide polymorphism using GFP-display.

The single nucleotide polymorphism (SNP) of aldehyde dehydrogenase-2 (ALDH2) codon 487, GAA (Glu) or AAA (Lys), was examined using green fluorescent protein (GFP)-display, an electrophoretic detection method for single amino acid changes. Although no shift in migration between the GFP-ALDH (Glu487) and GFP-ALDH (Lys487) fusion proteins was observed on SDS/urea gel, the two migrated to different positions when tagged with Asp. The SNP analysis was performed with GFP-ALDH-Asp3, and GFP-ALDH-Asp3 constructed from donors having the codon GAA/GAA, GAA/AAA or AAA/AAA was detected as different patterns as expected. GFP-display is potentially a unique method in SNP analysis, which does not require any special equipment or chemicals.

Aldehyde Dehydrogenase↗
PubMed2003

Mutation detection in rice waxy mutants by PCR-RF-SSCP.

PCR-RF-SSCP (PRS), which combines cleaved amplified polymorphic sequence (CAPS) and single-strand conformation polymorphism (SSCP), is expected to be a useful technique for DNA polymorphism analysis. We evaluated the ability of PRS to detect single nucleotide polymorphism (SNP) using the Waxy gene, Wx, of rice, and subsequently were able to identify point mutations in wx mutant lines. The approximately 6-kb Wx gene was divided into five regions for PCR amplification. Two regions, in which most of the point mutations of the wx mutants have been identified, were amplified by PCR and cloned into a vector, and those clones containing SNPs produced as a result of the inherent inaccuracy of PCR were used for the evaluation of PRS. The efficiency of PRS in the detection of SNPs of these clones was over 70%. PRS analysis of the wx genes in 18 waxy mutants was carried out in the five regions using two different restriction endonucleases and two gel conditions, with and without glycerol. Of the 18 lines tested, 17 showed band patterns different from that of the wild type. Most of the mutations identified in this study were nucleotide changes in exons, which result in amino acid changes. One mutation generated an in-frame stop codon, and another was a frame shift mutation by one-base deletion. Two mutations found at a splice site were considered to inhibit normal splicing of mRNA. These results show that PRS is a useful technique for detecting point mutations in large plant genes.

Chromosome Mapping↗
PubMed2005

Characterization of linkage disequilibrium structure, mutation history, and tagging SNPs, and their use in association analyses: ELAC2 and familial early-onset prostate cancer.

In association analyses, it is critical that informative single-nucleotide polymorphisms (SNPs) be selected for study and utilized appropriately. We sequenced 38 kb, including exons of ELAC2, promoter region and conserved upstream intergenic sequences. A comprehensive characterization of linkage disequilibrium (LD) structure and mutation history was performed using our principal components analysis (PCA) method and a phylogenetic analysis. We identified a complex pattern of LD structure consistent with the occurrence of both recombination and mutation events within ELAC2. Four overlapping and noncontiguous LD groups were defined. Eight tagging SNPs (tSNPs) were identified, accounting for over 90% of the genetic variation of the 19 total variants. We tested associations between familial early-onset prostate cancer (PRCA) and each variant independently and in haplotypes. We performed these tests using all 19 variants and the 8 tSNPs; the results using tSNP haplotypes accurately represent the association evidence for the full haplotypes. We observed increased evidence for association when SNPs were analyzed in haplotypes. The phylogenetic analysis indicated three haplotypes, clustered farthest from the root-node, all of which were found more often in cases than controls. These three haplotypes together showed the best evidence of association with familial, early-onset PRCA (P=0.0024; odds ratio=2.23; 95% CI, 1.33-3.74), indicating possible allelic heterogeneity. Our results suggest that 8 tSNPs are required to comprehensively assess associations in ELAC2, and that haplotypes should be considered for analysis, and that a knowledge of mutation history may be helpful in parsing allelic heterogeneity and suggesting combinations of haplotypes to be tested.

Aged↗
PubMed2006

Sex steroid hormone pathway genes and health-related measures in women of 4 races/ethnicities: the Study of Women's Health Across the Nation (SWAN).

We synthesized findings relating health outcomes and genetic variants of the sex steroid hormone pathway in women from the Study of Women's Health Across the Nation (SWAN) Genetics Study. The SWAN Genetics Study, a component of the longitudinal SWAN study, describes selected genetics characteristics of health-related attributes during the menopausal transition in African American, Caucasian, Chinese, and Japanese women. At baseline, SWAN recruited menstruating women aged 42 to 52 years, who were not using exogenous hormones. Immortalized cell lines were developed and genotyped in 1,538 specimens from 1,757 participants in the genetics study. Genotypes and haplotypes from 6 genes (27 single nucleotide polymorphisms [SNPs]) in the sex steroid hormone pathway were related to circulating hormone concentrations, menstrual cycle profiles, and health-related outcomes, including lipids, diabetes mellitus, depressive symptoms, measures of cognition, bone mineral density (BMD), and vasomotor symptoms. Allele frequencies and distances differed substantially in the 4 race/ethnicity-specific groups evaluated, leading to variable patterns of association with health-related measures. For example, 17HSD genotypes were highly associated with diabetes risk in Caucasian women, whereas its haplotypes were associated with diabetes risk in both African American and Caucasian women. Several SNPs were associated with multiple outcomes. ESR1 rs3798577 was significantly associated with circulating estradiol concentrations, indicators of ovarian aging, high-density lipoprotein (HDL) cholesterol, apolipoprotein A-1, insulin sensitivity, and lumbar spine BMD. CYP1A1 rs2606345 was related to estrogen metabolite concentrations, vasomotor symptoms, and depressive symptoms. Some associations were much more prominent in specific races/ethnicities; Chinese women had statistically significant relations between ESR2 rs1256030 and HDL cholesterol, lumbar spine BMD, hip BMD, and metabolic syndrome. Importantly, women in the SWAN Genetics Study were typical of women in the community-based SWAN sample. This community-based sample of women from the SWAN Genetics Study identified important genetic sex steroid hormone pathway variants in relation to measures of health status. The magnitude and breadth of these relationships should motivate further research to verify and extend the findings.

Adult↗
PubMed2004

Optimum sample medium for single-nucleotide polymorphism and mutation detection by capillary electrophoresis.

Capillary electrophoresis (CE) is a versatile analytical platform widely used for nucleic acids analysis. Its applications in research and diagnostics include scanning and screening for mutations and polymorphisms by such reliable methods as single-strand conformation polymorphism (SSCP), heteroduplex analysis (HA), and combined SSCP/HA. This study, aimed at the further development of these methods, is focused on detailed sample-media characteristics. Factors affecting single-strand conformer stability and DNA intake efficiency were analyzed. The sample media optimal for efficient mutation or SNP detection were determined, and complex SSCP-CE patterns arising from unpurified PCR products were explained. It turns out, that the nondenaturing aqueous media assure both efficient DNA intake, and single-strand conformers stability required for the SSCP and combined SSCP/HA. The results of this study are applicable to all these areas of biomedical research, in which capillary electrophoresis is used for the characterization of nucleic acids.

DNA↗
PubMed2000

Identification of porcine intestinal spirochetes by PCR-restriction fragment length polymorphism analysis of ribosomal DNA encoding 23S rRNA.

The Brachyspira (formerly Serpulina) species rrl gene encoding 23S ribosomal RNA (rRNA) was used as a target for amplification of a 517bp DNA fragment by polymerase chain reaction (PCR). The primers for PCR amplification had sequences that were conserved among Brachyspira 23S rRNA gene and were designed from nucleotide sequences of Brachyspira hyodysenteriae, Serpulina intermedia, Brachyspira innocens and Brachyspira pilosicoli available from the GenBank database. Digestion of PCR-generated products from reference and field isolates of swine intestinal spirochetes with restriction enzymes Taq I and Alu I revealed five restriction fragment length polymorphism (RFLP) patterns. Each RFLP pattern corresponded to previously established genetic groups including B. hyodysenteriae (I), S. intermedia/B. innocens (II), Brachyspira murdochii (III), B. pilosicoli (IV) and B. alvinipulli (V). The 23S rRNA PCR/RFLP provided a relatively simple genotypic method for identification of porcine pathogenic B. hyodysenteriae and B. pilosicoli.

Animals↗
PubMed2005

Mosaic nature of the wolbachia surface protein.

Lateral gene transfer and recombination play important roles in the evolution of many parasitic bacteria. Here we investigate intragenic recombination in Wolbachia bacteria, considered among the most abundant intracellular bacteria on earth. We conduct a detailed analysis of the patterns of variation and recombination within the Wolbachia surface protein, utilizing an extensive set of published and new sequences from five main supergroups of Wolbachia. Analysis of nucleotide and amino acid sequence variations confirms four hypervariable regions (HVRs), separated by regions under strong conservation. Comparison of shared polymorphisms reveals a complex mosaic structure of the gene, characterized by a clear intragenic recombining of segments among several distinct strains, whose major recombination effect is shuffling of a relatively conserved set of amino acid motifs within each of the four HVRs. Exchanges occurred both within and between the arthropod supergroups. Analyses based on phylogenetic methods and a specific recombination detection program (MAXCHI) significantly support this complex partitioning of the gene, indicating a chimeric origin of wsp. Although wsp has been widely used to define macro- and microtaxonomy among Wolbachia strains, these results clearly show that it is not suitable for this purpose. The role of wsp in bacterium-host interactions is currently unknown, but results presented here indicate that exchanges of HVR motifs are favored by natural selection. Identifying host proteins that interact with wsp variants should help reveal how these widespread bacterial parasites affect and evolve in response to the cellular environments of their invertebrate hosts.

Amino Acid Sequence↗
PubMed1991

Several groups among human herpesvirus 6 strains can be distinguished by Southern blotting and polymerase chain reaction.

Eight human herpesvirus 6 (HHV-6) strains were studied by Southern blot and polymerase chain reaction. DNA from infected cells was digested by a panel of restriction enzymes and hybridized with cloned BamHI fragments corresponding to about 30% of the HHV-6 strain SIE genome. In parallel, this DNA was amplified by polymerase chain reaction using pairs of primers derived from the strain SIE nucleotide sequence. Subsequently, amplification products were analyzed by hybridization, digestion with restriction endonucleases, and partial nucleotide sequencing. Overall results indicated that all strains were closely related to one another. However, concordant differences in restriction patterns allowed at least two groups to be distinguished, typified by strains SIE and HST, respectively. Differences between the two groups were found to reflect a limited number of punctual changes in nucleotide sequences. These results strengthen the idea of a unique HHV-6 species with genetic polymorphism. In addition, this study provides useful markers for the diagnosis and molecular epidemiology of HHV-6 infections.

Base Sequence↗
PubMed2025

Should neighbours of tuberculosis (TB) cases be prioritised for active case finding in high TB-burden settings? A prospective molecular epidemiological study.

INTRODUCTION: In high tuberculosis (TB)-burden countries, considerable transmission of Mycobacterium tuberculosis (M. tb) likely occurs outside of households. We aimed to estimate the TB prevalence and incidence in households and neighbourhoods around known TB cases and to understand transmission patterns. METHODS: Household and neighbourhood contacts of pulmonary TB index cases from contiguous areas in Bandung, Indonesia, were screened and followed up for 12 months. Sputum samples underwent smear microscopy, M. tb culture, Xpert MTB/RIF, DNA isolation and whole-genome sequencing (WGS). Pairwise single-nucleotide polymorphism (SNP) distance ≤12 defined transmission for pairs with known epidemiological links, or SNP≤3 for pairs without epidemiological link. An SNP=12 cut-off was used to characterise transmission clusters. RESULTS: From 213 index cases, 514 household and 4141 neighbourhood contacts underwent TB screening: 19 household (3.70%, 95% CI 2.24 to 5.71) and 45 neighbourhood (1.09%, 95% CI 0.79 to 1.45) contacts were identified with TB, of whom 18 (3.50%, 95% CI 2.20 to 5.48) and 38 (0.92%, 95% CI 0.65 to 1.13) respectively, were bacteriologically confirmed. During follow-up, 11 household and 13 neighbourhood contacts were identified with TB (incidence per 100 000 person-years: 2286 (95% CI 1286 to 4148) and 350 (95% CI 190 to 563)), of whom 6 and 8, respectively, were bacteriologically confirmed (incidence per 100 000 person-years: 1247 (95% CI 560 to 2776) and 201 (95% CI 101 to 402)). A total of 223 patient M. tb isolates underwent WGS. Of 15 intra-household pairs, 8 (53.3%) were transmission pairs. Of 24 neighbour to index case pairs, 1 (4.2%) was a transmission pair. 11 of 19 transmission pairs shared no epidemiological link. We identified 25 M. tb genetic clusters from 205 mono-TB isolates overall. CONCLUSION: Neighbours have lower prevalence and incidence of TB than household contacts, but twice as many cases. Very few received M. tb from their index case, suggesting uncontrolled community-wide transmission. Whole population active case finding may be necessary in high TB-burden settings.

Humans↗
PubMed1999

A novel polymorphism (-357 G/A) of the ALDH2 gene: linkage disequilibrium and an association with alcoholism.

BACKGROUND: Human mitochondrial aldehyde dehydrogenase (ALDH2) is a major enzyme responsible for the oxidation of acetaldehyde derived from ethanol metabolism. The human ALDH2 gene shows genetic polymorphism at position 1510 with a G to A transition in exon 12. This mutation leads to ALDH2 enzyme deficiency and protection against alcoholism. As yet, no polymorphism for the promoter region of the ALDH2 gene has been reported. METHODS: We analyzed 600 nucleotides of the promoter region in addition to exon 12 from 571 Japanese, 68 Chinese, 80 Myanmar, 60 Mongolians, and 82 North-American Caucasians using single-strand conformational change polymorphism (SSCP) analysis and the polymerase chain reaction (PCR). PCR products that showed an aberrant banding pattern detected by the SSCP analysis were subjected to PCR direct sequencing. RESULTS: A novel polymorphism at -357 with a G to A substitution was found in all the population groups, including North-American Caucasians. In addition, the polymorphic status in the promoter and exon 12 suggested linkage disequilibrium between the two loci, which indicated that among Japanese, the ALDH2*2 allele is linked to the G promoter allele, and theALDH2*1 allele is linked to the A allele. A total of 206 healthy male controls and 185 alcoholic male patients with the homozygous ALDH2*1 genotype were analyzed for the polymorphism in the promoter. Genotypic frequencies of GG, GA, and AA for alcoholics were 54.1%, 44.3%, and 1.6%, and those for controls were 52.9%, 40.3%, and 6.8%, respectively. The A allele frequencies for alcoholics and controls were 0.24 and 0.27, respectively. A chi2 test for the entire 3 x 2 table indicated significant variations in the three genotypes (chi2 = 6.40, p < 0.05). However, no significant difference in allelic frequencies between the two groups was observed. CONCLUSION: This new polymorphism in the ALDH2 promoter is present in all populations studied. Further analysis in other ethnic groups is necessary to establish this as an additional risk factor for alcoholism.

Adult↗
PubMed2006

No association of DYNC1H1 with sporadic ALS in a case-control study of a northern European derived population: a tagging SNP approach.

The cytoplasmic dynein-dynactin complex has been implicated in the aetiology of motor neuron degeneration in both mouse models and human forms of motor neuron disease. We have previously shown that mutations in the cytoplasmic dynein 1 heavy chain 1 gene (Dync1h1) are causal in a mouse model of late-onset motor neuron degeneration but have found no association of the homologous sites in human DYNC1H1 with human motor neuron disease. Here we extend these analyses to investigate the DYNC1H1 genomic locus to determine if it is associated with sporadic amyotrophic lateral sclerosis (ALS) in a northern European-derived population. Among the 16 single nucleotide polymorphisms (SNPs) we examined, just two SNPs (rs2251644 and rs941793) were sufficient to tag the majority of haplotypic variation (r2 > or = 0.85) and these were tested in a case-control association study with 266 North American sporadic ALS patients and 225 matched controls. We found no association between genetic variation at DYNC1H1 and sporadic ALS (rs2251644; p = 0.538, rs941793; p = 0.204, haplotype; p = 0.956). In addition we investigated patterns of diversity at DYNC1H1 in Japanese and Cameroonian populations to establish the evolutionary history for this gene and observed reduced genetic diversity in the northern Europeans suggestive of selection at this locus.

Amyotrophic Lateral Sclerosis↗
PubMed2004

Data mining and genetic algorithm based gene/SNP selection.

OBJECTIVE: Genomic studies provide large volumes of data with the number of single nucleotide polymorphisms (SNPs) ranging into thousands. The analysis of SNPs permits determining relationships between genotypic and phenotypic information as well as the identification of SNPs related to a disease. The growing wealth of information and advances in biology call for the development of approaches for discovery of new knowledge. One such area is the identification of gene/SNP patterns impacting cure/drug development for various diseases. METHODS: A new approach for predicting drug effectiveness is presented. The approach is based on data mining and genetic algorithms. A global search mechanism, weighted decision tree, decision-tree-based wrapper, a correlation-based heuristic, and the identification of intersecting feature sets are employed for selecting significant genes. RESULTS: The feature selection approach has resulted in 85% reduction of number of features. The relative increase in cross-validation accuracy and specificity for the significant gene/SNP set was 10% and 3.2%, respectively. CONCLUSION: The feature selection approach was successfully applied to data sets for drug and placebo subjects. The number of features has been significantly reduced while the quality of knowledge was enhanced. The feature set intersection approach provided the most significant genes/SNPs. The results reported in the paper discuss associations among SNPs resulting in patient-specific treatment protocols.

Algorithms↗
PubMed2003

High-resolution SNPs and microsatellite haplotypes point to a single, recent entry of Native American Y chromosomes into the Americas.

A total of 63 binary polymorphisms and 10 short tandem repeats (STRs) were genotyped on a sample of 2,344 Y chromosomes from 18 Native American, 28 Asian, and 5 European populations to investigate the origin(s) of Native American paternal lineages. All three of Greenberg's major linguistic divisions (including 342 Amerind speakers, 186 Na-Dene speakers, and 60 Aleut-Eskimo speakers) were represented in our sample of 588 Native Americans. Single-nucleotide polymorphism (SNP) analysis indicated that three major haplogroups, denoted as C, Q, and R, accounted for nearly 96% of Native American Y chromosomes. Haplogroups C and Q were deemed to represent early Native American founding Y chromosome lineages; however, most haplogroup R lineages present in Native Americans most likely came from recent admixture with Europeans. Although different phylogeographic and STR diversity patterns for the two major founding haplogroups previously led to the inference that they were carried from Asia to the Americas separately, the hypothesis of a single migration of a polymorphic founding population better fits our expanded database. Phylogenetic analyses of STR variation within haplogroups C and Q traced both lineages to a probable ancestral homeland in the vicinity of the Altai Mountains in Southwest Siberia. Divergence dates between the Altai plus North Asians versus the Native American population system ranged from 10,100 to 17,200 years for all lineages, precluding a very early entry into the Americas.

Analysis of Variance↗
PubMed1994

A method for fast database search for all k-nucleotide repeats.

A significant portion of DNA consists of repeating patterns of various sizes, from very small (one, two and three nucleotides) to very large (over 300 nucleotides). Although the functions of these repeating regions are not well understood, they appear important for understanding the expression, regulation and evolution of DNA. For example, increases in the number of trinucleotide repeats have been associated with human genetic disease, including Fragile-X mental retardation and Huntington's disease. Repeats are also useful as a tool in mapping and identifying DNA; the number of copies of a particular pattern at a site is often variable among individuals (polymorphic) and is therefore helpful in locating genes via linkage studies and also in providing DNA fingerprints of individuals. The number of repeating regions is unknown as is the distribution of pattern sizes. It would be useful to search for such regions in the DNA database in order that they may be studied more fully. The DNA database currently consists of approximately 150 million basepairs and is growing exponentially. Therefore, any program to look for repeats must be efficient and fast. In this paper, we present some new techniques that are useful in recognizing repeating patterns and describe a new program for rapidly detecting repeat regions in the DNA database where the basic unit of the repeat has size up to 32 nucleotides. It is our hope that the examples in this paper will illustrate the unrealized diversity of repeats in DNA and that the program we have developed will be a useful tool for locating new and interesting repeats.

Base Sequence↗
PubMed2004

Electrophoretic variants of cardiac myosin heavy chain-alpha in Sprague Dawley rats.

Analysis of cardiac myosin revealed differences in gel electrophoretic migration patterns of the alpha-isoform of myosin heavy chain, but not the beta-isoform, in Sprague Dawley rats. No differences in the migration patterns of the alpha-or beta-isoforms were observed in other rat strains. Three electrophoretic migration patterns of the alpha-isoforms were observed in individual rats: a slower migrating isoform alone (4% of all rats tested), a faster migrating isoform alone (55%), and both isoforms (41%). The isoform expression pattern was identical in all myocardial regions in each rat. Frequency of expression patterns suggests multiple gene sequences for alpha-cardiac myosin heavy chain in Sprague Dawley rats. Sequence analysis of amplified regions of the Sprague Dawley and Brown Norway rat alpha-myosin genes, specifically the 5'-untranslated region, exons 1-3, and associated introns, showed numerous single nucleotide polymorphisms in coding and noncoding regions, including putative regulatory sites in Sprague Dawley rats, but not in Brown Norway rats. All Sprague Dawley rats varied from Brown Norway rats and no heterogeneity was observed in Brown Norway rats. Several deletions and dimorphic positions were also observed. Dimorphic positions were evident on automated sequencing comparisons. The data indicate that at least two alpha-myosin heavy chain isoforms exist in Sprague Dawley rats and these rats exhibit sequence diversity within that portion of the alpha-myosin heavy chain gene reported in this study.

Animals↗
PubMed1995

Identification of differentially expressed Leishmania donovani genes using arbitrarily primed polymerase chain reactions.

Arbitrarily primed polymerase chain reactions (AP-PCR) were used to amplify polymorphic DNA fragments from the genomes of a variety of geographic isolates of Leishmania donovani (Ld). From the latter, five polymorphic DNA fragments were cloned and sequence analysis identified 15 unique clones. Northern blot analysis showed that 13 of the 15 clones hybridized to transcribed RNAs isolated from Ld. Eight of these 13 AP-PCR clones specifically hybridized to Ld RNAs that were differentially expressed in promastigote and 'amastigote' cells. Comparative Northern analysis of four differentially expressed AP-PCR clones indicated that two clones, LdS-14-14 and LdI-9-7, were expressed in Ld and several other Leishmania species. However, RNAs corresponding to two other AP-PCR clones, LdE-6-1 and LdI-9-5, were detected only in members of the Ld complex, and not in L. major (Lm) or L. tropica (Lt). Comparative Southern blot analysis of the LdS-14-14 locus revealed numerous restriction-fragment length polymorphisms (RFLP) distinguishing Lm and Lt from the Ld isolates and L. infantum. However, the LdS-14-14 loci were mapped to similar-sized chromosomes observed among all Old World Leishmania species tested, indicating that localized nucleotide divergence, not chromosomal rearrangement, was responsible for altered Southern blot patterns. These results demonstrate that AP-PCR is a very useful method for identifying expressed gene sequences in organisms of relatively low-complexity genomes. Interestingly, the majority of these sequences identified in this study correspond to differentially expressed genes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗