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At least 883 records · Page 49Linked to original sources
PubMed2001

Single nucleotide polymorphism identification in candidate gene systems of obesity.

We have constructed a large panel of single nucleotide polymorphisms (SNP) identified in 68 candidate genes for obesity. Our panel combines novel SNP identification methods based on EST data, with public SNP data from largescale genomic sequencing, to produce a total of 218 SNPs in the coding regions of obesity candidate genes, 178 SNPs in untranslated regions, and over 1000 intronic SNPs. These include new non-conservative amino acid changes in thyroid receptor beta, esterase D, acid phosphatase 1. Our data show evidence of negative selection among these polymorphisms implying functional impacts of the non-conservative mutations. Comparison of overlap between SNPs identified independently from EST data vs genomic sequencing indicate that together they may constitute about one half of the actual total number of amino acid polymorphisms in these genes that are common in the human population (defined here as a population allele frequency above 5%). We have analyzed our polymorphism panel to construct a database of detailed information about their location in the gene structure and effect on protein coding, available on the web at http://www.bioinformat ics.ucla.edu/snp/obesity. We believe this panel can serve as a valuable new resource for genetic and pharmacogenomic studies of the causes of obesity.

Databases, Genetic↗
PubMed2006

Candidate genes for barley mutants involved in plant architecture: an in silico approach.

To individuate candidate genes (CGs) for a set of barley developmental mutants, a synteny approach comparing the genomes of barley and rice has been introduced. Based on map positions of mutants, sequenced RFLP markers linked to the target loci were selected. The markers were mapped in silico by BLAST searches against the rice genome sequence and chromosomal regions syntenous to barley target intervals were identified. Rice syntenous regions were defined for 15 barley chromosomal intervals hosting 23 mutant loci affecting plant height (brh1; brh2; sld4), shoot and inflorescence branching (als; brc1; cul-2, -3, -5, -15, -16; dub1; mnd6; vrs1), development of leaves (lig) and leaf-like organs (cal-b19, -C15, -d4; lks5; suKD-25; suKE-74; suKF-76; trd; trp). Annotation of 110 Mb of rice genomic sequence made it possible to screen for putative CGs which are listed together with the reasons supporting mutant-gene associations. For two loci, CGs were identified with a clear probability to represent the locus considered. These include FRIZZY PANICLE, a candidate for the brc1 barley mutant, and the rice ortholog of maize Liguleless1 (Lg1), a candidate for the barley lig locus on chromosome 2H. For this locus, the validity of the approach was supported by the PCR-amplification of a genomic fragment of the orthologous barley sequence. SNP mapping located this fragment on chromosome 2H in the region hosting the lig genetic locus.

Amino Acid Sequence↗
PubMed2006

Genotyping of triallelic SNPs using TaqMan PCR.

Methods for analysis of single nucleotide polymorphisms (SNP) are well developed. However, most ready-made SNP genotyping kits (e.g., those that use TaqMan PCR) are based on the assumption that the SNP is biallelic. Thus, most kits are unsuitable for triallelic SNPs. We have experienced difficulty genotyping an SNP using TaqMan PCR. In the present study, we developed a method of genotyping a triallelic SNP (rs3091244: alleles C, A and T) using TaqMan PCR. We used 2 different genotyping kits: one for C/A allele genotyping, and one for C/T allele genotyping. The results of these 2 kits were combined to complete the genotyping. The subjects were 320 essentially healthy elderly Japanese. The frequencies of the C, A and T alleles were 0.78, 0.155 and 0.065, respectively. This double-tube method using TaqMan SNP Genotyping Assays was very accurate and convenient, and it should be useful for genotyping in case-control association studies or linkage studies.

Aged↗
PubMed2000

Genome-wide detection of allelic imbalance using human SNPs and high-density DNA arrays.

Most human cancers are characterized by genomic instability, the accumulation of multiple genetic alterations and allelic imbalance throughout the genome. Loss of heterozygosity (LOH) is a common form of allelic imbalance and the detection of LOH has been used to identify genomic regions that harbor tumor suppressor genes and to characterize tumor stages and progression. Here we describe the use of high-density oligonucleotide arrays for genome-wide scans for LOH and allelic imbalance in human tumors. The arrays contain redundant sets of probes for 600 genetic loci that are distributed across all human chromosomes. The arrays were used to detect allelic imbalance in two types of human tumors, and a subset of the results was confirmed using conventional gel-based methods. We also tested the ability to study heterogeneous cell populations and found that allelic imbalance can be detected in the presence of a substantial background of normal cells. The detection of LOH and other chromosomal changes using large numbers of single nucleotide polymorphism (SNP) markers should enable identification of patterns of allelic imbalance with potential prognostic and diagnostic utility.

Adenocarcinoma↗
PubMed2025

Reference-Free Variant Calling with Local Graph Construction with ska lo (SKA).

The study of genomic variants is increasingly important for public health surveillance of pathogens. Traditional variant-calling methods from whole-genome sequencing data rely on reference-based alignment, which can introduce biases and require significant computational resources. Alignment- and reference-free approaches offer an alternative by leveraging k-mer-based methods, but existing implementations often suffer from sensitivity limitations, particularly in high mutation density genomic regions. Here, we present ska lo, a graph-based algorithm that aims to identify within-strain variants in pathogen whole-genome sequencing data by traversing a colored De Bruijn graph and building variant groups (i.e. sets of variant combinations). Through in silico benchmarking and real-world dataset analyses, we demonstrate that ska lo achieves high sensitivity in single-nucleotide polymorphism (SNP) calls while also enabling the detection of insertions and deletions, as well as SNP positioning on a reference genome for recombination analyses. These findings highlight ska lo as a simple, fast, and effective tool for pathogen genomic epidemiology, extending the range of reference-free variant-calling approaches. ska lo is freely available as part of the SKA program (https://github.com/bacpop/ska.rust).

Polymorphism, Single Nucleotide↗
PubMed2003

[Evaluation of the usefulness of multitemperature single-stranded conformational polymorphism (MSSCP) for differentiation of selected bacterial gene variants (alleles)].

Recently, the single strand conformation polymorphism (SSCP) analyses were shown to be useful for identification a variety of bacterial genes. Although, SSCP was successfully applied for detection of single nucleotide polymorphism (SNP), it was also considered a time consuming and insufficiently reliable technique. Therefore, the modified Multitemperature-SSCP method was introduced. It was shown to be reliable and time effective technique due to a stringent control of the gel temperature and utilization of a high voltage up to 1 kV. In this study the usefulness of MSSCP for differentiation of gene variants and detection of the single point mutations was evaluated, using Yersinia enterocolitica O3 and O8 ail alleles or genes blaCTX-M-15 and blaCTX-M-3, which differs by a single point mutation. The 425 and 251 bp fragments of O3 and O8 ail alleles containing 15 and 11 point mutations respectively, as well as 277 and 208 bp fragments of both blaCTX-M genes differing in positions 243 and 62 were PCR amplified, denatured and loaded onto 7% and 9% polyacrylamide nondenaturing gel. Electrophoresis was carried out in the DNA-Pointer apparatus (Kuchrczyk, Poland) at voltage ranging from 500 to 750 V. The thermal profile consisted of 50 min. at 35 degrees C, 40 min at 20 degrees C and 40 min at 5 degrees C. Obtained results showed, MSSCP was capable to differentiate ail alleles independently of the length of analyzed fragment. However, the 425 bp fragment profile consisted of three bands, whereas 251 bp revealed two bands. The single point mutation in blaCTM, genes was also successfully distinguished by MSSCP in both tested fragments. Surprisingly, 277 bp fragment profile showed differences more apparently than 208 bp. Summarizing, MSSCP was found to be useful, sensitive and time efficient tool for detection of multiple and single point mutations in DNA fragments ranging from 208-425 bp.

Alleles↗
PubMed2005

[Detection of major gene on litter size in sheep].

The current study was designed to detect SNPs within BMP15 and BMPR-IB gene and investigate the effect of the genes on sheep litter size. Four sheep lines, HU-Yang, Chinese Merino monotocous, Chinese Merino multiparous for wool production and Chinese Merino multiparous for mutton production, were used in this study. Litter sizes were recorded for each ewe in the four lines. Primers for BMP15 and BMPR-IB gene were designed from database sheep sequence and polymorphisms were detected by PCR-RFLP method. The results showed that there was no polymorphism with BMP15 gene among the four lines, and there was an A / G SNP with BMPR-IB gene at base 746 among the four lines. Three types of genotype (BB, B+ and ++), based on A / G locus, were found within each line. The frequencies of genotypes were significantly different among the lines (P<0.001), with BB genotype primarily existing in HU-Yang, ++ genotype in Chinese Merino monotocous line, and B+ genotype in Chinnese Merino multiparous lines. The A / G mutation influence significantly the sheep litter sizes, and the BB and B+ ewes had significant higher litter sizes than ++ ewes. The results of present study showed simultaneously that the genotype of BMPR-IB was a perfect predictor of the sheep litter sizes. These results intensively indicated that BMPR-IB is a major gene to affect litter size in sheep, and could be used as the molecular genetic marker to select litter size in sheep.

Animals↗
PubMed2007

Mutation screen of the GAD2 gene and association study of alcoholism in three populations.

Synaptic actions of gamma-amino butyric acid (GABA) have been implicated in many facets of ethanol's effects and risk for alcoholism. We examined whether variation in glutamate decarboxylase-2 (GAD2), a gene encoding for a major enzyme in the synthesis of GABA, contributes to risk of alcohol dependence (AD). We screened GAD2 for sequence variants using dHPLC in a population of 96 individuals. Several single nucleotide polymorphisms (SNPs), including four rare non-synonymous polymorphisms, were identified. Thirteen SNPs located in the GAD2 gene were genotyped in a sample of 113 Russian males with AD and 100 Russian male controls. These analyses revealed a modest association between the functional GAD2 -243 A > G SNP (rs2236418) and AD (allele P = 0.038, genotype P = 0.008). An additional sample of 138 Russian males with AD were genotyped for the GAD2 -243 A > G. These analyses supported an association of this polymorphism with AD (combined sample allele P = 0.038, genotype P = 0.0009). We extended these findings to additional populations: a sample of 538 college students assessed using the AUDIT and a sample of European-American (EA) AD subjects (n = 235) and controls (n = 310). Analyses in these populations did not support a role for GAD2 in alcoholism. In summary, the results of an extensive search for an association of GAD2 with AD suggest that variation in GAD2 is not a major risk factor for AD in EAs. The functional promoter GAD2 -243 A > G variant may influence risk for AD in some populations, or its role may be limited to susceptibility to severe AD.

Adult↗
PubMed2006

Identification of a risk haplotype of the alpha-synuclein gene in Japanese with sporadic Parkinson's disease.

alpha-Synuclein is one of the main components of Lewy bodies, a pathological marker of Parkinson's disease (PD). Certain missense mutations of the alpha-synuclein gene cause familial PD, but the role of the gene in sporadic PD is still controversial. We scrutinized polymorphisms of the alpha-synuclein gene in a Japanese population and investigated their associations with sporadic cases of PD. The 5' flanking region to intron 2 of the alpha-synuclein gene (3.8 kb) and two polymorphisms in intron 4 previously reported in Caucasian sporadic cases of PD were analyzed in 185 sporadic PD and 191 controls. Five novel single nucleotide polymorphisms (SNPs), 16 reported SNPs, and one reported polynucleotide polymorphism (PNP) were found. Most of the polymorphisms examined were in linkage disequilibrium. Significant associations with PD were found in 15 of 21 SNPs, especially in intron 1 (IVS1+155 TmAn PNP and the IVS1+719 C>T SNP, P < 0.0001). Haplotype analysis showed that T10A7-A-A and T11A6-G-G haplotypes at three loci (IVS1+155 - IVS1+273 - IVS1+608) were strongly negative and positive risk factors of sporadic PD, respectively (odds ratios were 0.23 [95% confidence interval, 0.16-0.32] and 1.51 [95% confidence interval, 1.29-1.75]). In conclusion, our findings indicate that genetic variations of the alpha-synuclein gene affect the development of sporadic PD.

Adult↗
PubMed2005

The construction of bifunctional fusion proteins consisting of MutS and GFP.

MutS as a mismatch binding protein is a promising tool for SNP detection. Green fluorescent protein (GFP) is known as an excellent reporter domain. We constructed chimeric proteins consisting of MutS from Thermus thermophilus and GFPuv from Aequorea victoria by cloning the GFPuv gene into the plasmid vectors carrying the mutS gene. The GFPuv domain fused to the N-terminus of MutS (histag-GFP-MutS) exhibited the same level of green fluorescence as free GFPuv. To obtain the fluorescing histag-GFP-MutS protein the expression at 30 degrees C was required, while free GFPuv fluoresces when expressed both at 30 and 37 degrees C. The chimeric protein where the GFPuv domain was fused to the C-terminus of MutS exhibited much weaker green fluorescence (20-25% compared with those of histag-GFP-MutS or free GFPuv). The insertion of (ProGly)5 peptide linker between the MutS and GFP domains resulted in no significant improvement in GFP fluorescence. No shifts in the excitation and emission spectra have been observed for the GFP domain in the fusion proteins. The fusion proteins with GFP at the N- and C-terminus of MutS recognised DNA mismatches similarly like T. thermophilus MutS. The fluorescent proteins recognising DNA mismatches could be useful for SNP scanning or intracellular DNA analysis. The fusion proteins around 125 kDa were efficiently expressed in E. coli and purified in milligram amounts using metal chellate affinity chromatography.

Base Pair Mismatch↗
PubMed2003

Fra-1 targets the AP-1 site/2G single nucleotide polymorphism (ETS site) in the MMP-1 promoter.

The matrix metalloproteinase (MMP) family degrades the extracellular matrix. One member of this family, MMP-1, initiates the breakdown of interstitial collagens. The expression of MMP-1 is controlled by the mitogen activated protein kinase (MAPK) pathway(s) via the activity of activator protein-1 (AP-1) and polyoma enhancing activity-3/E26 virus (PEA3/ETS) transcription factors through consensus binding sites present in the promoter. Another ETS site in the MMP-1 promoter is created at -1607 bp by a single nucleotide polymorphism (SNP), which contains two guanines (5'-GGAT-3'; '2G SNP'), rather one guanine (5'-GAT-3'; '1G SNP'), adjacent to an AP-1 binding site at -1602 bp. The 2G SNP displays greater transcriptional activity than the 1G SNP, and AP-1 and Ets families of transcription factors cooperate to increase transcription. The 2G SNP has been linked to the incidence and the progression of several cancers and is also associated with non-neoplastic diseases; although the underlying mechanism(s) has yet to be elucidated. In this study we demonstrate that the expression of Fos-like region antigen (Fra-1), an AP-1 transcription factor component that also correlates strongly with neoplastic disease, is necessary for MMP-1 transcription in A2058 melanoma cells. The inhibition of Fra-1 expression preferentially downregulates transcription from the MMP-1 promoter DNA containing the 2G SNP, compared to DNA containing the 1G SNP. This study provides evidence that, in cooperation with the 2G DNA polymorphism, the AP-1 family member, Fra-1, contributes to the high constitutive expression of MMP-1 in melanoma cells.

DNA Mutational Analysis↗
PubMed2006

LAMARC 2.0: maximum likelihood and Bayesian estimation of population parameters.

UNLABELLED: We present a Markov chain Monte Carlo coalescent genealogy sampler, LAMARC 2.0, which estimates population genetic parameters from genetic data. LAMARC can co-estimate subpopulation Theta = 4N(e)mu, immigration rates, subpopulation exponential growth rates and overall recombination rate, or a user-specified subset of these parameters. It can perform either maximum-likelihood or Bayesian analysis, and accomodates nucleotide sequence, SNP, microsatellite or elecrophoretic data, with resolved or unresolved haplotypes. It is available as portable source code and executables for all three major platforms. AVAILABILITY: LAMARC 2.0 is freely available at http://evolution.gs.washington.edu/lamarc

Bayes Theorem↗
PubMedDate not supplied

Properties and kinetics of development of Rous sarcoma virus-infected cells evidenced by methylene blue staining.

Three different kinds of areas of infected cells corresponding to different focus formation stages can be evidenced by methylene blue (MB) staining in cultures of chick embryo (CE) fibroblasts infected at low multiplicity with the temperature-sensitive (ts) mutant of Rous sarcoma virus (RSV), FU19, which transforms these fibroblasts at 37 degrees but not at 41 degrees. These are: (a) areas of MB-stainable cells with transformed phenotype (STP areas=foci); (b) areas of MB-stainable cells with normal phenotype (SNP areas), and (c) areas of MB-unstainable cells with normal phenotype (USNP areas). DNA and RNA synthesis and virus production were followed in these various stages at 37 degrees and at 41 degrees. The results show that when cultures are shifted from 37 degrees to 41 degrees, virus production in the SNP and USNP areas which arise by phenotypic reversion of STP foci remains comparable to that of the latter foci. On the contrary, DNA and RNA synthesis are markedly reduced in SNP and USNP areas, DNA synthesis falling down to the level of uninfected cells, and RNA synthesis remaining somewhat higher. The kinetics of development of SNP and STP areas in cultures infected with FU19 and with the parental virus SR4 were also compared. The results confirm that SNP areas are precursors of STP areas but that this passage occurs at a slower rate in cultures infected with FU19.

Animals↗
PubMed2002

Response to infliximab treatment in Crohn's disease is not associated with mutations in the CARD15 (NOD2) gene: an analysis in 534 patients from two multicenter, prospective GCP-level trials.

Infliximab induces remission in 30-40% of patients with active Crohn's disease. Treatment response is a stable trait over repeated doses yet the clinical predictors of response are still unknown. Recently, three variants in the CARD15 gene have been identified as major genetic risk factors for Crohn's disease. Single nucleotide polymorphisms (SNPs) 8, 12 and 13, have been shown to be independently associated with Crohn's disease susceptibility. The aim of the present study was to investigate these variants in relation to the therapeutic efficacy of infliximab. SNPs were genotyped (TaqMan) in two cohorts ( n= 90 and n= 444 (ACCENT I)) of active Crohn's disease patients (CDAI 220-450). The patients were recruited from independent multicenter trials conducted according to GCP. At the start of both trials, patients received a single infusion of open label infliximab (5 mg/kg bodyweight). The genotypic and allelic frequencies of each SNP were significantly associated with Crohn's disease in comparison to 370 healthy controls as reported previously. Response to infliximab (drop in CDAI 70 points or remission, respectively) was not associated with the genetic variants in the CARD15 gene in either cohort. The subsequent negative findings in a two-cohort model exclude SNPs 8, 12 and 13 of the CARD15 gene as predictors for therapeutic response to infliximab treatment.

Antibodies, Monoclonal↗
PubMed2007

DNA sequence variability in isolates recovered from patients with postvaccination rash or herpes zoster caused by Oka varicella vaccine.

Little is known about the pathogenic potential of individual strains in the varicella vaccine. We analyzed genomic variation among specimens obtained from vaccine recipients with postvaccination rash or herpes zoster (HZ), focusing on polymorphisms between live attenuated varicella vaccine virus and wild-type varicella-zoster virus. Eleven of 18 postvaccination HZ specimens contained >1 strain, and 7 of 18 appeared to be clonal. All 21 postvaccination rash specimens contained mixtures of vaccine strains. Four single-nucleotide polymorphisms (SNPs) consistently occurred in every isolate; all were polymorphisms in open-reading frame (ORF) 62, and 2 confer amino acid substitutions in the immediate-early protein 62. Four wild-type SNPs occurred in every isolate: one each occurred in ORF 10, ORF 21, ORF 62, and a noncoding region upstream of ORF 64. The frequencies of the remaining wild-type SNPs were variable, with the SNPs uniformly expressed (even in mixtures) in 20.5%-97.4% of isolates (mean frequency, 67.7%). No 2 clinical isolates had identical SNP profiles; as such, vaccine latency usually involves >1 strain.

Adolescent↗
PubMed2005

Human SNPs reveal no evidence of frequent positive selection.

We compared the single-nucleotide polymorphisms (SNPs) in humans in 182 housekeeping and 148 tissue-specific genes. SNPs were divided into rare and common polymorphisms based on their frequencies. We found that housekeeping genes tend to be less polymorphic than tissue-specific genes for both rare and common SNPs. Using mouse as a second species for computing sequence divergences, we found no evidence of positive selection: for both housekeeping and tissue-specific genes, the ratio of nonsynonymous to synonymous common SNPs per site showed no significant difference from that of divergence. Similarly, we observed no evidence of positive selection for the 289 and 149 genes that have orthologs available for divergence calculation between humans and chimpanzees and between humans and Old World monkeys, respectively. A comparison with previous SNP studies suggests that approximately 20% of the nonsynonymous SNPs in the human population are nearly neutral and that positive selection in the human genome might not be as frequent as previously thought.

Animals↗
PubMed2006

Association between ABCC2 gene haplotypes and tenofovir-induced proximal tubulopathy.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) may induce renal proximal tubulopathy (rPT). There are no data on pharmacogenomic predictors of rPT in the genes encoding the multidrug-resistance protein (MRP) 2 and MRP4 transporters. METHODS: Mutational screening of the genes for MRP2 (ABCC2) and MRP4 (ABCC4) was performed using genomic DNA from 13 human immunodeficiency virus type 1 (HIV-1)-infected patients (group 1) presenting with TDF-induced rPT. Concomitantly, 17 unrelated HIV-1-infected patients who had received TDF therapy and who did not have rPT (group 2) were included in a case-control analysis, to assess the influence of single-nucleotide polymorphisms (SNPs) identified in ABCC2 and ABCC4. RESULTS: Six SNPs were identified in ABCC2. A significant allelic association between the 1249 G-->A SNP and TDF-induced rPT was observed (odds ratio, 6.11 [95% confidence interval, 1.19-31.15]; P<.02). ABCC2 haplotypes were significantly associated with the onset of TDF-induced rPT--CATC appeared to be a predisposing haplotype, as it was found in 40.9% of the group 1 case patients and in 13.7% of the group 2 control subjects (P<.01), whereas CGAC appeared to be a protective haplotype, as it was not observed in the group 1 case patients but was present in 20.2% of the group 2 control subjects (P<.01). No association was observed between ABCC4 polymorphism and TDF-induced rPT in the present study. CONCLUSION: ABCC2 haplotypes are associated with rPT induced by TDF in HIV-1-infected patients.

Adenine↗
PubMed2001

Sequence analysis using logic regression.

Logic Regression is a new adaptive regression methodology that attempts to construct predictors as Boolean combinations of (binary) covariates. In this paper we use this algorithm to deal with single-nucleotide polymorphism (SNP) sequence data. The predictors that are found are interpretable as risk factors of the disease. Significance of these risk factors is assessed using techniques like cross-validation, permutation tests, and independent test sets. These model selection techniques remain valid when data is dependent, as is the case for the family data used here. In our analysis of the Genetic Analysis Workshop 12 data we identify the exact locations of mutations on gene 1 and gene 6 and a number of mutations on gene 2 that are associated with the affected status, without selecting any false positives.

Algorithms↗