SEARCH · PubMed Health

Results for “nucleotide polymorphism patterns”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 109 records · Page 6Linked to original sources

PubMed2004

Variation of gene-based SNPs and linkage disequilibrium patterns in the human genome.

A principal goal in human genetics is to provide the tools necessary to enable genome-wide association studies. Extensive information on the distribution of gene-based single-nucleotide polymorphisms (SNPs) and linkage disequilibrium (LD) patterns across the genome is required in order to choose markers for efficient implementation of this approach. To obtain such information, we have genotyped a large Japanese cohort for SNPs identified by systematic resequencing of more than 14 000 autosomal genes. Analysis of these data led to the conclusion that the Japanese population contains approximately 130 000 common autosomal gene haplotypes (frequency >0.05), of which more than 35% are identified in the present study. We also examined allele frequencies and LD patterns according to the position of variants within genes, and their distribution across the genome. We found lower allele variability at exonic SNP sites (both non-synonymous and synonymous) compared with non-exonic SNP sites, and greater average LD between SNPs within exons of the same gene compared with other SNP combinations, both of which could be signals of selection. LD was correlated with the recombination rate per physical distance as estimated from the meiotic map, but the strength of the relationship varied considerably in different regions of the genome. Unique LD patterns, characterized by frequent instances of high LD between non-adjacent SNPs punctuated by blocks of low LD, were found in a 7 Mb region on chromosome 6p that includes the MHC (major histocompatibility complex) locus and many non-MHC genes. These results demonstrate the complexity that must be taken into account when considering SNP variability and LD patterns, while also providing tools necessary for implementation of efficient genome-wide association studies.

Chromosomes, Human, Pair 6↗

PubMed2005

Geographical distribution of selected and putatively neutral SNPs in Southeast Asian malaria parasites.

Loci targeted by directional selection are expected to show elevated geographical population structure relative to neutral loci, and a flurry of recent papers have used this rationale to search for genome regions involved in adaptation. Studies of functional mutations that are known to be under selection are particularly useful for assessing the utility of this approach. Antimalarial drug treatment regimes vary considerably between countries in Southeast Asia selecting for local adaptation at parasite loci underlying resistance. We compared the population structure revealed by 10 nonsynonymous mutations (nonsynonymous single-nucleotide polymorphisms [nsSNPs]) in four loci that are known to be involved in antimalarial drug resistance, with patterns revealed by 10 synonymous mutations (synonymous single-nucleotide polymorphisms [sSNPs]) in housekeeping genes or genes of unknown function in 755 Plasmodium falciparum infections collected from 13 populations in six Southeast Asian countries. Allele frequencies at known nsSNPs underlying resistance varied markedly between locations (F(ST) = 0.18-0.66), with the highest frequencies on the Thailand-Burma border and the lowest frequencies in neighboring Lao PDR. In contrast, we found weak but significant geographic structure (F(ST) = 0-0.14) for 8 of 10 sSNPs. Importantly, all 10 nsSNPs showed significantly higher F(ST) (P < 8 x 10(-5)) than simulated neutral expectations based on observed F(ST) values in the putatively neutral sSNPs. This result was unaffected by the methods used to estimate allele frequencies or the number of populations used in the simulations. Given that dense single-nucleotide polymorphism (SNP) maps and rapid SNP assay methods are now available for P. falciparum, comparing genetic differentiation across the genome may provide a valuable aid to identifying parasite loci underlying local adaptation to drug treatment regimes or other selective forces. However, the high proportion of polymorphic sites that appear to be under balancing selection (or linked to selected sites) in the P. falciparum genome violates the central assumption that selected sites are rare, which complicates identification of outlier loci, and suggests that caution is needed when using this approach.

Animals↗

PubMed2001

Synonymous codon bias is not caused by mutation bias in G+C-rich genes in humans.

It is has been suggested that synonymous codon bias is a consequence of mutation bias in mammals. We tested this hypothesis in humans using single-nucleotide polymorphism data. We found a pattern of polymorphism which was inconsistent with the mutation bias hypothesis in G+C-rich genes. However, the data were consistent with the action of natural selection or biased gene conversion. Similar patterns of polymorphism were also observed in noncoding DNA, suggesting that natural selection or biased gene conversion may affect large tracts of the human genome.

Base Composition↗

PubMed2006

Forest-tree population genomics and adaptive evolution.

Forest trees have gained much attention in recent years as nonclassical model eukaryotes for population, evolutionary and ecological genomic studies. Because of low domestication, large open-pollinated native populations, and high levels of both genetic and phenotypic variation, they are ideal organisms to unveil the molecular basis of population adaptive divergence in nature. Population genomics, in its broad-sense definition, is an emerging discipline that combines genome-wide sampling with traditional population genetic approaches to understanding evolution. Here we briefly review traditional methods of studying adaptive genetic variation in forest trees, and describe a new, integrated population genomics approach. First, alleles (haplotypes) at candidate genes for adaptive traits and their effects on phenotypes need to be characterized via sequencing and association mapping. At this stage, functional genomics can assist in understanding gene action and regulation by providing detailed transcriptional profiles. Second, frequencies of alleles in native populations for causative single-nucleotide polymorphisms are estimated to identify patterns of adaptive variation across heterogeneous environments. Population genomics, through deciphering allelic effects on phenotypes and identifying patterns of adaptive variation at the landscape level, will in the future constitute a useful tool, if cost-effective, to design conservation strategies for forest trees.

Adaptation, Physiological↗

PubMed2006

Genetic and structural analysis of the basolateral amygdala complex in BXD recombinant inbred mice.

The amygdala integrates and coordinates emotional and autonomic responses. The genetics that underlie variation in amygdala structure may be coupled to variation in levels of aggression, fear, anxiety, and affiliated behaviors. We systematically quantified the volume and cell populations of the basolateral amygdala complex (BLAc) across 35 BXD recombinant inbred (RI) lines, the parental strains--C57BL/6J (B6) and DBA/2J (D2)--and F1 hybrids (n cases=199, bilateral analysis). Neuron number and volume vary 1.7- to 2-fold among strains (e.g., neuron number ranged from 88,000 to 170,000). Glial and endothelial populations ranged more widely (5- to 8-fold), in part because of higher technical error. A quantitative trait locus (QTL) for the BLAc size is located on chromosome (Chr) 8 near the Large gene. This locus may also influence volume of other regions including hippocampus and cerebellum. Cell populations in the BLAc appear to be modulated more weakly by loci on Chrs 11 and 13. Candidate genes were selected on the basis of correlation with BLAc traits, chromosomal location, single nucleotide polymorphism (SNP) density, and expression patterns in the Allen Brain Atlas. Neurod2, a gene shown to be significant for the formation of the BLAc by knockout studies, is among the candidates genes. Other candidates include Large, and Thra. Responses to drugs of abuse and locomotor activity were the most notable behavioral correlates of the BLAc traits.

Amygdala↗

PubMed2006

Systematic evaluation of association between the microsomal glutathione S-transferase 2 common variation and psoriasis vulgaris in Chinese population.

Several recent studies have demonstrated the possible involvement of the microsomal glutathione S-transferase 2 (MGST2) gene in the pathogenesis of psoriasis. The objectives of this work are to determine whether the genetic polymorphisms of the MGST2 gene were associated with an increased risk of psoriasis in Chinese patients. We first characterized the linkage disequilibrium pattern within MGST2 and identified single-nucleotide polymorphisms (SNPs) for tagging common genetic variants. Genotype- and haplotype-based analyses were then performed by genotyping the Tag SNPs in a large-scale sample of cases and controls. We characterized the linkage disequilibrium pattern within MGST2 using 12 densely distributed SNPs and identified 6 SNPs for tagging common genetic variants. We then performed an association analysis by genotyping the six SNPs in 552 cases and 384 controls, but none of the genotype- and haplotype-based analyses revealed significant evidence for association. We also performed family-based association analysis by genotyping the six SNPs in 95 trios; no evidence for association was identified. Our comprehensive genetic analysis of MGST2 common variants in a large Chinese sample of psoriasis did not provide any supporting evidence for MGST2 to be the susceptibility gene within the PSORS9 locus.

Adolescent↗

PubMed2004

The FU gene and its possible protein isoforms.

BACKGROUND: FU is the human homologue of the Drosophila gene fused whose product fused is a positive regulator of the transcription factor Cubitus interruptus (Ci). Thus, FU may act as a regulator of the human counterparts of Ci, the GLI transcription factors. Since Ci and GLI are targets of Hedgehog signaling in development and morphogenesis, it is expected that FU plays an important role in Sonic, Desert and/or Indian Hedgehog induced cellular signaling. RESULTS: The FU gene was identified on chromosome 2q35 at 217.56 Mb and its exon-intron organization determined. The human developmental disorder Syndactyly type 1 (SD1) maps to this region on chromosome 2 and the FU coding region was sequenced using genomic DNA from an affected individual in a linked family. While no FU mutations were found, three single nucleotide polymorphisms were identified. The expression pattern of FU was thoroughly investigated and all examined tissues express FU. It is also clear that different tissues express transcripts of different sizes and some tissues express more than one transcript. By means of nested PCR of specific regions in RT/PCR generated cDNA, it was possible to verify two alternative splicing events. This also suggests the existence of at least two additional protein isoforms besides the FU protein that has previously been described. This long FU and a much shorter isoform were compared for the ability to regulate GLI1 and GLI2. None of the FU isoforms showed any effects on GLI1 induced transcription but the long form can enhance GLI2 activity. Apparently FU did not have any effect on SUFU induced inhibition of GLI. CONCLUSIONS: The FU gene and its genomic structure was identified. FU is a candidate gene for SD1, but we have not identified a pathogenic mutation in the FU coding region in a family with SD1. The sequence information and expression analyses show that transcripts of different sizes are expressed and subjected to alternative splicing. Thus, mRNAs may contain different 5'UTRs and encode different protein isoforms. Furthermore, FU is able to enhance the activity of GLI2 but not of GLI1, implicating FU in some aspects of Hedgehog signaling.

Chromosome Mapping↗

PubMed2006

Evaluation of variation in control region sequences for Hispanic individuals in the SWGDAM mtDNA data set.

The Scientific Working Group on DNA Analysis Methods (SWGDAM) Hispanic data set was analyzed to determine the diversity, phylogeny, and relevant single nucleotide polymorphisms (SNPs) that describe haplogroup patterns for Hispanic Americans (N=686), and to assess the degree of admixture regarding mitochondrial DNA (mtDNA). The largest component of admixture based on mtDNA analysis derives from the four major haplogroups previously observed in Native American ancestry, including A (29.3%), B (15.7%), C (20.6%), and D (4.8%). European (17.8%) and African (11.8%) haplogroups also were observed within this data set. Hispanic SWGDAM samples from the southwest, compared with other SWGDAM Hispanic samples, were observed to have a greater percent of Native American haplogroups present (79.9%), and fewer African American haplogroups (4.5%). A total of 234 SNPs were observed in the data set, including 36 newly reported variable positions. These SWGDAM Hispanic data set SNPs ranged from having 1 to 31 changes (Length=L) on the phylogenetic tree, with site 16519 being the most variable. On average, there were 3.9 character changes for each variable position on the tree. The most variable sites (with 13 or more changes each listed from fastest to slowest) observed were 16519 (L=31), 16189 (L=23), 152 (L=23), 16311 (L=19), 146 (L=17), 195 (L=17), 16093 (L=15), 16362 (L=14), 16129 (L=13), 150 (L=13), and 153 (L=13). These sites are consistent with other reports on highly variable positions. A total of 27 SNPs were chosen to identify all clusters containing 1% (N=7) or more individuals in the SWGDAM Hispanic data set. The descriptive analyses revealed that the SWGDAM Hispanic data set is similar to published Native American and Hispanic data sets.

DNA Fingerprinting↗

PubMed2006

Survey of microarray technologies suitable to elucidate transcriptional networks as exemplified by studying KRAB zinc finger gene families.

Current microarray systems are suitable to monitor genome-wide expression patterns, to detect single-nucleotide polymorphisms (SNP), to identify target genes of transcription factors and DNA-protein interaction sites thereof as well as to determine genomic sites that are modified by methylation of CpG islands. In this review, advantages and limitations of individual microarray technologies are presented as well as experiences from ongoing studies on KRAB zinc finger gene families are taken to exemplify how different microarray approaches are applicable to elucidate complex transcriptional networks of gene regulation. However, bioinformaticians should be aware that each microarray technology has limitations in its sensitivity and selectivity that has to be taken into account once data mining on comprehensive genome-wide microarray data is conducted. In many cases, microarray results are the initial step to identify target genes of interest and to study the molecular regulation of biological processes thereof followed and validated by complementary proteome, metabolome or toponome analysis. Thus, microarray technologies can be considered a reliable approach for determining gene functions that might be modulated by electromagnetic fields.

Gene Expression Profiling↗

PubMed1998

Genetic heterogeneity of the 5' uncoding region of the catalase gene in Hungarian acatalasemic and hypocatalasemic subjects.

The 5' uncoding region (165 bp), exon 1 (63 bp) and part of intron 1 (20 bp) of the catalase gene was amplified by PCR in acatalasemic (2), hypocatalasemic (19) patients and healthy individuals (10). The single strand conformational polymorphism of PCR products showed a highly polymorphic pattern. This polymorphism was supported by nucleotide sequence analyses yielding eight mutations. They are A to T, C to A and C to T at positions -21, -20, -18 of the 5' flanking region, T to C at positions 4, 44, 49 of the non-coding region and C to T and C to A at positions 12, 27 of exon 1. Of these nucleotide substitutions, the fourth, fifth, seventh and eighth are novel mutations. The mutations 1, 3, 6, 8 were present at least at heterozygous level in all acatalasemics and hypocatalasemics. None of these mutations may be the causal mutation(s) of acatalasemia as each of these nucleotide substitutions were detected in healthy subjects with normal blood catalase activity.

Acatalasia↗

PubMed1997

Size and sequence polymorphism in the isocitrate dehydrogenase kinase/phosphatase gene (aceK) and flanking regions in Salmonella enterica and Escherichia coli.

The sequence of aceK, which codes for the regulatory catalytic enzyme isocitrate dehydrogenase kinase/phosphatase (IDH K/P), and sequences of the 5' flanking region and part or all of the 3' flanking region were determined for 32 strains of Salmonella enterica and Escherichia coli. In E. coli, the aceK gene was 1734 bp long in 13 strains, but in three strains it was 12 bp shorter and the stop codon was TAA rather than TGA. Strains with the shorter aceK lacked an open reading frame (f728) downstream between aceK and iclR that was present, in variable length, in the other strains. Among the 72 ECOR strains, the truncated aceK gene was present in all isolates of the B2 group and half of those of the D group. Other variant conditions included the presence of IS1 elements in two strains and large deletions in two strains. The aceK-aceA intergenic region varied in length from 48 to 280 bp in E. coli, depending largely on the number of repetitive extragenic palindromic (REP) sequences present. Among the ECOR strains, the number of REP elements showed a high degree of phylogenetic association, and sequencing of the region in the ECOR strains permitted partial reconstruction of its evolutionary history. In S. entica, the normal length of aceK was 1752 bp, but three other length variants, ranging from 1746 to 1785 bp, were represented in five of the 16 strains examined. The flanking intergenic regions showed relatively minor variation in length and sequence. The occurrence of several nonrandom patterns of distribution of polymorphic synonymous nucleotide sites indicated that intragenic recombination of horizontally exchanged DNA has contributed to the generation of allelic diversity at the aceK locus in both species.

Bacterial Proteins↗

PubMed2006

Mutations in the testis-specific NALP14 gene in men suffering from spermatogenic failure.

BACKGROUND: Because of the common use of ICSI and the potential genetic aetiology of spermatogenic failure, concern has been raised about transmitting genetic disorders to ICSI offspring. However, to date, in only approximately 15% of all cases of spermatogenic failure, an underlying genetic cause can be identified. We have previously established an association between spermatogenic failure and chromosomal region 11p15. In this study, we set out to explore whether NALP14, a gene recently mapped to 11p15, has a function in spermatogenesis and whether mutations in NALP14 can cause spermatogenic failure. METHODS: We applied two different multiple tissue northern (MTN) blots to determine tissue specificity of NALP14 and performed immunohistochemistry on human testis with anti-NALP14 antiserum. To determine imprinting status of NALP14, we tested the expression pattern of two single-nucleotide polymorphisms (SNPs) in human testis. Finally, we performed a mutation screen of the NALP14 gene in 157 men with azoospermia or severe oligozoospermia by direct sequencing; 158 normospermic men served as controls. RESULTS: NALP14 was, as are the three other genes in 11p15, exclusively expressed in testis. Within the testis, the NALP14 protein was mainly expressed in A dark spermatogonia, mid and late spermatocytes and spermatids. The mutation screen revealed five mutations that occurred only in the patient group. One of these unique mutations introduced an early stop codon in the NALP14 sequence, predicted to result in a severely truncated protein. CONCLUSION: Our data suggest that NALP14 has a function in spermatogenesis and that mutations in this gene might cause spermatogenic failure.

Amino Acid Sequence↗

PubMed2006

Transferability of tag SNPs to capture common genetic variation in DNA repair genes across multiple populations.

Genetic association studies can be made more cost-effective by exploiting linkage disequilibrium patterns between nearby single-nucleotide polymorphisms (SNPs). The International HapMap Project now offers a dense SNP map across the human genome in four population samples. One question is how well tag SNPs chosen from a resource like HapMap can capture common variation in independent disease samples. To address the issue of tag SNP transferability, we genotyped 2,783 SNPs across 61 genes (with a total span of 6 Mb) involved in DNA repair in 466 individuals from multiple populations. We picked tag SNPs in samples with European ancestry from the Centre d'Etude du Polymorphisme Humain, and evaluated coverage of common variation in the other samples. Our comparative analysis shows that common variation in non-African samples can be captured robustly with only marginal loss in terms of the maximum r2. We also evaluated the transferability of specified multi-marker haplotypes as predictors for untyped SNPs, and demonstrate that they provide equivalent coverage compared to single-marker tests (pairwise tags) while requiring fewer SNPs for genotyping. The efficacy of a tagging-based approach in studying genotype-phenotype correlations in complex traits is strongly supported by our empirical results.

Computational Biology↗

PubMed1999

Current intraspecific dynamics of sequence evolution differs from long-term trends and can account for the AT-richness of honeybee mitochondrial DNA.

The very high AT content of hymenopteran mtDNA has warranted speculation about nucleotide substitution processes in this group. Here we investigate the pattern of honeybee, Apis mellifera, mtDNA nucleotide polymorphisms inferred from phylogeny in terms of differences between the ATPase6, COI, COII, COIII, cytochrome b, and ND2 genes and strand asymmetry in mutation rates. The observed transition/transversion ratios and the distribution of nonsynonymous substitutions between regions differed significantly. The pattern of differences between genes leading to these heterogeneities (the ATPase6 and COIII genes group apart from the rest) differed markedly from that predicted on the basis of long-term evolutionary change and may indicate differences between current and long-term dynamics of sequence evolution. Also, there is strong strand asymmetry in substitutions, which probably results in a mutability of G and C sufficiently high to account for the AT-richness of honeybee mtDNA.

Adenosine Triphosphatases↗

PubMed2003

Modeling linkage disequilibrium and identifying recombination hotspots using single-nucleotide polymorphism data.

We introduce a new statistical model for patterns of linkage disequilibrium (LD) among multiple SNPs in a population sample. The model overcomes limitations of existing approaches to understanding, summarizing, and interpreting LD by (i) relating patterns of LD directly to the underlying recombination process; (ii) considering all loci simultaneously, rather than pairwise; (iii) avoiding the assumption that LD necessarily has a "block-like" structure; and (iv) being computationally tractable for huge genomic regions (up to complete chromosomes). We examine in detail one natural application of the model: estimation of underlying recombination rates from population data. Using simulation, we show that in the case where recombination is assumed constant across the region of interest, recombination rate estimates based on our model are competitive with the very best of current available methods. More importantly, we demonstrate, on real and simulated data, the potential of the model to help identify and quantify fine-scale variation in recombination rate from population data. We also outline how the model could be useful in other contexts, such as in the development of more efficient haplotype-based methods for LD mapping.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

SNPNB: analyzing neighboring-nucleotide biases on single nucleotide polymorphisms (SNPs).

UNLABELLED: SNPNB is a user-friendly and platform-independent application for analyzing Single Nucleotide Polymorphism NeighBoring sequence context and nucleotide bias patterns, and subsequently evaluating the effective SNP size for the bias patterns observed from the whole data. It was implemented by Java and Perl. SNPNB can efficiently handle genome-wide or chromosome-wide SNP data analysis in a PC or a workstation. It provides visualizations of the bias patterns for SNPs or each type of SNPs. AVAILABILITY: SNPNB and its full description are freely available at http://bioinfo.vipbg.vcu.edu/SNPNB/

Algorithms↗

PubMed2001

Linkage of the human inducible nitric oxide synthase gene to type 1 diabetes.

Exposure of human pancreatic islets to a mixture of cytokines induces expression of the inducible nitric oxide synthase (iNOS), impairs beta-cell function, and induces apoptosis. We performed a mutational scanning of all 27 exons of the human NOS2 gene and linkage transmission disequilibrium testing of identified NOS2 polymorphisms in a Danish nationwide type 1 diabetes mellitus (IDDM) family collection. Mutational screening was performed using PCR-amplified exons, followed by single stranded conformation polymorphism and verification of potential polymorphisms by sequencing. The transmission disequilibrium test was performed in an IDDM family material comprising 257 Danish families; 154 families were affected sibling pair families, and 103 families were simplex families. In total, 10 polymorphisms were identified in 8 exons, of which 4 were tested in the family material. A C/T single nucleotide polymorphism in exon 16 resulting in an amino acid substitution, Ser(608)Leu, showed linkage to IDDM in human leukocyte antigen DR3/4-positive affected offspring (P = 0.008; corrected P = 0.024). No other distorted transmission patterns were found for any other tested single nucleotide polymorphism or constructed haplotypes with the exception of those including data from exon 16. In conclusion, linkage of the human NOS2 gene to IDDM in a subset of patients supports a pathogenic role of nitric oxide in human IDDM.

Diabetes Mellitus, Type 1↗

PubMed2002

Intron presence-absence polymorphism in Drosophila driven by positive Darwinian selection.

Comparisons of intron-exon structures between homologous genes in different eukaryotic species have revealed substantial variation in the number of introns. These observations imply that, in each case, an intron presence-absence polymorphism must have existed in the past. Such a polymorphism, created by a recent intron-loss mutation, is reported here in a eukaryotic organism. This gene structure, detected in the jingwei (jgw) gene, segregates at high frequency (77%) in natural populations of Drosophila teissieri and is associated with a marked change in mRNA levels. Furthermore, the intron loss does not result from a mRNA-mediated mechanism as is usually proposed, but from a partial deletion at the DNA level that also results in the addition of four new amino acids to the JGW protein. Population genetic analyses of the pattern of nucleotide variation surrounding the intron polymorphism indicate the action of positive Darwinian selection on the intron-absent variant. Forward simulations suggest that the intensity of this selection is weak to moderate, roughly equal to the selection intensity on most replacement mutations in Drosophila.

Animals↗