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At least 199 records · Page 11Linked to original sources
PubMed2006

Integrating patterns of polymorphism at SNPs and STRs.

Single nucleotide polymorphisms (SNPs) and short tandem repeats (STRs) differ in mutation rate and mechanism. As a result of these differences, simultaneous consideration of polymorphism patterns at SNPs and STRs can provide insights that are difficult to obtain from analysis of either marker type in isolation. Here, we use coalescent simulations to model the opposing effects of contrasting mutational dynamics and of shared genealogical history on the correlation between polymorphism at linked SNPs and STRs. Results show that polymorphism patterns are correlated only weakly despite the shared underlying genealogy, underscoring the importance of divergent mutational processes. Examples illustrate how knowledge of these relationships could aid population genetic inference, indicating the need for thorough theoretical studies.

Animals↗
PubMedDate not supplied

A renaissance of "biochemical genetics"? SNPs, haplotypes, function, and complex diseases.

We have made remarkable progress in understanding the molecular bases of many Mendelian diseases over the past 2-3 decades. The current interest in discovering the molecular basis of complex diseases uses either linkage or candidate gene approaches. The latter often uses case/control (or case/cohort) study designs. We believe it is critically important to have a thorough understanding of SNP (single nucleotide) and haplotype function in such endeavors. Functionally neutral SNPs and haplotypes are probably best suited for linkage studies (far away from the locus of interest). Functionally relevant SNPs and haplotypes seem best suited for candidate gene approaches. The need for functional data may result in a renaissance of biochemical genetics with a new twist in the genomic era. We propose that the functional characterization of SNPs and haplotypes be advanced with great vigor for those genes with defined assayable phenotypes. These systematic investigations will involve classical biochemistry, modern genetics, and genomics and will probably also draw on newer technologies such as microarrays. In short, a renaissance of biochemical genetics will advance our understanding of complex diseases.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2001

The use of the LightCycler for the detection of Y chromosome SNPs.

A novel methodology based on PCR monitoring on-line with fluorescent formats using the LightCycler for Y chromosome SNP typing is proposed. The main advantages of the system are the time necessary for the analysis (which is around 20 min), the robustness and the accuracy of the method and especially its sensitivity, which permits the detection of the male component in male-female mixtures up to 1:300 for some of the SNPs. Singleplexes of four different SNPs (M9, sY81, SRY-1532 and SRY-2627) as well as two duplexes (M9 and sY81 on the one hand and SRY-1532 and SRY-2627 on the other) were efficiently implemented. A simultaneous amplification and analysis of the four SNPs is also possible. It seems difficult with the current methodology to implement more than a quadruplex.

Alleles↗
PubMed1999

Single nucleotide polymorphisms (SNPs) in the estrogen receptor gene and breast cancer susceptibility.

In order to evaluate the role of inherited variation in the estrogen receptor (ESR1) gene in human breast cancer, we determined intronic sequences flanking each ESRI exon; identified multiple SNPs and length polymorphisms in the ESR1 coding sequence, splice junctions and regulatory regions; and genotyped families at high risk of breast cancer and population-based breast cancer patients and controls. Of 10 polymorphic sites in ESR1, four are synonymous SNPs, two are nonsynonymous SNPs and four are length polymorphisms; five are novel. No ESR1 polymorphisms were associated with breast cancer, either in the high-risk families or the case-control study. We therefore conclude that inherited genetic variation is not a mechanism by which the estrogen receptor is commonly involved in breast cancer development.

5' Untranslated Regions↗
PubMed2003

Enterobacterial adhesins and the case for studying SNPs in bacteria.

Single-nucleotide polymorphisms (SNPs) in structural genes can have a dramatic effect on the biology of whole organisms, from bacteria and viruses to mammals. Here, we underscore the importance of SNPs in bacterial genes that contribute to the ability of pathogens to cause disease. SNPs that confer an adaptive advantage for bacterial pathogens have been discovered in the genes encoding the FimH and Dr adhesins of Escherichia coli and, most recently, Salmonella enterica sv. Typhimurium FimH.

Adhesins, Bacterial↗
PubMed2002

Identification of two SNPs in the 5' flanking region of the ACP1 gene and evaluation of disequilibrium among polymorphic sites.

We have studied the 5' flanking region of the ACP1 gene looking for new polymorphisms. Two SNPs, DdeI and FokI restricted, have been found in this region. We determined the genotype of DdeI and FokI SNPs, as well as of three other known SNPs, codon 43 (CfoI restricted), codon 41 and codon 105 (TaqI restricted), located respectively in exons 3, 4 and 6 in 62 unrelated subjects from the Italian population. Haplotype distribution for the ten possible pairs of loci were determined by a maximum likelihood procedure. Overall, statistically significant deviations from expected frequencies assuming equilibrium have been observed for the following pairs: FokI/codon 41, FokI/TaqI, codon 41/TaqI (complete association), DdeI/FokI, DdeI/codon 41 and DdeI/TaqI. The data suggest that the FokI area could include sequences operating in strict functional association with sequences included in the codon 41/TaqI area, possibly in order to regulate the F/S isoforms ratio of the A* and *B alleles. Since the ratio between the concentration of the two F and S isoforms is different for the three ACP1 alleles, we suggest that the ACP1 locus has been subjected to strong selective pressure to obtain an optimal alternative splicing mechanism of the *A and *B alleles. The *C variant, on the other hand, seems completely independent from sequences in the FokI/codon 41/TaqI areas, resulting in an inverted F/S ratio compared to that found for *A and *B alleles.

5' Flanking Region↗
PubMed2004

Functional analysis of SNPs variants of BCRP/ABCG2.

PURPOSE: The aim of the current study was to identify the effect of single nucleotide polymorphisms (SNPs) in breast cancer resistance protein (BCRP/ABCG2) on its localization, expression level, and transport activity. METHODS: The cellular localization was identified using the wild type and seven different SNP variants of BCRP (V12M, Q141K, A149P, R163K, Q166E, P269S, and S441N BCRP) after transfection of their cDNAs in plasmid vector to LLC-PK1 cells. Their expression levels and transport activities were determined using the membrane vesicles from HEK293 cells infected with the recombinant adenoviruses containing these kinds of BCRP cDNAs. RESULTS: Wild type and six different SNP variants of BCRP other than S441N BCRP were expressed on the apical membrane, whereas S441N BCRP showed intracellular localization. The expression levels of Q141K and S441N BCRP proteins were significantly lower compared with the wild type and the other five variants. Furthermore, the transport activity of E1S, DHEAS, MTX, and PAH normalized by the expression level of BCRP protein was almost the same for the wild type, V12M, Q141K, A149P, R163K, Q166E, and P269S BCRP. CONCLUSIONS: These results suggest that Q141K SNPs may associate with a lower expression level, and S441N SNPs may affect both the expression level and cellular localization. It is possible that subjects with these polymorphisms may have lower expression level of BCRP protein and, consequently, a reduced ability to export these substrates.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2002

IL-4 receptor alpha chain genetic polymorphism and total IgE levels in the English population: two-locus haplotypes are more informative than individual SNPs.

The IL-4RA locus encodes for the alpha chain of the IL-4 receptor, and is both a functional and positional candidate gene for atopy and allergic disease. Recently Ober et al. have shown that the study of haplotypes at multiple loci in the IL-4RA gene could be more informative than the separate study of single nucleotide polymorphisms (SNPs). One hundred and fifty subjects affected by atopic asthma and 150 healthy control subjects were studied in the English population (Oxford district). Subjects and controls were genotyped for the Ile50Val, Ser478Pro and Gln551Arg polymorphism of the IL-4 receptor alpha chain. The distribution of haplotypes 50-478 shows a highly significant association with IgE levels. In particular, the haplotype Val50/Pro478 is much less frequent in subjects with IgE levels > 100 U mL-1 than in those with IgE levels < 100 U mL-1. Furthermore, the distribution of haplotype 50-551 shows a weak association with IgE levels that is lacking for 478-551 haplotypes. A lower frequency of the Val50/Pro478 haplotype is also observed among asthmatic subjects as compared to healthy controls. With regard to individual SNPs (50 478 and 551), no significant association has been observed with IgE levels or with asthma, thus confirming the higher informative value of the haplotype analysis as compared to separate study on SNPs.

England↗
PubMed2001

3rd International Meeting on Single Nucleotide Polymorphism and Complex Genome Analysis: SNPs: 'some notable progress'.

Fervent activities for the collection and exploitation of single nucleotide polymorphism (SNP) data continue, amid concerns about their real utility. The desire to understand complex disease aetiology remains a key driving force for this activity. Recent developments provided a level of cautious optimism not seen in previous International Meetings on Single Nucleotide Polymorphism and Complex Genome Analysis. The 3rd such meeting, held 8-11 September 2000 in Taos, New Mexico, covered research on technologies for SNP scoring, analytical tools for using SNPs to map disease genes, examples from researchers using SNPs for specific disease studies, and databases and tools for facilitating these activities. Studies of human history, and a range of studies upon model organisms were also represented. Whilst the transition from technology oriented work (methods, discovery, etc.) to successful biological application is occurring relatively slowly, a clear trend in this direction is now apparent, and it will surely gain momentum in future months and years. Many fundamental properties of SNPs remain unknown, and many other basic questions are still unanswered, but the field is moving forward on all necessary fronts, promising exciting advances just around the corner.

Genetic Techniques↗
PubMed2002

Comparison of family based haplotype methods using intragenic SNPs in candidate genes.

The choice of an optimal marker strategy while analysing intragenic SNPs is presently of crucial importance, given the increasing amount of available data. Classical case/control association studies or family based association tests such as the TDT are very popular. However, as these methods are not able to analyse multiple markers simultaneously, different extensions have been proposed in order to use multiple markers. In the present study, the efficiency of five family based haplotypic methods to detect the role of candidate genes is evaluated and compared between them and with the classical single point TDT. Simulations of intragenic SNP maps are performed in recently founded populations. One or several SNPs are assumed to be the functional polymorphisms following different genetic models. Different modes of SNP combinations underlying the genetic susceptibility (epistasis or heterogeneity) are considered. Whereas haplotypic methods perform better in situations of heterogeneity, the TDT remains the most powerful approach in epistasis models as long as the marginal effect of one the SNPs involved in the susceptibility remains important. Haplotypic methods perform better than the TDT when the marginal effect of each SNP is small. Given the similar characteristics of intragenic LD in both old large populations and recently founded populations, in particular the weak correlation between LD and distance, our results are not likely to be specific to founder populations and can be generalized.

Epistasis, Genetic↗
PubMed2006

Analysis of chromosome 5q31-32 and psoriasis: confirmation of a susceptibility locus but no association with SNPs within SLC22A4 and SLC22A5.

We have previously reported a region on chromosome 5q as a possible susceptibility region for psoriasis. This cytokine cluster-rich region has also been suggested as a susceptibility locus in other autoimmune or inflammatory diseases including Crohn's disease (CD) and rheumatoid arthritis (RA). Three specific single-nucleotide polymorphisms (SNPs) have been reported to associate with RA and CD and to change the functional activity of two organic cation transporters, solute carrier family 22 member 4/5 (SLC22A4) and (SLC22A5). In this study, we have analyzed these SNPs for an association with psoriasis. We have also performed a denser linkage analysis of this region with an additional 31 microsatellite markers. We were not able to detect any association with any of the three SNPs analyzed. However, our linkage result supports the involvement of this region in the etiology of psoriasis. We obtained a peak non-parametric linkage value of 3.1 for marker D5S436 in a subgroup of patients with joint complaints. This result supports the findings in another study of psoriasis patients originating from Iceland in which the authors obtained a peak logarithm of the odds score of 2.6 for marker D5S2090, only 2 Mb from D5S436. This suggests a psoriasis susceptibility locus on chromosome 5q32 that is involved in the arthritic phenotype of the disease.

Chromosome Mapping↗
PubMed2001

Identification of single nucleotide polymorphisms (SNPs) and other sequence changes and estimation of nucleotide diversity in coding and flanking regions of the NMDAR1 receptor gene in schizophrenic patients.

Glutamatergic dysregulation has been hypothesized to play a role in schizophrenia. The N-methyl-D-aspartate (NMDA) type of glutamate receptor especially is of interest because, in addition to binding sites for glutamate and glycine, a necessary co-agonist, this receptor also contains noncompetitive binding sites for the psychotomimetics phencyclidine (PCP), MK-801, and ketamine. PCP-induced psychosis has been a useful disease model in that both the positive as well as the negative symptomatologies seen in schizophrenia are observed. Recently, a mouse deficient in expression of the NR1 subunit gene (NMDAR1) of the heteromeric receptor has been developed and shown to display aberrant behaviors, with reduced social and sexual interactions as well as increased stereotypic motor activity. In an extensive examination of the NMDAR1 gene in our laboratory in approximately 100 chronic schizophrenic patients, 28 unique sequence changes were identified, including eight single nucleotide polymorphisms (SNPs) in the 5' untranslated region (5'UTR), six SNPs in coding regions (cSNPs), eleven intronic SNPs, two intronic deletions of 7 and 30 bp, and an intronic microinsertion/deletion. With the exception of one previously reported cSNP, all of the identified changes were novel. The frequency of polymorphisms differed significantly by ethnicity and several appeared to be in linkage disequilibrium. None of the changes appeared likely to be of functional significance, thus suggesting that changes in the genomic NMDAR1 are unlikely to contribute to the etiology of schizophrenia. Estimates of nucleotide diversity are comparable to those observed in studies of other genes.

Asian People↗
PubMed2004

Association of SNPs and haplotypes in GABAA receptor beta2 gene with schizophrenia.

Disturbances in GABAergic system have been observed in schizophrenics. In the present study, population association analysis was performed on 19 SNPs in the alpha(1), beta(2), gamma(2), epsilon and pi subunit genes of GABA(A) receptor. Five SNPs in GABRB2, namely B2I7G1584T, rs1816071, rs194072, rs252944 and rs187269, were found to be significantly associated, and their haplotypes in linkage disequilibrium, with schizophrenia. This represents the first report on any disease association of SNPs in the human GABA(A) receptor genes, and focuses attention on the GABAergic hypothesis of schizophrenia etiology.

Amino Acid Sequence↗
PubMed2001

Two newly identified SNPs in the APO AI-CIII intergenic region are strongly associated with familial combined hyperlipidaemia.

BACKGROUND: We previously reported linkage and association of the apoAI-CIII-AIV gene region on chromosome 11 with familial combined hyperlipidaemia (FCHL). However, the observed epistasis resulting in an increased susceptibility to FCHL still remains unexplained. We hypothesize that the region between the apo AI and apo CIII genes may harbour functional mutations that might be in linkage disequilibrium with the already identified SstI and MspI polymorphisms, and provide an alternative explanation for the observed relationship. METHODS: Using sequence analysis, we identified four new single nucleotide polymorphisms (SNPs) in the apo AI-CIII intergenic region. These four variants, T(3213)C, A(3235)C, T(3287)C and A(5132)C, were studied in 30 FCHL probands, 159 hyperlipidaemic relatives, 327 normolipidaemic relatives, and 218 spouses from the same families in which the original results were obtained. RESULTS: The allele frequencies were significantly different between probands and spouses (P < 0.05). Transmission/disequilibrium test (TDT) analyses revealed more frequent transmission of the minor alleles to the affected offspring. The minor genotype was associated with elevated plasma cholesterol and triglyceride levels. The T(3213)C and MspI, and the A(3235)C and SstI SNPs were in complete linkage disequilibrium, resulting in two different major haplotypes 2-2-1-2-2-1 and 1-1-2-2-2-2 (MspI-T(3213)C-A(3235)C-T(3287)C-A(5132)C-SstI). Both haplotypes appear to predispose to FCHL independently, and account, together with the wild-type, for almost 90% of those occurring in these FCHL families, extending the high-risk combination of haplotypes that were reported previously. CONCLUSION: These newly identified additional intergenic SNPs therefore provide an alternative explanation for the observed association of the SstI and MspI polymorphisms to the increased susceptibility for FCHL.

Adult↗
PubMed2000

Selecting SNPs in two-stage analysis of disease association data: a model-free approach.

For large numbers of marker loci in a genomic scan for disease loci, we propose a novel 2-stage approach for linkage or association analysis. The two stages are (1) selection of a subset of markers that are 'important' for the trait studied, and (2) modelling interactions among markers and between markers and trait. Here we focus on stage 1 and develop a selection method based on a 2-level nested bootstrap procedure. The method is applied to single nucleotide polymorphisms (SNPs) data in a cohort study of heart disease patients. Out of the 89 original SNPs the method selects 11 markers as being 'important'. Conventional backward stepwise logistic regression on the 89 SNPs selects 7 markers, which are a subset of the 11 markers chosen by our method.

Algorithms↗
PubMed2005

Fine mapping functional sites or regions from case-control data using haplotypes of multiple linked SNPs.

Previously, we reported an algorithm for scanning a large number of tightly linked single nucleotide polymorphisms (SNPs) for LD mapping of functional sites or regions from a family-based association design. In the present study, we extend our method to a case-control design. We first use the expectation maximization (EM) algorithm to estimate haplotype frequencies of multiple linked SNPs, and follow this by constructing a contingency table statistic S for LD analysis, based on the estimated haplotype frequencies. An empirical p-value is obtained based on the null distribution of the maximum of S (S*) from a large number (e.g., 1,000 or more) of randomized permutations. The proposed algorithm has been implemented in a computer program in which window searching for functional SNP sites can cover any number of loci without limitation, except that of computer storage. Unlike other programs for a case-control design that always conduct tests at a fix window width, in our program after setting a maximum size of haplotype window width, for a given maximum window width all possible widths of haplotypes are utilized to find the maximum statistic S * for each locus under investigation. The sensitivity of the proposed algorithm has been examined with simulated and real genotyping datasets. Association analyses indicate that our program is powerful enough to detect most, if not all, functional SNPs simulated in the original model or identified in the original report. Moreover, the program is very flexible and can be used in either regional or genome-wide scanning for association analysis with SNP markers.

Algorithms↗
PubMed2005

The effect of SNP marker density on the efficacy of haplotype tagging SNPs--a warning.

We investigate here the efficacy of selecting haplotype tagging SNPs at different marker densities (2kb-10kb). Our results are based on publicly available data on 5324 markers with a median spacing of 1kb from chromosome 20. We find that whatever density of SNPs is used, htSNP analysis indicates in most cases that at least 80% of the variation can be captured using a subset of SNPs. However, as marker density decreases these htSNPs become increasingly unreliable. In this dataset htSNPs were selected to capture at least 80% of the variation at every observed SNP. At an observed SNP density of 2kb, htSNP analysis suggests that the htSNPs capture on average 95% of the observed variation, when in fact they capture 88% of the unobserved variation. At a density of 10kb, htSNP analysis suggests that 93% of the observed variation was captured, when in fact they capture on average only 78%. Our results indicate that htSNP analysis is only reliable when markers are dense--a spacing of even 2kb shows a considerable loss of information. Such findings are important both for individual studies utilising htSNPs to reduce costs, and for projects such as HapMap which try to characterise human genomic variation using htSNPs.

Chromosomes, Human, Pair 20↗