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At least 847 records · Page 47Linked to original sources
PubMed2006

No role for estrogen receptor 1 gene intron 1 Pvu II and exon 4 C325G polymorphisms in migraine susceptibility.

BACKGROUND: We have previously reported an association between the estrogen receptor 1 (ESR1) gene exon 8 G594A polymorphism and migraine susceptibility in two independent Australian cohorts. In this paper we report results of analysis of two further single nucleotide polymorphisms (SNPs) in the ESR1 gene in the same study group, the T/C Pvu II SNP in intron 1 and the C325G SNP in exon 4, as well as results of linkage disequilibrium (LD) analysis on these markers. METHODS: We investigated these variants by case-control association analysis in a cohort of 240 migraineurs and 240 matched controls. The SNPs were genotyped using specific restriction enzyme assays. Results were analysed using contingency table methods incorporating the chi-squared statistic. LD results are presented as D' statistics with associated P values. RESULTS: We found no evidence for association of the Pvu II T/C polymorphism and the C325G polymorphism and migraine susceptibility and no evidence for LD between these two SNPs and the previously implicated exon 8 G594A marker. CONCLUSION: We have found no role for the polymorphisms in intron 1 and exon 4 with migraine susceptibility. To further investigate our previously implicated exon 8 marker, we suggest the need for studies with a high density of polymorphisms be undertaken, with particular focus on markers in LD with the exon 8 marker.

Case-Control Studies↗
PubMed2006

SNP genotyping using alkali cleavage of RNA/DNA chimeras and MALDI time-of-flight mass spectrometry.

Single nucleotide polymorphisms (SNPs) are now widely used for many DNA analysis applications such as linkage disequilibrium mapping, pharmacogenomics and traceability. Many methods for SNP genotyping exist with diverse strategies for allele-distinction. Mass spectrometers are used most commonly in conjunction with primer extension procedures with allele-specific termination. Here we present a novel concept for allele-preparation for SNP genotyping. Primer extension is carried out with an extension primer positioned immediately upstream of the SNP that is to be genotyped, a complete set of four ribonucleotides and a ribonucleotide incorporating DNA polymerase. The allele-extension products are then treated with alkali, which results in the cleavage immediately after the first added ribonucleotide. In addition, to obtain fragments easily detectable by mass spectrometry, we have included a ribonucleotide in the primer usually at the fourth nucleotide from the 3' terminus. The method was tested on four SNPs each with a different combination of nucleotides. The advantage over other mass spectrometry-based SNP genotyping assays is that this one only requires a PCR, a primer extension reaction with a universal extension mix and an inexpensive facile cleavage reaction, which makes it overall very cost effective and easy in handling.

Alleles↗
PubMed2005

A variant in XPNPEP2 is associated with angioedema induced by angiotensin I-converting enzyme inhibitors.

Angiotensin I-converting enzyme inhibitors (ACEi), which are used to treat common cardiovascular diseases, are associated with a potentially life-threatening adverse reaction known as angioedema (AE-ACEi). We have previously documented a significant association between AE-ACEi and low plasma aminopeptidase P (APP) activity. With eight large pedigrees, we hereby demonstrate that this quantitative trait is partially regulated by genetic factors. We tested APP activity using a variance-component QTL analysis of a 10-cM genomewide microsatellite scan enriched with seven markers over two candidate regions. We found significant linkage (LOD = 3.75) to a locus that includes the XPNPEP2 candidate gene encoding membrane-bound APP. Mutation screening of this QTL identified a large coding deletion segregating in one pedigree and an upstream single-nucleotide polymorphism (C-2399A SNP), which segregates in the remaining seven pedigrees. Measured genotype analysis strongly suggests that the linkage signal for APP activity at this locus is accounted for predominantly by the SNP association. In a separate case-control study (20 cases and 60 controls), we found significant association of this SNP to ACEi-induced AE (P=.0364). In conclusion, our findings provide supporting evidence that the C-2399A variant in XPNPEP2 is associated with reduced APP activity and a higher incidence of AE-ACEi.

Aminopeptidases↗
PubMed2003

Association of the multidrug resistance-1 gene single-nucleotide polymorphisms with the tacrolimus dose requirements in renal transplant recipients.

The immunosuppressive drug tacrolimus, whose pharmacokinetic characteristics display large interindividual variations, is a substrate for P-glycoprotein (P-gp), the product of the multidrug resistance-1 (MDR1) gene. Some of the single nucleotide polymorphisms (SNP) of MDR1 reported correlated with the in vivo activity of P-gp. Because P-gp is known to control tacrolimus intestinal absorption, it was postulated that these polymorphisms are associated with tacrolimus pharmacokinetic variations in renal transplant recipients. The objective of this study was to evaluate in a retrospective study of 81 renal transplant recipients the effect on tacrolimus dosages and concentration/dose ratio of four frequent MDR1 SNP possibly associated with P-gp function (T-129C in exon 1b, 1236C>T in exon 12, 2677G>T,A in exon 21, and 3435C>T in exon 26). As in the general population, the SNP in exons 12, 21, and 26 were frequent (16, 17.3, and 22.2% for the variant homozygous genotype, respectively) and exhibited incomplete linkage disequilibrium. One month after tacrolimus introduction, exon 21 SNP correlated significantly with the daily tacrolimus dose (P < or = 0.05) and the concentration/dose ratio (P < or = 0.02). Tacrolimus dose requirements were 40% higher in homozygous than wild-type patients for this SNP. The concentration/dose ratio was 36% lower in the wild-type patients, suggesting that, for a given dose, their tacrolimus blood concentration is lower. Haplotype analysis substantiated these results and suggested that exons 26 and 21 SNP may be associated with tacrolimus dose requirements. Genotype monitoring of the MDR1 gene reliably predicts the optimal dose of tacrolimus in renal transplant recipients and may predict the initial daily dose needed by individual patients to obtain adequate immunosuppression.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Interaction of heme oxygenase-2 with nitric oxide donors. Is the oxygenase an intracellular 'sink' for NO?

Heme oxygenase-2 (HO-2) is the constitutive cognate of the heat-shock protein-32 family of proteins. These proteins catalyze oxidative cleavage of heme to CO and biliverdin, and release Fe. HO-2 is a hemoprotein and binds heme at heme regulatory motifs (HRMs) with a conserved Cys-Pro pair; two copies of HRM are present in HO-2 (Cys264 and Cys281). The HO-2 HRMs are not present in HO-1 and are not involved in HO-2 catalytic activity. Optical CD, and spectral and activity analyses were used to examine reactivity of HO isozymes with NO species produced by NO donors. Purified Escherichia coli-expressed HO preparations, wild-type HO-2, Cys264/Cys281 --> Ala/Ala HO-2-mutant (HO-2-mut) and HO-1 preparations were used. A type II change (red shift) of the Soret band (405 nm --> 413-419 nm) was observed when wild-type HO-2 was treated with sodium nitroprusside (SNP), S-nitroglutathione (GSNO), S-nitroso-N-acetylpenicillamine (SNAP) or 3-morpholinosydnonimine (SIN-1); the NO scavenger, hydroxocobalamin (HCB) prevented the shift. Only SIN-1, which produces peroxynitrite by generating both NO and superoxide anion, decreased the Soret region absorption and the pyridine hemochromogen spectrum of HO-2; superoxide dismutase (SOD) blocked the decrease. Binding of heme to HO-2 protein was required for shift and/or decrease in absorption of the Soret band. NO donors significantly inhibited HO-2 activity, with SNP being the most potent inhibitor (> 40%). Again, trapping NO with HCB blocked HO-2 inactivation. HO-1 and HO-2-mut were not inactivated by NO donors. CD data suggest that the decrease in HO-2 activity was not related to change by NO species of the secondary structure of HO-2. Western blot analysis suggests that NO donors did not cause HO-1 protein loss and Northern blot analysis of HeLa cells treated with SIN-1 and SNP indicates that, unlike HO-1 mRNA, which is remarkably responsive to the treatments, HO-2 mRNA levels were modestly increased ( approximately two to threefold) by NO donors. The data are consistent with the possibility that NO interaction with HO-2-bound heme effects electronic interactions of residues involved in substrate binding and/or oxygen activation. The findings permit the hypothesis that HO-2 and NO are trans-inhibitors, whereby biological activity of NO is attenuated by interaction with HO-2, serving as an intracellular 'sink' for the heme ligand, and NO inhibits HO-2 catalytic activity. As such, the cellular level of both signaling molecules, CO and NO would be moderated.

Animals↗
PubMed2005

Haplotype analysis indicates an association between the DOPA decarboxylase (DDC) gene and nicotine dependence.

DOPA decarboxylase (DDC; also known as L-amino acid decarboxylase; AADC) is involved in the synthesis of dopamine, norepinephrine and serotonin. Because the mesolimbic dopaminergic system is implicated in the reinforcing effects of many drugs, including nicotine, the DDC gene is considered a plausible candidate for involvement in the development of vulnerability to nicotine dependence (ND). Further, this gene is located within the 7p11 region that showed a 'suggestive linkage' to ND in our previous genome-wide scan in the Framingham Heart Study population. In the present study, we tested eight single nucleotide polymorphisms (SNPs) within DDC for association with ND, which was assessed by smoking quantity (SQ), the heaviness of smoking index (HSI) and the Fagerstrom test for ND (FTND) score, in a total of 2037 smokers and non-smokers from 602 nuclear families of African- or European-American (AA or EA, respectively) ancestry. Association analysis for individual SNPs using the PBAT-GEE program indicated that SNP rs921451 was significantly associated with two of the three adjusted ND measures in the EA sample (P=0.01-0.04). Haplotype-based association analysis revealed a protective T-G-T-G haplotype for rs921451-rs3735273-rs1451371-rs2060762 in the AA sample, which was significantly associated with all three adjusted ND measures after correction for multiple testing (min Z=-2.78, P=0.006 for HSI). In contrast, we found a high-risk T-G-T-G haplotype for a different SNP combination in the EA sample, rs921451-rs3735273-rs1451371-rs3757472, which showed a significant association after Bonferroni correction with the SQ and FTND score (max Z=2.73, P=0.005 for FTND). In summary, our findings provide the first evidence for the involvement of DDC in the susceptibility to ND and, further, reveal the racial specificity of its impact.

Adult↗
PubMed2004

The functional SNP in the matrix metalloproteinase-3 promoter modifies susceptibility and lymphatic metastasis in esophageal squamous cell carcinoma but not in gastric cardiac adenocarcinoma.

The matrix metalloproteinases (MMPs), a family of proteolytic enzymes that degrade different components of the extracellular matrix, play important roles in tumor development and invasion. A single adenine insertion/deletion polymorphism (6A/5A) in the MMP3 promoter region causes transcriptional elevation. The aim of this study was to assess the effects of this single nucleotide polymorphism (SNP) on the development and clinical staging of esophageal squamous cell carcinoma (ESCC) and gastric cardiac adenocarcinoma (GCA). The MMP3 SNP was genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis in 417 cancer patients (234 ESCC and 183 GCA) and 350 controls in north China. The overall distribution of the MMP3 SNP in ESCC and GCA patients was not significantly different from that in healthy controls. However, smoking individuals with the 5A/5A or 5A/6A genotype were significantly more common in ESCC patients than in controls (37.5 versus 23.3%, xi(2) = 5.13, P = 0.02). Thus, smokers with at least one 5A allele had a significantly increased risk of ESCC, compared with 6A homozygotes (age and sex adjusted OR = 1.95, 95% CI = 1.08-3.53). The significant difference in the SNP distribution between ESCC patients, GCA patients and controls was not observed when stratified by family history of upper gastrointestinal cancer. In addition, the frequency of the 5A/5A + 5A/6A genotypes in ESCC patients with and without lymphatic metastasis was significantly different (45.8 versus 27.8%, xi(2) = 4.56, P = 0.03). Therefore, patients with at least one 5A allele were significantly more prone to lymphatic metastasis of ESCC. In contrast, no significant difference in the SNP distribution between patients with and without lymphatic metastasis was observed in GCA. The present study suggests that the MMP3 promoter SNP might be associated with a risk of development and lymphatic metastasis in ESCC but not in GCA.

Adenocarcinoma↗
PubMed2006

A case study of the utility of the HapMap database for pharmacogenomic haplotype analysis in the Taiwanese population.

BACKGROUND: Single nucleotide polymorphisms (SNPs) can be used in clinical association studies to determine the contribution of genes to drug efficacy. The goal of this work was to evaluate the feasibility of using SNP information of the Han Chinese in Beijing (CHB) population from the HapMap database for clinical association studies in the Taiwanese (TWN) population. METHODS: We compared the HapMap populations with our TWN study population with regard to allele frequencies for common SNPs in two candidate genes for antidepressant treatment response to determine the applicability of the HapMap CHB data for SNP selection in the TWN population. RESULTS AND CONCLUSION: Our preliminary results suggest that there was no significant difference, in terms of allele and haplotype frequencies, between the CHB population of the HapMap database and the TWN population collected by Vita Genomics Inc. Therefore, it is possible to use the CHB population of the HapMap database for SNP selection in association studies for the TWN population. Using haplotype analysis, we generated a panel of SNPs that may be strongly relevant to antidepressant response in this population.

Asian People↗
PubMed2026

Fine-Scale Landscape Genomics Show Asymmetric Patterns of Gene Flow for the Invasive Mosquito Aedes albopictus.

Mosquito-borne viruses like dengue, Zika, and chikungunya pose increasing health risks in the United States due to the expanding range of Aedes albopictus, a highly invasive mosquito species that now has a global distribution. Aedes albopictus thrive in artificial containers associated with anthropogenic land use, allowing populations to reach high numbers in urban and suburban environments. While the global spread of Ae. albopictus has been well characterized, the effects of heterogeneous urban landscapes on dispersal and gene flow at fine spatial scales remain unclear. This study analyzed the genetic connectivity of Aedes albopictus populations collected in Wake County, North Carolina in 2018. We used single nucleotide polymorphisms (SNP) data from double-digest restriction-enzyme associated DNA sequencing (ddRADseq) and examined genetic connectivity through principal component analysis (PCA) and genetic network analysis. We then evaluated migration and source-sink dynamics using a Bayesian approach for SNP data (BA3-SNP). We found little evidence of genetic clustering or isolated populations of Ae. albopictus in Wake County, suggesting high gene flow between sites. Migration analysis demonstrated asymmetric gene flow from rural to urban regions within Wake County, with greater gene flow occurring between and within urban regions. These findings suggest that the pattern of gene flow of Ae. albopictus populations within local metropolitan areas may involve urban city centers serving as genetic sinks and surrounding suburban and rural regions serving as sources. This study highlights how heterogeneous landscapes shape mosquito population connectivity and migration at fine spatial scales, which is critical for informing vector control and public health intervention strategies.

Aedes albopictus↗
PubMed2001

Computation and visualization of regional-scale forest disturbance and associated dissolved nitrogen export from Shenandoah National Park, Virginia.

Long-term watershed research conducted in Shenandoah National Park (SNP) in Virginia and elsewhere in the eastern U.S. indicates that annual export of dissolved nitrogen (N) from gaged forested watersheds to surface waters increases dramatically in response to vegetation disturbances. Dissolved N leakage is a common, well-documented response of small forested watersheds to logging in the larger region, while recent defoliation outbreaks of the gypsy moth ( Lymantria dispar) larva in the deciduous forests of SNP have been shown to generate similar biogeochemical responses. A recent modeling analysis further suggests that a parsimonious, empirical, unit N export response function (UNERF) model can explain large percentages of the temporal variation in annual N export from a group of small gaged forested watersheds in the years following disturbance. The empirical UNERF modeling approach is completely analogous to the unit hydrograph technique for describing storm runoff, with the model representing annual N export as a linear deterministic process both in space and in time. The purposes of this analysis are to (1) test the applicability of the UNERF model using quarterly streamwater nitrate data from a group of ungaged watersheds in SNP; (2) demonstrate a park-wide application of a regional UNERF model that references the geographic distributions of bedrock geology and the timing and extent of gypsy moth defoliation over the entire SNP area; and (3) visualize the temporal and spatial patterns in vegetation disturbance and annual dissolved N export through the use of computer animation software. During water year 1992, the year of peak defoliation, our modeling study suggests that park-wide export had transiently increased by 1700% from a baseline rate of about 0.1 kg/ha/year. SNP forests appear to be characteristic of other N-limited second-growth forests in the eastern U.S. that leak little N under undisturbed conditions, despite receiving relatively large inputs of N from atmospheric deposition sources. Vegetation disturbances can apparently cause major changes in N input-output balances with potentially important ramifications for low-order forest streams and downstream receiving waters.

Animals↗
PubMed2003

Molecular detection of the G(-248)A BAX promoter nucleotide change in B cell chronic lymphocytic leukaemia.

BACKGROUND: A novel single nucleotide polymorphism (SNP), G(-248)A, in the 5' untranslated region of the BAX promoter and its association with reduced protein expression, progression beyond Rai stage 0, and treatment resistance in chronic lymphocytic leukaemia (CLL) has been reported previously. AIM: To develop a restriction enzyme analysis (REA) based method for routine detection of BAX promoter SNP in a clinical laboratory. METHODS: The BAX promoter was analysed in duplicate by REA and sequencing in 90 samples (from 45 patients with CLL, 43 controls, and two cell lines). The promoter region was amplified, digested with restriction endonucleases (Aci I and Tau I), and separated by gel electrophoresis. RESULTS: After digestion, the normal GG genotype samples produced three distinct bands. The homozygous AA replacement abolished the cleavage site, resulting in a single band. Although the heterozygous samples produced three bands, the two smaller visible bands were reduced in intensity (> 50%). The test characteristics of Aci I REA were better than those of Tau I REA, in terms of sensitivity (100% v 77.8%), specificity (98.6% v 92.3%), positive predictive value (95.03% v 87.4%), and negative predictive value (100% v 85.83%). CONCLUSIONS: REA using Aci I is a highly sensitive and specific method for detecting the BAX G(-248)A SNP in CLL.

5' Untranslated Regions↗
PubMed2004

Association of protein tyrosine phosphatase 1B gene polymorphisms with type 2 diabetes.

The PTPN1 gene codes for protein tyrosine phosphatase 1B (PTP1B) (EC 3.1.3.48), which negatively regulates insulin signaling by dephosphorylating the phosphotyrosine residues of the insulin receptor kinase activation segment. PTPN1 is located in 20q13, a genomic region linked to type 2 diabetes in multiple genetic studies. Surveys of the gene have previously identified only a few uncommon coding single nucleotide polymorphisms (SNPs). We have carried out a detailed association analysis of 23 noncoding SNPs spanning the 161-kb genomic region, which includes the PTPN1 gene. These SNPs have been assessed for association with type 2 diabetes in two independently ascertained collections of Caucasian subjects with type 2 diabetes and two control groups. Association is observed between multiple SNPs and type 2 diabetes. The most consistent evidence for association occurred with SNPs spanning the 3' end of intron 1 of PTPN1 through intron 8 (P values ranging from 0.043 to 0.004 in one case-control set and 0.038-0.002 in a second case-control set). Analysis of the combined case-control data increased the evidence of SNP association with type 2 diabetes (P = 0.005-0.0016). All of the associated SNPs lie in a single 100-kb haplotype block that encompasses the PTPN1 gene. Analysis of haplotypes indicates a significant difference between haplotype frequencies in type 2 diabetes case and control subjects (P = 0.0035-0.0056), with one common haplotype (36%) contributing strongly to the evidence for association with type 2 diabetes. Odds ratios calculated from single SNP or haplotype data are in the proximity of 1.3. Haplotype-based calculation of population-attributable risk (PAR) results in an estimated PAR of 17-20% based on different models and assumptions. These results suggest that PTPN1 is a significant contributor to type 2 diabetes susceptibility in the Caucasian population. This risk is likely due to noncoding polymorphisms.

Diabetes Mellitus, Type 2↗
PubMed2004

Design and synthesis of a photocleavable biotinylated nucleotide for DNA analysis by mass spectrometry.

We report here the design, synthesis and evaluation of a novel photocleavable (PC) biotinylated nucleotide analog, dUTP-PC-Biotin, for DNA polymerase extension reaction to isolate DNA products for mass spectrometry (MS) analysis. This nucleotide analog has a biotin moiety attached to the 5-position of 2'-deoxyribouridine 5'-triphosphate via a photocleavable 2-nitrobenzyl linker. We have demonstrated that dUTP-PC-Biotin can be faithfully incorporated by the DNA polymerase Thermo Sequenase into the growing DNA strand in a DNA polymerase extension reaction and that its incorporation does not hinder the addition of the subsequent nucleotide. Therefore, the DNA extension fragments generated by using the dUTP-PC-Biotin can be efficiently isolated by a streptavidin-coated surface and recovered by near-UV light irradiation at room temperature in mild condition for further analysis without using any chemicals or heat. Single and multiple primer extension reactions were performed using the dUTP-PC-Biotin to generate DNA products for MALDI-TOF MS analysis. Such nucleotide analogs that carry a biotin and a photocleavable linker will allow the isolation and purification of DNA products under mild conditions for MS-based genetic analysis by DNA sequencing or multiplex single nucleotide polymorphism (SNP) detection. Furthermore, these nucleotide analogs should also be useful in isolating DNA-protein complexes under non-denaturing conditions.

Biotin↗
PubMed2007

Role of the STK15 Phe31Ile polymorphism in renal cell carcinoma.

The search of inherited cancer susceptibility factors is an important subject in cancer epidemiology. Analyses of single nucleotide polymorphisms (SNP) in various genes revealed a correlation between the presence of specific allelic variants and cancer predisposition in diverse malignancies. STK15 is an important protein in control of the integrity of the mitotic spindle apparatus and genomic stability. We analysed the distribution of the functionally important T91A SNP in the STK15 gene in a cohort of renal cell carcinoma (RCC) patients and compared it to the distribution in a control group without malignancies. DNA from formalin-fixed, paraffin-embedded healthy renal tissue (RCC patients) or peripheral blood samples (control group) was isolated according to standard protocols. Allelic variant of STK15 nucleotide 91 was determined using restriction fragment length polymorphism (RFLP) analysis. Overall, 156 RCC patients and 158 patients without any malignancy were analysed. The distribution of the STK15 SNP in RCC patients (T/T, 58.97%; A/T, 36.53%; A/A, 4.49%) did not significantly differ from that of the control group (T/T, 51.27%; A/T, 41.14%; A/A, 7.59%). There was also no correlation between genotype and tumour grade or stage or other histopathological characteristics of the tumours. This first analysis of the STK15 T91A SNP in RCC patients revealed no correlation between a certain allelic variant and an increased risk for RCC.

Aurora Kinase A↗
PubMed2003

SNP-based codominant markers for a recessive gene conferring resistance to corky root rot (Rhizomonas suberifaciens) in lettuce (Lactuca sativa).

The analysis of F2 progeny and derived F3 families of Lactuca sativa segregating for resistance to corky root rot caused by Rhizomonas suberifaciens permitted the identification of restriction fragment length polymorphism (RFLP) and single nucleotide polymorphism (SNP) markers linked to the recessive resistance gene cor. PCR-based markers were identified by bulked segregant analysis (BSA). Allele-specific primers were generally designed with the 3 terminal base coinciding with an SNP, matching one of the alleles and mismatching the other, and with an additional subterminal 3 base mismatching both alleles. Codominant, robust, and inexpensive molecular markers were obtained that used standardized PCR conditions. Some of the markers could be analyzed in multiple Lactuca mapping populations that did not segregate for disease resistance allowing the cor locus to be located on several maps. The consistent low density of markers around cor in these maps suggests that cor may be in an area with an elevated rate of recombination. Evaluation of these markers in a large sample of cultivars and landraces identified pairs of flanking polymorphic markers that can be used for marker-assisted selection of corky root resistance.

Chromosome Mapping↗
PubMed2002

Characteristics of genetic markers and maps for cost-effective genome screens using diallelic markers.

New technologies for genotyping diallelic markers (SNPs) were recently developed that may be lower in cost, and more easily automated than microsatellite markers (STRPs). The reduction in genotyping costs resulting from such automation may significantly impact the overall cost of studies of complex traits, which generally require large sample sizes. Use of multiple SNPs in linkage analysis can recapture the linkage information otherwise lost with such markers. Here we derive a measure of the multilocus polymorphic information content (MPIC) in the context of linkage analysis for a cluster of SNPs, and we explore the characteristics of uniform vs. clustered SNP maps, relative to STRP maps. Issues addressed in comparing the map structures include the information content for clustered or single markers, and map accuracy. To be cost-effective, SNPs should have a common allele frequency between 0.5-0.75. No more than five loci per cluster are needed. Some linkage disequilibrium between loci in a cluster is tolerable. In the ideal case, a uniformly spaced SNP map is more cost-effective than one composed of clustered loci. However, the genotyping cost per marker for diallelic markers can be at most 60% of the genotyping cost per marker for STRPs. The consequences of using clustered vs. uniform SNP maps are considered in the context of map inaccuracy and use of multipoint vs. pairwise linkage analysis. Overall, when marker information, map accuracy, and flexibility of analysis are jointly considered, an optimal solution may be use of maps with 2-3 SNPs per cluster.

Alleles↗
PubMed2001

SNPing away at candidate genes.

We develop regression methodology to identify subsets of single nucleotide polymorphisms (SNPs) within candidate genes related to quantitative traits and apply our methods to the simulated Genetic Analysis Workshop (GAW) 12 data set. In the data set we find 694 SNP loci with minimum allele frequencies of at least 0.01. We assume an additive casual model between these SNPs and all five quantitative traits. After initial screening using one-way analysis of variance, we employ a computationally efficient, simulated annealing algorithm to select among all possible subsets of SNP loci, using a generalization of Mallows' Cp as our optimality criterion. The simple transition kernel we develop evaluates new subsets in O(1), by requiring just three arithmetic operations to calculate the proposed RSS based on the Gauss-Jordan pivot. We identify an SNP loci located at 6-5782 related to traits 2 and 3 and several sites on gene 2 related to trait 5 using a subsample of 1,000 individuals and the full data set (n = 8,250) for comparison.

Alleles↗
PubMed2004

Segmental phylogenetic relationships of inbred mouse strains revealed by fine-scale analysis of sequence variation across 4.6 mb of mouse genome.

High-density SNP screening of panels of inbred mouse strains has been proposed as a method to accelerate the identification of genes associated with complex biomedical phenotypes. To evaluate the potential of these studies, a more detailed understanding of the fine structure of sequence variation across inbred mouse strains is needed. Here, we use high-density oligonucleotide arrays to discover an extremely dense set of SNPs in 13 classical and two wild-derived inbred strains in five genomic intervals totaling 4.6 Mb of DNA sequence, and then analyze the segmental haplotype structure defined by these high-density SNPs. This analysis reveals segments ranging from 12 to 608 kb in length within which the inbred strains have a simple and distinct phylogenetic relationship with typically two or three clades accounting for the 13 classical strains examined. The phylogenetic relationships among strains change abruptly and unpredictably from segment to segment, and are distinct in each of the five genomic regions examined. The data suggest that at least 12 strains would need to be resequenced for exhaustive SNP discovery in every region of the mouse genome, that approximately 97% of the variation among inbred strains is ancestral (between clades) and approximately 3% private (within clades), and provides critical insights into the proposed use of panels of inbred strains to identify genes underlying quantitative trait loci.

Animals↗