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PubMed2026

Unveiling the power of TIIC: A prognostic tool for esophageal adenocarcinoma.

BACKGROUND: Esophageal adenocarcinoma (EAC) remains a lethal malignancy with limited prognostic tools for guiding immunotherapy. Tumor-infiltrating immune cells (TIICs) play a critical role in EAC prognosis and treatment response. METHODS: We integrated single-cell RNA sequencing and bulk transcriptome data from TCGA and GEO databases. TIIC-specific RNAs were identified via tissue specificity index calculation combined with machine learning feature selection. Twenty machine learning algorithms were benchmarked to construct an optimal TIIC signature score (TIIC-Score) based on the comprehensive C-index. Immunotherapy response, genomic mutation, and copy number variation were analyzed. Summary-data-based Mendelian randomization (SMR) and two-sample Mendelian randomization (MR) were performed to explore genetic associations. Core prognostic TIIC-related genes were functionally validated in esophageal cancer cell lines through loss-of-function assays. RESULTS: The TIIC-Score demonstrated robust prognostic value for 1-, 2-, and 3-year overall survival across multiple cohorts, outperforming 22 published models. High TIIC-Score was associated with poor survival and increased chromosomal instability. Mutation profiling revealed high frequencies of TP53 (78.2%), TTN (48.7%), and SYNE1 (30.8%). MR analysis identified a significant association between gastro-oesophageal reflux and EAC risk at SNP rs8130507. Functionally, CCNI was upregulated in esophageal cancer cells, and its knockdown suppressed malignant phenotypes while promoting apoptosis, supporting its pro-tumorigenic role. CONCLUSION: The TIIC-Score provides a novel prognostic framework for EAC that effectively stratifies patient risk and may help identify individuals most likely to benefit from immunotherapy.

Esophageal adenocarcinoma↗

PubMed2001

NO-cGMP pathway increases the hyperpolarisation-activated current, I(f), and heart rate during adrenergic stimulation.

OBJECTIVES: The role of the nitric oxide (NO)-cGMP pathway in the autonomic modulation of cardiac pacemaking is controversial and may involve an interplay between the L-type calcium current, I(CaL), and the hyperpolarisation activated current, I(f). We tested the hypothesis that following adrenergic stimulation, the NO-cGMP pathway stimulates phosphodiesterase 2 (PDE2) to reduce cAMP dependent stimulation of I(f) and heart rate (HR). METHODS: In the presence of norepinephrine (NE, 1 microM), the effects of the NO donor sodium nitroprusside (SNP) were evaluated in sinoatrial node (SAN)/atria preparations and isolated SAN cells from adult guinea pigs. RESULTS: Contrary to our hypothesis, SNP (10 and 100 microM, n=5) or the membrane permeable cGMP analogue, 8Br-cGMP (0.5 mM, n=6) transiently increased HR by 5+/-1, 12+/-1 and 12+/-2 beats/min, respectively. The guanylyl cyclase inhibitor 1H-(1,2,4)-oxadiazolo-(4,3-a)-quinoxalin-1-one (ODQ, 10 microM, n=5) abolished the increase in HR to SNP (100 microM) as did the I(f) blockers caesium chloride (2 mM, n=7) and 4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino)-pyrimidinium chloride (ZD7288, 1 microM, n=7). Addition of SNP (10 microM) also transiently increased I(f) in SAN cells (n=5). After inhibition of PDE2 with erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA, 10 microM, n=5), the increase in HR to SNP in the presence of NE was significantly augmented and maintained. RT-PCR analysis confirmed the presence of PDE2 in addition to cGMP inhibited PDE3 mRNA in central SAN tissue. CONCLUSIONS: These results suggest that during adrenergic stimulation, activation of the NO-cGMP pathway does not decrease HR, but has a transient stimulatory effect that is I(f) dependent, and is limited in magnitude and duration by stimulation of PDE2.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1999

Up-regulation by human recombinant transforming growth factor beta-1 of collagen production in cultured dermal fibroblasts is mediated by the inhibition of nitric oxide signaling.

BACKGROUND: Hypertrophic scarring remains the most disabling sequela for burn survivors. Little is known about its pathogenesis. Collagen accumulation, however, has been consistently observed in burn hypertrophic scars (HS). STUDY DESIGN: We have studied collagen production in the dermal fibroblasts derived from HS, which has developed for 9 months to 2 years. Reconstructive surgery was performed to remove HS from which the fibroblasts were cultured. Similarly, the normal cells were grown from the patient's donor site (DS), which provided autografting to the HS site. Collagen production in HS and DS fibroblasts was compared and analyzed in minimal essential amino acid medium containing 5% fetal bovine serum with inclusion of L-ascorbic acid (100 microg/mL) and beta-aminopropoinitrile (100 microg/mL) by monitoring a 20-h [3H]proline incorporation into bacterial collagenase III-digestible protein in the conditioned media. RESULTS: We failed to detect any significant difference in collagen production in vitro between HS and DS. Irrespective of the fibroblasts from HS or DS, collagen production was substantially stimulated by human recombinant transforming growth factor beta-1 (TGF-beta1) (20 ng/mL) by approximately 250% after a 3-day pretreatment. In contrast, sodium nitroprusside (SNP) at 100 microM exhibited significant suppression (68%), which was rescued by hemoglobin (10 microM). TGF-beta1 significantly decreased nitric oxide (NO) production by 55%. In contrast, NO level drastically increased by 350% following SNP treatment. Epidermal growth factor showed no effect on either collagen production or NO level. The linear regression analysis shows a significant inverse correlation (r = 0.72; p < 0.05) of NO level with collagen production, suggesting the involvement of NO signaling in the modulation of collagen production. Consistent with the notion, we further showed that N-nitro-L-arginine methyl ester (100 microM) caused a synergistic stimulation and an arrested inhibition of collagen production in the presence of TGFbeta-1 and SNP, respectively. 8-BrcGMP (300 microM) mimicked the NO inhibitory action, while methylene blue (50 microM) restored the collagen production which was inhibited by SNP. Moreover, 8-BrcGMP offset the stimulation of collagen production. CONCLUSIONS: The dermal fibroblasts derived from HS were not different from normals with respect to collagen production and their responses to regulations. The inhibition of collagen production was achieved by a cGMP-dependent NO action. TGFbeta-1 inhibited NO/cGMP signaling to ensure its stimulatory effect on collagen production in the dermal fibroblasts.

Burns↗

PubMed2005

Concordance of multiple analytical approaches demonstrates a complex relationship between DNA repair gene SNPs, smoking and bladder cancer susceptibility.

Study results of single nucleotide polymorphisms (SNPs) and cancer susceptibility are often conflicting, possibly because of the analytic challenges of testing for multiple genetic and environmental risk factors using traditional analytic tools. We investigated the relationship between DNA repair gene SNPs, smoking, and bladder cancer susceptibility in 355 cases and 559 controls enrolled in a population-based study of bladder cancer in the US. Our multifaceted analytical approach included logistic regression, multifactor dimensionality reduction, and hierarchical interaction graphs for the analysis of gene-gene and gene-environment interactions followed by linkage disequilibrium and haplotype analysis. Overall, we did not find an association between any single DNA repair gene SNP and bladder cancer risk. We did find a marginally significant elevated risk of the XPD codon 751 homozygote variant among never smokers [adjusted odds ratio (OR) 2.5, 95% confidence interval (CI) 1.0-6.2]. In addition, the XRCC1 194 variant allele was associated with a reduced bladder cancer risk among heavy smokers [adjusted OR 0.4, 95% CI 0.2-0.9)]. The best predictors of bladder cancer included the XPD codon 751 and 312 SNPs along with smoking. Interpretation of this multifactor model revealed that the relationship between the XPD SNPs and bladder cancer is mostly non-additive while the effect of smoking is mostly additive. Since the two XPD SNPs are in significant linkage disequilibrium (D' = 0.52, P = 0.0001), we estimated XPD haplotypes. Individuals with variant XPD haplotypes were more susceptible to bladder cancer [e.g. adjusted OR 2.5, 95% CI 1.7-3.6] and the effect was magnified when smoking was considered. These results support the hypothesis that common polymorphisms in DNA repair genes modify bladder cancer risk and emphasize the need for a multifaceted statistical approach to identify gene-gene and gene-environment interactions.

Adult↗

PubMed2006

MERTK polymorphisms associated with risk of haematological disorders among Korean SLE patients.

OBJECTIVE: The MER receptor tyrosine kinase (MERTK) gene is critical for the efficient clearance of apoptotic cells and has implications for inflammation and autoimmune diseases such as systemic lupus erythematosus (SLE). We investigated the genetic polymorphisms in MERTK to evaluate it as a potential candidate gene for a host genetic study of SLE and clinical manifestations in patients with SLE. METHODS: By resequencing the coding and flanking regions of the MERTK gene in 24 unrelated Koreans, 37 polymorphisms were identified. Based on gene position, minor allele frequency and inter-single-nucleotide polymorphism (SNP) linkage disequilibrium, six of these polymorphisms were selected for subsequent genotyping and association analysis with the risk of SLE and haematological disorders in 350 Korean SLE patients and 330 controls. RESULTS: Although no significant associations with the risk of SLE were found, logistic regression analyses revealed that variants +465C > G (P = 0.05) and +130215insdelT (P = 0.0005) were significantly associated with decreased risk of leucopenia in SLE patients. Further, +465C > G, +95616G > A, +123157A > G and the haplotype ht1 also showed significant associations (P = 0.006-0.05) with a decreased risk of lymphopenia in SLE patients. CONCLUSION: Our findings suggest that polymorphisms in MERTK might be one of the genetic risk factors for presenting leucopenia and lymphopenia in SLE patients.

Adolescent↗

PubMed2006

Association study of four dopamine D1 receptor gene polymorphisms and clozapine treatment response.

Dopamine D1 receptors (D1) in the prefrontal cortex have been implicated in the modulation of cognitive processes as well as both positive and negative symptoms of schizophrenia. Therefore pharmacologic agents with potent D1 effects such as clozapine may influence the symptoms of schizophrenia (SCZ). Genetic variation in the D1 receptor gene (DRD1) may help to explain some of the variability in patient response to antipsychotics (APs). This study investigates the effect of four single nucleotide polymorphisms (SNPs) in DRD1 on clozapine response in two distinct SCZ populations (Caucasian and African American) refractory or intolerant to conventional APs. This study included 183 Caucasian and 49 African American schizophrenics diagnosed using the Diagnostic and Statistical Manual of Mental Disorders (revised third or fourth edition). Genotyping was determined by 5'-exonuclease fluorescence assays. Within each population genotype, allele, allele +/- and haplotype frequencies were compared against dichotomous and quantitative measures of treatment response. Linkage disequilibrium analysis was also performed. In the Caucasian sample, no associations were observed for individual SNP tests. However, a rare three-marker haplotype predicted poor response. In the African American sample, the rs265976 variant and another three-marker haplotype were associated with cLozapine response. Although we did not find an association between the rs4532 SNP (-48 A/G, recognized by a DdeI restriction cut site) and cLozapine response as reported by Potkin et al. (2003), a trend in the same direction was observed as well. Our findings suggest that the rs4532 SNP may have a small effect if any. Further studies in larger, independent samples are required to validate these findings.

Adult↗

PubMed2002

A novel rapid single nucleotide polymorphism (SNP)-based method for assessment of hematopoietic chimerism after allogeneic stem cell transplantation.

A major end point of nonmyeloablative hematopoietic stem cell transplantation is the attainment of either mixed chimerism or full donor hematopoiesis. Because the majority of human genetic disparity is generated by single nucleotide polymorphisms (SNPs), direct measurement of SNPs should provide a robust tool for the detection and quantitation of chimerism. Using pyrosequencing, a rapid quantitative sequencing technology, we developed a SNP-based assay for hematopoietic chimerism. Based on 14 SNPs with high allele frequencies, we were able to identify at least 1 informative SNP locus in 55 patients with HLA-identical donors. The median number of informative SNPs in related pairs was 5 and in unrelated pairs was 8 (P <.0001). Assessment of hematopoietic chimerism in posttransplantation DNA was shown to be quantitative, accurate, and highly reproducible. The presence of 5% donor cells was reliably detected in replicate assays. Compared with current measures of engraftment based on identification of short tandem repeats (STRs), variable number of tandem repeats (VNTRs), or microsatellite polymorphisms, this SNP-based method provides a more rapid and quantitative assessment of chimerism. A large panel of SNPs enhances the ability to identify an informative marker in almost all patient/donor pairs and also facilitates the simultaneous use of multiple markers to improve the statistical validity of chimerism measurements. The inclusion of SNPs that encode minor histocompatibility antigens or other genetic polymorphisms that may influence graft-versus-host disease or other transplantation outcomes can provide additional clinically relevant data. SNP-based assessment of chimerism is a promising technique that will assist in the analysis of outcomes following transplantation.

Case-Control Studies↗

PubMed2007

A sequence variation scan of the coagulation factor VIII (FVIII) structural gene and associations with plasma FVIII activity levels.

Plasma factor VIII coagulant activity (FVIII:C) level is a highly heritable quantitative trait that is strongly correlated with thrombosis risk. Polymorphisms within only 1 gene, the ABO blood-group locus, have been unequivocally demonstrated to contribute to the broad population variability observed for this trait. Because less than 2.5% of the structural FVIII gene (F8) has been examined previously, we resequenced all known functional regions in 222 potentially distinct alleles from 137 unrelated nonhemophilic individuals representing 7 racial groups. Eighteen of the 47 variants identified, including 17 single-nucleotide polymorphisms (SNPs), were previously unknown. As the degree of linkage disequilibrium across F8 was weak overall, we used measured-genotype association analysis to evaluate the influence of each polymorphism on the FVIII:C levels in 398 subjects from 21 pedigrees known as the Genetic Analysis of Idiopathic Thrombophilia project (GAIT). Our results suggested that 92714C>G, a nonsynonymous SNP encoding the B-domain substitution D1241E, was significantly associated with FVIII:C level. After accounting for important covariates, including age and ABO genotype, the association persisted with each C-allele additively increasing the FVIII:C level by 14.3 IU dL(-1) (P = .016). Nevertheless, because the alleles of 56010G>A, a SNP within the 3' splice junction of intron 7, are strongly associated with 92714C>G in GAIT, additional studies are required to determine whether D1241E is itself a functional variant.

ABO Blood-Group System↗

PubMed2005

A comparison between microsatellite and single-nucleotide polymorphism markers with respect to two measures of information content.

Using the Genetic Analysis Workshop 14 (GAW14) simulated dataset, we compare microsatellite and single-nucleotide polymorphism (SNP) markers in terms of two measures of information content, the traditional entropy-based information content measure, and a new "relative information" measure. Both attempt to measure the amount of information contained in the markers about the identity-by-descent (IBD) sharing among relatives. The performance of the two information measures are compared based on their variability and ability to predict change in the LOD score (Delta LOD) as map density increases for SNP markers. Although in a linked region, LOD scores are correlated with measures of information, we observe that none of the measures predict the LOD score itself very well. In an unlinked region, the LOD score is not related to either measures of information. The information content of microsatellite markers with 7.5-cM spacing is slightly higher than that of SNP markers with 3-cM spacing. At these map densities, microsatellites are found to be uniformly more informative than SNPs irrespective of their level of heterozygosity. For SNPs, we found that as the level of heterozygosity increases, the information content increases. As reported in all other previous studies, we also found that high-density SNPs have higher information content compared to low-density microsatellites. Performance of both the two information measures considered here are similar, but the relative information measure predicts Delta LOD as marker density increases better than the traditional entropy-based information measure.

Genetic Markers↗

PubMed2003

GAG BioScience GmbH.

Completion of the human genome project led to an explosion in available genomic information. Single nucleotide polymorphisms (SNPs) have emerged as a versatile and powerful tool for genotyping almost all variant species. The unique technological platform developed by GAG BioScience is exclusively based on SNP detection and allows genotyping of up to 60,000 samples per day. An analysis robot, a mass spectrometer and a database form a practically self-controlled analysis and documentation system that achieves high-throughput rates of samples with absolute precision. By using a Laboratory Information and Management System, up to 150 million genotypes can be simultaneously retrieved and stored. In cooperation with a partner, GAG BioScience develops new and powerful tools for further data analysis.

Animals↗

PubMed2026

Genomic and ecological systems-thinking framework for pathogenic Leptospira in Puerto Rico.

INTRODUCTION: Leptospirosis is a complex zoonotic disease requiring high-resolution surveillance. A systems-thinking framework was used to connect genomic and ecological data and map the geographic and host-based structuring of co-circulating pathogenic Leptospira lineages in Puerto Rico. METHODS: Forty-four core genomes of L. interrogans, L. borgpetersenii, and L. kirschneri from human, domestic, and wildlife hosts were analyzed. Spatiotemporal and landscape metadata were integrated using root-to-tip regression, isolation-by-distance profiling and calibrated single-nucleotide polymorphism (SNP) thresholds (≤1, ≤5, and ≤10 SNPs) to define transmission clusters. RESULTS: Leptospira species exhibited distinct ecological pathways partitioned by geography, explaining 56% of genomic variance for L. interrogans and 91% for L. borgpetersenii (PERMANOVA). L. interrogans displayed high landscape connectivity across multiple hosts, forming localized networks (≤1 to ≤10 SNPs) that capture active spillovers (human-to-rat linkages at ≤1 SNP) and resolved into rodent host-specific lineages (R2 = 0.34). Conversely, L. borgpetersenii showed spatial and temporal genomic homogeneity and a lack of host-associated structure within an unpartitioned transmission pool dominated by Mus musculus. As a result, fixed genomic thresholds yielded disparate outcomes: L. interrogans resolved into 4 to 5 discrete, expanding clusters, whereas L. borgpetersenii grouped into a single uniform population at the ≤10-SNP threshold. CONCLUSION: Co-circulating pathogenic leptospires occupy distinct ecological niches shaped by varying host restriction and environmental persistence. Fixed genomic thresholds lack universal applicability; effective genomic epidemiological surveillance must employ species-specific threshold calibration to accurately map transmission pathways.

Puerto Rico↗

PubMed2004

Fine mapping, gene content, comparative sequencing, and expression analyses support Ctla4 and Nramp1 as candidates for Idd5.1 and Idd5.2 in the nonobese diabetic mouse.

At least two loci that determine susceptibility to type 1 diabetes in the NOD mouse have been mapped to chromosome 1, Idd5.1 (insulin-dependent diabetes 5.1) and Idd5.2. In this study, using a series of novel NOD.B10 congenic strains, Idd5.1 has been defined to a 2.1-Mb region containing only four genes, Ctla4, Icos, Als2cr19, and Nrp2 (neuropilin-2), thereby excluding a major candidate gene, Cd28. Genomic sequence comparison of the two functional candidate genes, Ctla4 and Icos, from the B6 (resistant at Idd5.1) and the NOD (susceptible at Idd5.1) strains revealed 62 single nucleotide polymorphisms (SNPs), only two of which were in coding regions. One of these coding SNPs, base 77 of Ctla4 exon 2, is a synonymous SNP and has been correlated previously with type 1 diabetes susceptibility and differential expression of a CTLA-4 isoform. Additional expression studies in this work support the hypothesis that this SNP in exon 2 is the genetic variation causing the biological effects of Idd5.1. Analysis of additional congenic strains has also localized Idd5.2 to a small region (1.52 Mb) of chromosome 1, but in contrast to the Idd5.1 interval, Idd5.2 contains at least 45 genes. Notably, the Idd5.2 region still includes the functionally polymorphic Nramp1 gene. Future experiments to test the identity of Idd5.1 and Idd5.2 as Ctla4 and Nramp1, respectively, can now be justified using approaches to specifically alter or mimic the candidate causative SNPs.

Amino Acid Sequence↗

PubMed2003

A single round PCR method for genotyping human surfactant protein (SP)-A1, SP-A2 and SP-D gene alleles.

The genes coding for the human surfactant proteins (SP)-A and SP-D are located on chromosome 10q22-q23.1. SP-D is the product of a single gene whereas SP-A is the product of two highly homologous genes SP-A1 and SP-A2. Several single nucleotide polymorphisms (SNP) are present in the SP-A1, SP-A2 and SP-D genes. Because of this high degree of sequence homology between the SP-A1 and SP-A2 genes, current genetic analysis studies employ a nested PCR/radioactive hybridization or restriction fragment length polymorphism approach to initially isolate the genes and subsequently to detect the SNP in these isolates. In this manuscript, we report the primers and conditions of a sequence specific primer-PCR methodology that enables the identification of SP-A1, SP-A2 and SP-D gene allelic variants directly on genomic DNA material.

Alleles↗

PubMed1996

Effect of nitroglycerin on spinal cord ischemia after thoracic aortic cross-clamping.

BACKGROUND: Thoracic aortic cross-clamping with the use of sodium nitroprusside (SNP) has been shown to cause a decrease in spinal cord perfusion pressure and an increased incidence of paraplegia. Nitroglycerin is frequently used in this setting. This study investigated the effects of nitroglycerin and SNP on spinal cord ischemia. METHODS: Three-groups of 8 mongrel dogs underwent thoracic aortic cross-clamping for 45 minutes. Proximal pressure was maintained between 95 and 100 mm Hg with SNP, nitroglycerin, or phlebotomy. All animals were neurologically evaluated 24 hours later by a blinded observer, and the findings were confirmed by histopathologic study. Statistical analysis (p value of less than 0.05) of measured hemodynamic data was by analysis of variance and of Tarlov scores, the Mann-Whitney U test. RESULTS: Distal aortic pressures (p < 0.001), Tarlov scores, and spinal cord perfusion pressures (p < 0.01 and p < 0.05 for SNP group and nitroglycerin group, respectively) were significantly higher in the phlebotomy group compared with the SNP and NTG groups. Cerebrospinal fluid pressures were significantly lower in the phlebotomy group compared with the SNP group (p < 0.001). CONCLUSIONS: The use of either NTG or SNP was associated with a high incidence of paraplegia. Nitroglycerin appears to be no safer than SNP when used during thoracic aortic cross-clamping.

Animals↗

PubMed1993

Induction of nitric oxide synthase regulates atrial natriuretic peptide receptors in vascular smooth muscle cells.

In a previous study, we reported that cyclic GMP (cGMP) selectively down-regulates the atrial natriuretic peptide clearance receptor (ANPC receptor) in the vascular endothelial cells. The aim of the present study is to determine whether nitric oxide (NO) regulates ANP receptor by accumulating intracellular cGMP in cultured rabbit aortic smooth muscle cells. Treatment with interleukin-1 beta (IL-1), a cytokine known to induce NO synthase, dose-dependently increased the basal level of intracellular cGMP with a concomitant increase of nitrite in the conditioned media. These effects of IL-1 were attenuated in the presence of N omega-nitro-L-arginine. IL-1 (40 pM) significantly (P < 0.01) decreased [125I]atriopeptin III binding to the cells, an effect that was inhibited by N omega-nitro-L-arginine. Treatment with sodium nitroprusside (SNP) which releases NO also decreased [125I]atriopeptin III binding to the cells. In addition, further decrease in [125I]atriopeptin III binding following IL-1 or SNP treatment was observed in the presence of 0.1 mM zaprinast, a cGMP-specific phosphodiesterase inhibitor. Scatchard analysis of the binding data in the treated cells showed a decrease in Bmax without a significant change in Kd. Affinity cross-linking of [125I]atriopeptin III to the treated cells demonstrated a decrease in 70-kDa band corresponding to the ANPC receptor. MEanwhile, intracellular cGMP response to atriopeptin III was significantly (P < 0.01) enhanced in the cells pretreated with IL-1 or SNP despite the decrease in receptor density. These findings suggest that NO down-regulates the ANPC receptor by the accumulation of intracellular cGMP in cultured rabbit aortic smooth muscle cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Oxidoreductases↗

PubMed2000

SNP profile within the human major histocompatibility complex reveals an extreme and interrupted level of nucleotide diversity.

The human major histocompatibility complex (MHC) is characterized by polymorphic multicopy gene families, such as HLA and MIC (PERB11); duplications; insertions and deletions (indels); and uneven rates of recombination. Polymorphisms at the antigen recognition sites of the HLA class I and II genes and at associated neutral sites have been attributed to balancing selection and a hitchhiking effect, respectively. We, and others, have previously shown that nucleotide diversity between MHC haplotypes at non-HLA sites is unusually high (>10%) and up to several times greater than elsewhere in the genome (0.08%-0.2%). We report here the most extensive analysis of nucleotide diversity within a continuous sequence in the genome. We constructed a single nucleotide polymorphism (SNP) profile that reveals a pattern of extreme but interrupted levels of nucleotide diversity by comparing a continuous sequence within haplotypes in three genomic subregions of the MHC. A comparison of several haplotypes within one of the genomic subregions containing the HLA-B and -C loci suggests that positive selection is operating over the whole subgenomic region, including HLA and non-HLA genes. [The sequence data for the multiple haplotype comparisons within the class I region have been submitted to DDBJ/EMBL/GenBank under accession nos. AF029061, AF029062, and AB031005-AB031010. Additional sequence data have been submitted to the DDBJ data library under accession nos. AB031005-AB03101 and AF029061-AF029062.]

Base Composition↗

PubMed2002

High resolution mapping of quantitative trait loci by linkage disequilibrium analysis.

Two methods, linkage analysis and linkage disequilibrium (LD) mapping or association study, are usually utilised for mapping quantitative trait loci (QTL). Linkage mapping is appropriate for low resolution mapping to localise trait loci to broad chromosome regions within a few cM (<10 cM), and is based on family data. Linkage disequilibrium mapping, on the other hand, is useful in high resolution or fine mapping, and is based on both population and family data. Using only one marker, one may carry out single-point linkage analysis and linkage disequilibrium mapping. Using two or more markers, it is possible to flank the QTL by multipoint analysis. The development and thus availability of dense marker maps, such as single nucleotide polymorphisms (SNP) in human genome, presents a tremendous opportunity for multipoint fine mapping. In this article, we propose a regression approach of mapping QTL by linkage disequilibrium mapping based on population data. Assuming that two marker loci flank one quantitative trait locus, a two-point linear regression is proposed to analyse population data. We derive analytical formulas of parameter estimations, and non-centrality parameters of appropriate tests of genetic effects and linkage disequilibrium coefficients. The merit of the method is shown by the power calculation and comparison. The two-point regression model can capture much more linkage and linkage disequilibrium information than that derived when only one marker is used. For a complex disease with heritability h(2)> or =0.15, a study with sample size of 250 can provide high power for QTL detection under moderate linkage disequilibria.

Chromosome Mapping↗

PubMed2004

[Population genetic analysis of Y-chromosomal single nucleotide polymorphism in six Chinese populations].

OBJECTIVE: To analyze the genetic polymorphism of 15 single nucleotide polymorphism (SNP) loci on the nonrecombining portion of the Y chromosome in 6 populations in China. METHODS: Allelic specific polymerase chain reaction and 2% agarose gel electrophoresis and 6% PAGE were used to analyze the genetic polymorphism of 343 unrelated males, representing 6 populations in China, including Fujian Hans, Sichuan Hans, Mongolian, Hezhen, Sibo and Hui from the South, Northeast and Northwest. RESULTS: Thirty haplogroups were observed, and 3 of them (H15, H16, H18) were seen in all of the six populations. Although the heterozygosity levels of the Hezhen, Mongolian, Sibo populations are similar and those of the other 3 populations (Fujian Hans, Sichuan Hans, Hui) are similar, the pairwise differences among haplogroups are significant. Analysis of molecular variance (AMOVA) and principal component (PC) analysis of the haplogroup distributions suggested highly different allele diversity between group I including Hezhen, Mongolian, Sibo and group II including Hui, Fujian Hans, Sichuan Hans. CONCLUSION: The above analyses show more significant variance components in Northeast/South populations and clearly reveal the geographic genetic relationship among the six populations in the Northeast/Northwest/South. These results confirm the complexity of the genetic structure of Chinese populations and make a significant contribution for constructing the contemporary human gene pool and tracing genetic dispersal trail from Chinese populations.

Alleles↗