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PubMed2026

Exploring genomic regions regulating the liver transcriptome and energy homeostasis in pigs.

In pigs, energy homeostasis has an impact on meat quality and health. In a Duroc pig population, 30 quantitative trait locus (QTL) regions associated with fatty acid (FA) composition in adipose tissue, plasma, liver and muscle were previously identified. Mapping of expression quantitative trait locus (eQTL) regions will provide a molecular hypothesis for genotype-phenotype interactions and may allow the identification of shared causal variants, key to increasing our understanding of the genetic regulation of FA composition and energy homeostasis. However, gene expression is impacted by environmental factors, while individual-level allelic imbalance (AI) can be more reliable and can be surveyed via allelic-specific expression (ASE) analysis. Furthermore, treatment of ASE as a quantitative trait allows the identification of allele-specific expression quantitative trait loci (aseQTLs), which are variants whose heterozygosity is linked to the AI of a nearby single-nucleotide polymorphism (SNP), pointing to regulatory elements. In this study, liver was selected as a key metabolic hub with an important role in the regulation of energy homeostasis, and 310 liver RNA sequencing samples were analysed using a combination of (1) eQTL mapping, (2) ASE analysis, and (3) aseQTL mapping methods. A total of 2 188 eQTL regions were identified, mostly cis-eQTL regions (73.17%). ASE analysis reported 1 964 ASE SNPs, associated with 633 genes. Finally, aseQTL mapping reported 64 172 aseQTL, associated with the AI of 31 genes. Colocalisation analysis combined with ASE analysis showed that the expression of FADS1 and FADS2 genes is associated with the polyunsaturated FA composition in several tissues, where microRNA regulation may be present. Finally, in the DGAT2 gene, annotated in a QTL region associated with multiple FAs in adipose tissue, ASE revealed allelic imbalance in the 3' untranslated region (UTR) of this gene. Allelic differential expression can be caused by a 13-bp insertion affecting messenger RNA stability, previously described, exemplifying how allelic imbalance is caused by a post-transcriptional regulatory mechanism undetectable by eQTL mapping. Furthermore, aseQTLs were associated with this gene, linked to a previously identified copy number variant not yet associated with DGAT2 expression. These results demonstrate how ASE analysis and aseQTL mapping can complement eQTL mapping, as they resolved a complex region affected by allelic heterogeneity, a main confounding effect of QTL mapping. In conclusion, the combination of eQTL mapping, ASE analysis and aseQTL mapping allowed the characterisation of the regulation of liver gene expression, improving our understanding of the genetic determinism of energy homeostasis.

Allele-specific expression↗
PubMed2002

Genetic polymorphisms of the human CYP2A13 gene: identification of single-nucleotide polymorphisms and functional characterization of an Arg257Cys variant.

Human cytochrome P450 2A13 (CYP2A13), which is highly efficient in the metabolic activation of a major tobacco-specific carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), may play important roles in xenobiotic toxicity and tobacco-related tumorigenesis in the respiratory tract. The aim of this study was to identify any genetic polymorphisms of the CYP2A13 gene, which may alter the metabolic capacities of the enzyme. Polymerase chain reaction (PCR) single-strand conformational polymorphism analysis was used to identify single-nucleotide polymorphisms (SNPs) in all of the exons and at the exon-intron boundaries, and PCR-restriction fragment length polymorphism analysis and DNA sequencing were used to determine the frequencies of the newly identified variant alleles in the four major ethnic groups. Blood spot DNA from more than 100 individuals was used for these analyses. Seven variant alleles were found, but only one SNP was detected in the coding region, in exon 5, leading to an Arg257Cys amino acid change. The frequencies of the Arg257Cys allele in white, black, Hispanic, and Asian individuals are 1.9%, 14.4%, 5.8%, and 7.7%, respectively. Functional analysis of the variant protein was performed following its heterologous expression. The Arg257Cys variant was 37 to 56% less active than the wild-type Arg-257 protein toward all substrates tested. With NNK, Cys-257 had higher K(m) and lower V(max) values than did Arg-257, with a >2-fold decrease in catalytic efficiency. The Arg257Cys mutation could provide some protection against xenobiotic toxicity in the respiratory tract to individuals who are homozygous for the Cys-257 allele.

Amino Acid Substitution↗
PubMed2006

Association of genetic polymorphisms in the base excision repair pathway with lung cancer risk: a meta-analysis.

Lung cancer is a major cause of cancer-related death in the developed countries and the overall survival rate has still an extremely poor. Although cigarette smoking is the main cause of lung cancer, not all smokers develop lung cancer, and a fraction of lifelong non-smokers will die from lung cancer. Genetic host factors have recently been implicated to account for some of the observed differences in lung cancer susceptibility. Various DNA alterations can be caused by exposure to environmental and endogenous carcinogens. Most of these alterations, if not repaired, may result in genetic instability, mutagenesis and cell death. DNA repair mechanisms are important for maintaining DNA integrity and preventing carcinogenesis. Recent genetic association studies on lung cancer risk have focused on identifying effects of single nucleotide polymorphisms (SNPs) in candidate genes, among which DNA repair genes are increasingly studied. Genetic variations in DNA repair genes are thought to modulate DNA repair capacity and are suggested to be related to lung cancer risk. We identified a sufficient number of epidemiologic studies on lung cancer to conduct a meta-analysis for genetic polymorphisms in nucleotide base repair (BER) pathway, focusing on 8-oxoguanine DNA glycosylase 1, X-ray cross-complementing group 1 (XRCC1) and apurinic/apyrimidinic endonuclease 1. The 399Gln/Gln genotype of the XRCC1 Arg399Gln polymorphism was associated with an increased risk of lung cancer among Asians (OR=1.34, 95% CI=1.16-1.54) but not among Caucasians. Little evidence of associations has been found between other BER genes and lung cancer risk. Considering the data available, it can be conjectured that if there is any risk association between single SNP and lung cancer, this risk increase/decrease will probably be minimal. Advances in identification of new polymorphisms and in high-throughput genotyping techniques will facilitate analysis of multiple genes in multiple DNA repair pathways. Therefore, it is likely that the defining feature of future epidemiologic studies will be the simultaneous analysis of large samples of cases and controls.

DNA Glycosylases↗
PubMed2002

Determination of melting temperature for variant detection using dHPLC: a comparison between an empirical approach and DNA melting prediction software.

Detection of DNA sequence variants by the use of denaturing high-performance liquid chromatography (dHPLC) is a relatively new method (Underhill et al., 1997) and has distinct advantages over other methods such as single-strand conformation polymorphism (SSCP), direct sequencing, and DNA chip hybridization. The dHPLC-based single-nucleotide polymorphism (SNP) screening relies on different DNA thermodynamic properties between perfectly matched base pairs in homoduplex molecules and single base-pair mismatches in heteroduplex DNAs. Separation of the two forms of duplex DNAs by dHPLC is based on ionic forces between the negatively charged DNA and the hydrophobic stationary phase, which consists of C(18) chains on PSDVB (polystyrene-divinylbenzene) beads coated with a positively charged ion-pairing agent (TEAA, triethylammonium acetate). Removal of the DNA from the TEAA-coated beads is dependent upon a mobile organic phase, in the form of a linear acetonitrile gradient. The major factor that influences the success of dHPLC to detect sequence variation is the thermal stability of the duplex DNA, which is determined by the melting temperature (TM(50)), where 50% of the DNA strand is single stranded and 50% is double stranded. The TM(50) predicts the best probability of detecting a single base-pair change based on the altered thermodynamics it imparts to the DNA duplex. Generally, there are two ways to determine this melting temperature, either empirically or with the aid of predictive DNA melting analysis software. Such programs include the DNAMelt program located on the Stanford University DNA Sequencing and Technology Center website, MeltCalc (Schutz and von Ahsen 1999), and WAVEMAKER, the proprietary melting analysis software provided with the Transgenomic WAVE dHPLC system. The goal of the current study was to determine whether currently available predictive DNA melting programs could be used to increase efficiency and throughput of SNP detection. A wide range of amplicons, differing in both size and GC composition, were selected for analysis to simulate the broad spectrum of PCR products that may be encountered during a large-scale dHPLC screening project.

Chromatography, High Pressure Liquid↗
PubMed2001

Effects of systemic blockade of nitric oxide synthases on pulsatile LH, prolactin, and GH secretion in adult male rats.

BACKGROUND: Nitric oxide (NO) has emerged as an important neurotransmitter involved in the control of the neuroendocrine function. NO acts at hypothalamic, pituitary, and gonadal levels. Previous data from our laboratory showed that blockade of NO generation, after systemic administration of a NO synthase inhibitor (Nomega-nitro-arginine methyl ester, NAME), increased the luteinizing hormone (LH) secretion in intact and ovariectomized females, whereas a blockade of spontaneous and steroid-induced LH and prolactin surges after NO synthase inhibition has been also described. METHODS AND RESULTS: Adult male rats were implanted with chronic intra-auricular cannulae and 5 days later sampled at 15-min intervals during 6 h (10.00-16.00 h). Administration of NAME (40 mg/kg at 08.00 and 13.00 h) stimulated significantly (p < or = 0.01) the LH secretion, increasing LH pulse amplitude (0.58 +/- 0.14 vs. 0.08 +/- 0.01 ng/ml in controls), mean LH levels (0.64 +/- 0.15 vs. 0.15 +/- 0.03 ng/ml in controls), and area under curve (239 +/- 56 vs. 57 +/- 13 in controls). This effect was blocked by coadministration of sodium nitroprusside (SNP), a NO donor (0.5 mg/kg). The action of NAME was observed 3 h after administration, in contrast to the earlier response detected in female rats, and it appeared selective for LH, as prolactin and growth hormone secretion remained unchanged. Further analysis was carried out to determine whether the effect of NAME on the LH secretion was indirect and mediated by changes in testosterone release. To this end, adult male rats were decapitated 2 h after administration of NAME (40 mg/kg), SNP (0.5 mg/kg), or L-nitro-arginine methyl ester (L-AME), a substrate for NOS (1 g/kg). The serum testosterone concentrations were unchanged after NAME administration, but inhibited by SNP and L-AME. Finally, the effect of NAME and SNP on in vitro testosterone secretion was analyzed. NAME (10 mM) did not affect basal testosterone production, but inhibited the human chorionic gonadotropin stimulated testosterone secretion. CONCLUSIONS: These data strongly suggest that the stimulatory effect of NAME on LH secretion is not due to an inhibition of testosterone release and is exerted at the hypothalamic-pituitary level.

Animals↗
PubMed2001

Simultaneous allele-specific amplification: a strategy using modified primer-template mismatches for SNP detection--application to prothrombin 20210A (factor II) and factor V Leiden (1691A) gene mutations.

BACKGROUND: Inherited thrombophilia is caused by mutations in genes central to the clotting cascade. Analysis of the factor V Leiden (FVL) and prothrombin G20210A mutations are the most prevalent in thrombophilia. METHODS AND RESULTS: We have optimized an allele-specific PCR assay for the simultaneous detection of both wild-type and mutant alleles. This method is adapted for clinical use with the FVL and prothrombin G20210A assays and is significant in its intentional use of nucleotide mismatches at the 3' end of allele-specific primers. Two internal allele-specific primers are designed to amplify in opposite directions on opposite strands that reduce differential amplification. Our results show concordance with methods involving PCR with restriction endonuclease digestion, yet are simpler to perform. CONCLUSION: The simultaneous allele-specific amplification method allows simultaneous detection of wild-type and mutant alleles by PCR using four distinct primers. Nucleotide mismatches in the primers reduce competitive amplification.

Alleles↗
PubMed2005

A haplotype analysis of HER-2 gene polymorphisms: association with breast cancer risk, HER-2 protein expression in the tumor, and disease recurrence in Korea.

PURPOSE: A single-nucleotide polymorphism (SNP) in codon 655 of HER-2 has been extensively studied with inconclusive results. The purpose of this study was to investigate the association between common variants of HER-2 and breast cancer risk, HER-2 expression, and survival using a haplotype-based stepwise approach. EXPERIMENTAL DESIGN: Twenty-nine SNPs listed in the National Center for Biotechnology Information database were screened to identify novel polymorphisms of HER-2 gene in 90 healthy Korean women. Six of 29 SNPs were polymorphic and had greater than 10% of minor allele frequencies. Using these six SNPs, linkage disequilibrium and haplotype patterns were characterized. We tested association between the haplotypes and breast cancer in a large case-control study (n=1,039 cases and 995 controls). Six-hundred two breast cancer patients with follow-up at least 24 months were analyzed for outcome in relation to haplotype. Expression of HER-2 protein was determined by immunohistochemistry in 1,094 cases of invasive breast cancer. RESULTS: All six SNPs showed a strong linkage disequilibrium pattern and were considered to belong to one haplotype block. Two haplotype-tagging SNPs (I655V and P1170A) for three common haplotypes (>5%) were genotyped in cases and controls. The haplotypes and individual SNPs were not associated with breast cancer risk. In patients with at least one copy of haplotype I (the most common haplotype), HER-2 expression was 1.5 times higher (P = 0.009) and the prognosis was worse (P = 0.032) compared with patients without having that haplotype. CONCLUSIONS: Our results suggest that the currently identified genetic polymorphisms of HER-2 are not associated with an increased risk of breast cancer in Korean women, whereas one haplotype does affect protein expression of the tumor and disease outcome.

Adult↗
PubMed2003

Analysis of an interleukin-6 gene promoter polymorphism in women with endometriosis by pyrosequencing.

Interleukin (IL)-6 has been implicated in the etiology of endometriosis. A single nucleotide polymorphism (SNP) at position -174 in the IL-6 gene promoter appears to influence IL-6 transcription rates in vitro and basal IL-6 levels in vivo. We determined the genotype and the allele frequencies of the -174 IL-6 promoter polymorphism and the corresponding IL-6 serum levels in women with endometriosis. The pyrosequencing technique was used to assess the IL-6 genotypes in 94 women with histologically confirmed endometriosis (study group). A series of 70 healthy women without history of uterine disease served as clinical controls (control group).Allele frequencies for the G allele among women with and without endometriosis were 59.6% and 55.0%, respectively (P =.430; odds ratio [OR] 0.83, 95% confidence interval [CI] 0.53, 1.29). Homozygotes for the protective allele C were present in 17.0% of women with endometriosis and in 18.6% of controls were homozygous for the protective allele C (P =.797; OR 0.90, 95% CI 0.40, 2.02). When patients with various disease manifestations were compared, we found an association between the -174 G allele and chocolate cysts (P =.037). Serum levels of IL-6 were significantly higher in women with endometriosis than in controls (P <.001), with highest levels in women with chocolate cysts. There was no association between serum IL-6 levels and IL-6 genotype. The IL-6 promoter polymorphism -174 G/C does not contribute significantly to overall disease susceptibility but does predispose the carrier to distinct endometriosis with chocolate cysts. A genetically determined high IL-6 response might play a pathogenic role in this disease condition.

Alleles↗
PubMed1992

[Timed dose-response relationship analysis of pressor and hypotensive action of drugs].

The graded and timed dose-response relationship (TDRR) of pressor and hypotensive action by i.v. norepinephrine (NE) and sodium nitroprusside (SNP) respectively were studied in 13 male rabbits. The arterial blood pressure was dose-dependently raised by NE 0.98-125 micrograms.kg-1 and lowered by SNP 7.81-500 micrograms.kg-1 (F test, P < 0.01). The comparisons between dose groups showed that the latency and duration of both NE and SNP action were dose-dependent (P < 0.01), and the data were nonlinear least-square fit to the hyperbolic 4-parameter model II (HFPM): Y = cs + 1/(magnitude of ln X - a)s + b, weighting the square error inversely with the square of Sx. In duration data, the regression equation was Y = 462.9906/(6.6924 - ln X) 0.9701 - 24.3335 for NE and Y = 374935.1632/(12.8573 - ln X)3.3975 - 3.139 for SNP action, while in latency, Y = 345.5548/(ln X + 7.8428)2.4056 + 3.9809 and Y = 17.9595/(ln X - 0.4898)0.5763 + 1.4768 for NE and SNP, respectively. Moreover, the positive correlation was found between the peak-reaching time or average rising rate of the drug actions and the dose groups (P < 0.01). The results proved that the hyperbolic type of TDRR existed in the pressor and hypotensive action by iv drugs, and the HFPM was the common mathematical model to fit different TDRR data.

Animals↗
PubMed2001

Single nucleotide polymorphism (D68D, T to C) in the syntaxin 1A gene correlates to age at onset and insulin requirement in Type II diabetic patients.

AIM/HYPOTHESIS: Syntaxin 1A is a candidate gene for Type II (non-insulin-dependent) diabetes mellitus, because it plays an important role in insulin secretion from the islet beta cells. We aimed to scan this gene for mutations or genetic markers that correlate with Type II diabetes. METHODS: We identified and characterized coding exons of the syntaxin 1A gene and scanned the newly identified 10 exons using direct sequencing. RESULTS: In the single nucleotide polymorphism (SNP) of exon 3 (D68D, T to C) among three newly identified SNPs, genotype frequency of the homozygote of C allele (CC) occurred more frequently in a Type II diabetic group than in a non-diabetic group (16.48 %, n = 182, vs 11.05 %, n = 181, p = 0.0499). Among the diabetic patients, age of onset in patients with CC genotype was lower than that in patients with the TT and TC genotypes [40.10 +/- 1.50 years old (means +/- SEM) vs 44.20 +/- 0.58, p = 0.005]. Patients with the CC genotype had a higher frequency of insulin treatment (78.30 % vs 46.80 %, p = 0.006) with a duration equal to, or longer than, 10 years. Multiple regression analysis confirmed that the genotype was significantly and independently associated with age at onset and mode of treatment, respectively. CONCLUSION/INTERPRETATION: These data indicate that the SNP in the syntaxin 1A gene (D68D, T to C) correlates to the age of onset and insulin requirements of Type II diabetic Japanese patients.

Age of Onset↗
PubMed2002

Oligonucleotide arrays for high-throughput SNPs detection in the MHC class I genes: HLA-B as a model system.

A simple and efficient oligonucleotide array was developed to identify single nucleotide polymorphisms (SNPs) encoded within the highly polymorphic human major histocompatibility complex (MHC) using HLA-B as a model system. A total of 137 probes were designed to represent all known polymorphisms encoded in exons 2 and 3. PCR products were amplified from human genomic DNA and allowed to hybridize with the oligonucleotide array. Hybridization was detected by fluorescence scanning, and HLA-B alleles were assigned by quantitative analysis of the hybridization results. Variables known to influence the specificity of hybridization, such as oligonucleotide probe size, spacer length, surface density, hybridization conditions, and array uniformity and stability were studied. The efficiency and specificity of identifying HLA-B SNPs using the oligonucleotide arrays was evaluated by blinded analysis of 100 samples from unrelated individuals representing all HLA-B phenotypes. The oligonucleotide array method described in this paper provides unambiguous detection of complex heterozygous SNP combinations. This methodological approach may be applied to other highly polymorphic gene systems.

Alleles↗
PubMed2006

Lack of association with TNF-alpha-308 promoter polymorphism in patients with vitiligo.

Vitiligo is an acquired depigmentary disorder of the skin, characterized by incomplete penetrance, multiple susceptibility loci and genetic heterogeneity. An immunologic hypothesis is currently advanced as a possible pathogenesis of vitiligo. The cytokines have an important role in pathogenesis of autoimmunity in which tumor necrosis factor-alpha (TNF-alpha), a paracrine inhibitor of melanocytes, is especially important. Several single-nucleotide polymorphisms (SNP) have been identified in the human TNF gene promoter. The polymorphism at position -308 (TNF-308), which involves substituting G for A and designing the AA genotype, leads to a higher rate of TNF gene transcription than the wild-type GG genotype in in vitro expression studies. It has also been linked to increased susceptibility to several chronic metabolic, degenerative, inflammatory and autoimmune diseases. Therefore, we investigated the TNF-alpha-308 SNP in patients with vitiligo. We examined 61 patients with vitiligo. Healthy age-, ethnically- and sex-matched individuals (n = 123) served as controls. Polymerase chain reaction amplification was used for analysis of the polymorphism at position -308 in promoter of TNF-alpha gene. We found that the distribution of TNF-alpha genotypes in vitiligo patients did not differ from that in control subjects (P > 0.05). Moreover, there was no association between TNF-alpha genotypes and types of vitiligo. In conclusion, we suggest that TNF-alpha-308 SNP is not a genetic risk factor for vitiligo susceptibility.

Case-Control Studies↗
PubMed2003

Sequences associated with human iris pigmentation.

To determine whether and how common polymorphisms are associated with natural distributions of iris colors, we surveyed 851 individuals of mainly European descent at 335 SNP loci in 13 pigmentation genes and 419 other SNPs distributed throughout the genome and known or thought to be informative for certain elements of population structure. We identified numerous SNPs, haplotypes, and diplotypes (diploid pairs of haplotypes) within the OCA2, MYO5A, TYRP1, AIM, DCT, and TYR genes and the CYP1A2-15q22-ter, CYP1B1-2p21, CYP2C8-10q23, CYP2C9-10q24, and MAOA-Xp11.4 regions as significantly associated with iris colors. Half of the associated SNPs were located on chromosome 15, which corresponds with results that others have previously obtained from linkage analysis. We identified 5 additional genes (ASIP, MC1R, POMC, and SILV) and one additional region (GSTT2-22q11.23) with haplotype and/or diplotypes, but not individual SNP alleles associated with iris colors. For most of the genes, multilocus gene-wise genotype sequences were more strongly associated with iris colors than were haplotypes or SNP alleles. Diplotypes for these genes explain 15% of iris color variation. Apart from representing the first comprehensive candidate gene study for variable iris pigmentation and constituting a first step toward developing a classification model for the inference of iris color from DNA, our results suggest that cryptic population structure might serve as a leverage tool for complex trait gene mapping if genomes are screened with the appropriate ancestry informative markers.

Chromosomes, Human, Pair 10↗
PubMed2005

Evidence for a basal release of a cytochrome-related endothelium-derived hyperpolarizing factor in the radial artery in humans.

Whether a cytochrome P-450 (CYP)-related endothelium-derived hyperpolarizing factor (EDHF), acting through calcium-activated potassium (K(Ca)) channels, interacts with nitric oxide (NO) to regulate the basal diameter of human peripheral conduit arteries is unexplored in vivo. Radial artery diameter (echo tracking) and blood flow (Doppler) were measured, after oral aspirin (500 mg), in eight healthy volunteers during local infusion for 8 min of tetraethylammonium chloride (TEA; 9 micromol/min), as K(Ca) channel inhibitor, and fluconazole (0.4 micromol/min), as CYP inhibitor, alone and in combination with N(G)-monomethyl-L-arginine (L-NMMA; 8 micromol/min), as endothelial NO synthase inhibitor. Endothelium-independent dilatation was assessed by using sodium nitroprusside (SNP). Radial diameter was unaffected by L-NMMA (0.4 +/- 0.9%) and fluconazole (-1.6 +/- 0.8%) but was decreased by TEA (-5.0 +/- 1.0%), L-NMMA + fluconazole (-5.3 +/- 0.5%), and L-NMMA + TEA (-9.9 +/- 1.3%). These effects are still significant even when the concomitant decreases in blood flow induced by L-NMMA (-24 +/- 4%), TEA (-21 +/- 3%), L-NMMA + fluconazole (-26 +/- 5%), and L-NMMA + TEA (-35 +/- 4%) were taken as covariate into analysis. Conversely, fluconazole alone slightly but not significantly increased radial flow (13 +/- 6%). L-NMMA alone or with TEA and with fluconazole enhanced radial artery dilatation to SNP, whereas TEA and fluconazole alone did not modify this response. These results confirm in humans the involvement of NO and K(Ca) channels in the regulation of basal conduit artery diameter. Moreover, the synergistic effect of combined inhibition of NO synthesis and CYP on the decrease in radial diameter in the absence of such effect after L-NMMA and fluconazole alone unmasks the role of CYP in this regulation and shows the presence of an interaction between NO and a CYP-related EDHF to maintain peripheral conduit artery diameter in vivo. Furthermore, the higher vasoconstrictor effect of TEA compared with fluconazole suggests that different K(Ca) channel-dependent hyperpolarizing mechanisms could exist in conduit arteries.

Adult↗
PubMed2001

Microsphere-based molecular cytometry.

Flow cytometry has recently gained attention as a powerful high-throughput technology for the analysis of molecular interactions. This recognition is mostly because of the development and use of fluorescently distinct microsphere populations. Recent applications of this technology have included detecting analytes, monitoring enzymatic activity, and genotyping SNP. This article expands the list of applications by highlighting nuclear receptor-coactivator peptide binding studies. Nuclear receptors initiate gene transcription by binding to a wide variety of accessory factors. Small molecule ligand binding by nuclear receptors modulates the interaction with some of these cofactors. Because a typical cell contains numerous cofactors, multiplexed analysis of nuclear receptor binding to coactivator peptide-coupled microspheres is a valuable approach to rapidly assess this network of complex interactions. Understanding how ligand binding regulates these interactions should help in the design of improved small molecule therapeutics. The latter part of this article has focused on the recent application of multiplexing protein:protein interactions. Developing protein interaction networks will be paramount as a greater understanding of the human genome is developed. In the future, flow cytometric analysis of fluorescent microspheres may be applied to any array of interacting molecules and may have broader applications in the area of proteomics.

Binding Sites↗
PubMed2005

Gene expression and association analyses of LIM (PDLIM5) in bipolar disorder and schizophrenia.

We previously reported that expression level of LIM (ENH, PDLIM5) was significantly and commonly increased in the brains of patients with bipolar disorder, schizophrenia, and major depression. Expression of LIM was decreased in the lymphoblastoid cells derived from patients with bipolar disorders and schizophrenia. LIM protein reportedly plays an important role in linking protein kinase C with calcium channel. These findings suggested the role of LIM in the pathophysiology of bipolar disorder and schizophrenia. To further investigate the role of LIM in these mental disorders, we performed a replication study of gene expression analysis and performed genetic association studies. Upregulation of LIM was confirmed in the independent sample set obtained from Stanley Array Collection. No effect of sample pH or medication was observed. Genetic association study revealed the association of single nucleotide polymorphism (SNP)1 (rs10008257) with bipolar disorder. In an independent sample set, SNP2 (rs2433320) close to SNP1 was associated with bipolar disorder. In total samples, haplotype of these two SNPs was associated with bipolar disorder. No association was observed in case-control analysis and family-based association analysis in schizophrenia. These results suggest that SNPs in the upstream region of LIM may confer the genetic risk for bipolar disorder.

Adaptor Proteins, Signal Transducing↗
PubMed2026

A GWAS-derived histone H4 variant linked to ear row number reveals functional insights into the maize ZmHistone gene family.

Ear row number (ERN) is a major yield determinant in maize and a key target for breeding of high-yielding varieties. This study utilized a multi-parent population (MPP) of 780 recombinant inbred lines (RILs) derived from seven inbred lines across three environments. Genotyping-by-sequencing (GBS) of the MPP yielded 638,646 high-quality SNPs. Using genome-wide association study (GWAS), we detected 80 significant SNPs including S2-15316355 and S4-224453431, which were consistently detected in all environments and best linear unbiased prediction (BLUP) analysis. A linkage disequilibrium-defined &#xb1;20&#x202f;kb window around these two lead SNPs contained three positional candidate genes: Zm00001eb072840, Zm00001eb072850 and Zm00001eb202890. Zm00001eb072850 (ZmHistone12), a histone H4 variant, was prioritized for hypothesis-driven follow-up because the lead SNP lies within its coding sequence and the gene is expressed in ear-related tissues. Additionally, we identified 91 ZmHistone genes in the maize genome and described their phylogeny, promoter motif and expression patterns. Public transcriptome and qRT-PCR analysis in seven parental lines provide descriptive evidence of Histone variant genes in maize ear development. These results suggest a potential involvement of chromatin-associated regulation of ERN in maize and provide a foundation for future functional validation.

Ear development↗