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An Integrated Meta-Analysis of Two Variants in HOXA1/HOXB1 and Their Effect on the Risk of Autism Spectrum Disorders  [PDF]
Ran-Ran Song,Li Zou,Rong Zhong,Xia-Wen Zheng,Bei-Bei Zhu,Wei Chen,Li Liu,Xiao-Ping Miao
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0025603
Abstract: HOXA1 and HOXB1 have been strongly posed as candidate genes for autism spectrum disorders (ASD) given their important role in the development of hindbrain. The A218G (rs10951154) in HOXA1 and the insertion variant in HOXB1 (nINS/INS, rs72338773) were of special interest for ASD but with inconclusive results. Thus, we conducted a meta-analysis integrating case-control and transmission/disequilibrium test (TDT) studies to clearly discern the effect of these two variants in ASD.
Allele-Specific Methylation Occurs at Genetic Variants Associated with Complex Disease  [PDF]
John N. Hutchinson, Towfique Raj, Jes Fagerness, Eli Stahl, Fernando T. Viloria, Alexander Gimelbrant, Johanna Seddon, Mark Daly, Andrew Chess, Robert Plenge
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0098464
Abstract: We hypothesize that the phenomenon of allele-specific methylation (ASM) may underlie the phenotypic effects of multiple variants identified by Genome-Wide Association studies (GWAS). We evaluate ASM in a human population and document its genome-wide patterns in an initial screen at up to 380,678 sites within the genome, or up to 5% of the total genomic CpGs. We show that while substantial inter-individual variation exists, 5% of assessed sites show evidence of ASM in at least six samples; the majority of these events (81%) are under genetic influence. Many of these cis-regulated ASM variants are also eQTLs in peripheral blood mononuclear cells and monocytes and/or in high linkage-disequilibrium with variants linked to complex disease. Finally, focusing on autoimmune phenotypes, we extend this initial screen to confirm the association of cis-regulated ASM with multiple complex disease-associated variants in an independent population using next-generation bisulfite sequencing. These four variants are implicated in complex phenotypes such as ulcerative colitis and AIDS progression disease (rs10491434), Celiac disease (rs2762051), Crohn's disease, IgA nephropathy and early-onset inflammatory bowel disease (rs713875) and height (rs6569648). Our results suggest cis-regulated ASM may provide a mechanistic link between the non-coding genetic changes and phenotypic variation observed in these diseases and further suggests a route to integrating DNA methylation status with GWAS results.
An evaluation of the performance of HapMap SNP data in a Shanghai Chinese population: Analyses of allele frequency, linkage disequilibrium pattern and tagging SNPs transferability on chromosome 1q21-q25
Cheng Hu, Weiping Jia, Weihua Zhang, Congrong Wang, Rong Zhang, Jie Wang, Xiaojing Ma, The International Type 2 Diabetes 1q Consortium, Kunsan Xiang
BMC Genetics , 2008, DOI: 10.1186/1471-2156-9-19
Abstract: Three thousand and forty-two SNPs were analyzed after removal of SNPs that failed quality control and those not in the HapMap panel. We compared the allele frequency distributions, linkage disequilibrium patterns, haplotype frequency distributions and tagging SNP sets transferability between the HapMap population and Shanghai Chinese population. Among the four HapMap populations, Beijing Chinese showed the best correlation with Shanghai population on allele frequencies, linkage disequilibrium and haplotype frequencies. Tagging SNP sets selected from four HapMap populations at different thresholds were evaluated in the Shanghai sample. Under the threshold of r2 equal to 0.8 or 0.5, both HapMap Chinese and Japanese data showed better coverage and tagging efficiency than Caucasian and African data.Our study supported the applicability of HapMap Beijing Chinese SNP data to the study of complex diseases among southern Chinese population.The International HapMap Project aimed at determining the common patterns of DNA sequence variants, their frequencies, and correlations between them, through genotyping samples from four large populations, Centre d'Etude du Polymorphisme Humain reference individuals from Utah, USA (CEU), Han Chinese in Beijing, China (CHB), Japanese in Tokyo, Japan (JPT), and Yoruba in Ibadan, Nigeria (YRI), at a density of 1 SNP every 5 kb. The populations genotyped in the HapMap can serve as reference populations for the selection of tagging SNPs (tSNPs) that capture most of the variations in the genome. It provides an important shortcut to carry out candidate-gene and genome-wide association studies in a certain population by minimizing the numbers of SNPs need to be genotyped [1-3].As stated by the International HapMap Consortium, the general applicability of the HapMap data should be confirmed in other populations [1]. Several studies previously performed showed high concordance with HapMap data in allele frequencies and haplotype distributions, and
ATRA Inhibits the Proliferation of DU145 Prostate Cancer Cells through Reducing the Methylation Level of HOXB13 Gene  [PDF]
Zhiwei Liu, Guoling Ren, Chenyan Shangguan, Lijing Guo, Zhixiong Dong, Yueyang Li, Weina Zhang, Li Zhao, Pingfu Hou, Yu Zhang, Xiuli Wang, Jun Lu, Baiqu Huang
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0040943
Abstract: All-trans retinoic acid (ATRA) has been widely investigated for treatments of many cancers including prostate cancer. HOXB13, silenced in androgen receptor-negative (AR?) prostate cancer cells, plays a role in AR? prostate cancer cell growth arrest. In this study we intended to elucidate the mechanisms that are involved in the proliferation inhibition of AR? prostate cancer cells triggered by ATRA. We discovered that ATRA was able to induce the growth arrest and to increase HOXB13 expression in AR? prostate cancer cells. Both EZH2 and DNMT3b participated in the repression of HOXB13 expression through an epigenetic mechanism involving DNA and histone methylation modifications. Specifically, EZH2 recruited DNMT3b to HOXB13 promoter to form a repression complex. Moreover, ATRA could upregulate HOXB13 through decreasing EZH2 and DNMT3b expressions and reducing their interactions with the HOXB13 promoter. Concurrently, the methylation level of the HOXB13 promoter was reduced upon the treatment of ATRA. Results from this study implicated a novel effect of ATRA in inhibition of the growth of AR? resistant human prostate cancer cells through alteration of HOXB13 expression as a result of epigenetic modifications.
HOXB13 promotes androgen independent growth of LNCaP prostate cancer cells by the activation of E2F signaling
Young-Rang Kim, Kyung-Jin Oh, Ra-Young Park, Nguyen Xuan, Taek-Won Kang, Dong-Deuk Kwon, Chan Choi, Min Kim, Kwang Nam, Kyu Ahn, Chaeyong Jung
Molecular Cancer , 2010, DOI: 10.1186/1476-4598-9-124
Abstract: In this report, we first demonstrated that HOXB13 was highly overexpressed in hormone-refractory tumors compared to tumors without prostate-specific antigen after initial treatment. Functionally, in an androgen-free environment minimal induction of HOXB13 in LNCaP prostate cancer cells, to the level of the normal prostate, markedly promoted cell proliferation while suppression inhibited cell proliferation. The HOXB13-mediated cell growth promotion in the absence of androgen, appears to be mainly accomplished through the activation of RB-E2F signaling by inhibiting the expression of the p21waf tumor suppressor. Indeed, forced expression of HOXB13 dramatically decreased expression of p21waf; this inhibition largely affected HOXB13-mediated promotion of E2F signaling.Taken together, the results of this study demonstrated the presence of a novel pathway that helps understand androgen-independent survival of prostate cancer cells. These findings suggest that upregulation of HOXB13 is associated with an additive growth advantage of prostate cancer cells in the absence of or low androgen concentrations, by the regulation of p21-mediated E2F signaling.Hox homeobox genes contain highly homologous homeodomains and are considered transcription factors that regulate axial regional specification during embryonic development. Due to temporal and spatial colineality, Hox genes are expressed in a tissue-specific and frequently stage-related fashion. The Hox-13 paralog is especially important to the development of accessory sexual organs, including the prostate gland [1-3]. Hoxb13 has been shown to have limited expression at the caudal extent of the spinal cord, tail bud and urogenital sinus in an androgen-independent manner [4,5]. The expression of HOXB13 is restricted but abundant in the adult human prostate, representing almost one out of 2,000 transcripts [6]. However, the role of HOXB13 during the adult stage is mostly unknown. Mice homozygous for Hoxb13 loss-of-function mutati
Allele-specific Characterization of Alanine: Glyoxylate Aminotransferase Variants Associated with Primary Hyperoxaluria  [PDF]
Melissa D. Lage, Adrianne M. C. Pittman, Alessandro Roncador, Barbara Cellini, Chandra L. Tucker
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0094338
Abstract: Primary Hyperoxaluria Type 1 (PH1) is a rare autosomal recessive kidney stone disease caused by deficiency of the peroxisomal enzyme alanine: glyoxylate aminotransferase (AGT), which is involved in glyoxylate detoxification. Over 75 different missense mutations in AGT have been found associated with PH1. While some of the mutations have been found to affect enzyme activity, stability, and/or localization, approximately half of these mutations are completely uncharacterized. In this study, we sought to systematically characterize AGT missense mutations associated with PH1. To facilitate analysis, we used two high-throughput yeast-based assays: one that assesses AGT specific activity, and one that assesses protein stability. Approximately 30% of PH1-associated missense mutations are found in conjunction with a minor allele polymorphic variant, which can interact to elicit complex effects on protein stability and trafficking. To better understand this allele interaction, we functionally characterized each of 34 mutants on both the major (wild-type) and minor allele backgrounds, identifying mutations that synergize with the minor allele. We classify these mutants into four distinct categories depending on activity/stability results in the different alleles. Twelve mutants were found to display reduced activity in combination with the minor allele, compared with the major allele background. When mapped on the AGT dimer structure, these mutants reveal localized regions of the protein that appear particularly sensitive to interactions with the minor allele variant. While the majority of the deleterious effects on activity in the minor allele can be attributed to synergistic interaction affecting protein stability, we identify one mutation, E274D, that appears to specifically affect activity when in combination with the minor allele.
Candidate gene study of HOXB1 in autism spectrum disorder
Lucia A Muscarella, Vito Guarnieri, Roberto Sacco, Paolo Curatolo, Barbara Manzi, Riccardo Alessandrelli, Grazia Giana, Roberto Militerni, Carmela Bravaccio, Carlo Lenti, Monica Saccani, Cindy Schneider, Raun Melmed, Leonardo D'Agruma, Antonio M Persico
Molecular Autism , 2010, DOI: 10.1186/2040-2392-1-9
Abstract: Our sample includes 269 autistic individuals, belonging to 219 simplex and 28 multiplex families. A mutational analysis of the two exons and flanking intronic sequences of the HOXB1 gene was carried out in 84 autistic patients by denaturing high performance liquid chromatography, followed by DNA sequencing. Identified rare variants were then searched by a restriction analysis in 236 autistic patients and 325-345 controls. Case-control and family-based association studies were performed on two common variants in 169 Italian patients versus 184 Italian controls and in 247 trios.We identified three common polymorphisms, rs72338773 [c.82insACAGCGCCC (INS/nINS)], rs12939811 [c.309A>T (Q103H)], and rs7207109 [c.450G>A (A150A)] and three rare variants, namely IVS1+63G>A, rs35115415 [c.702G>A (V234V)] and c.872_873delinsAA (S291N). SNPs rs72338773 and rs12939811 were not associated with autism, using either a case-control (alleles, exact P = 0.13) or a family-based design [transmission/disequilibrium test (TDT)χ2 = 1.774, P = 0.183]. The rare variants, all inherited from one of the parents, were present in two Italian and in two Caucasian-American families. Autistic probands in two families surprisingly inherited a distinct rare variant from each parent. The IVS1+63A allele was present in 3/690 control chromosomes, whereas rare alleles at rs35115415 and c.872_873delinsAA (S291N) were not found in 662 and 650 control chromosomes, respectively. The INS-T309 allele influenced head size, but its effect appears more modest and shows no interaction with HOXA1 alleles. The INS-T309 allele is also associated with more severe stereotypic behaviours, according to ADI-R scores (N = 60 patients, P < 0.01).HOXB1 mutations do not represent a common cause of autism, nor do HOXB1 common variants play important roles in autism vulnerability. HOXB1 provides minor, albeit detectable contributions to head circumference in autistic patients, with HOXA1 displaying more prominent effects. HOXB1 v
Genetic Variants and Allele Frequencies of Kappa Casein in Egyptian Cattle and Buffalo Using PCR-RFLP  [cached]
Eman M. Gouda,Mona Kh. Galal,Samy A. Abdelaziz
Journal of Agricultural Science , 2013, DOI: 10.5539/jas.v5n2p197
Abstract: Kappa casein (K-Ca) genetic variations affected quality and composition of the milk. Several variants of Kappa casein (K-Ca) gene locus IV have been reported with special interest for the ‘B’ allele for its relation to the milk protein and fat yields. Genotyping and allelic frequencies of K-Ca among Native Egyptian breeds of cattle and buffalo were the aim of the present study. PCR amplification of DNA isolated from 300 blood samples collected from Holstein and Baladi cattle and buffalo were performed followed by restriction fragment length polymorphism using Hind-III restriction endonuclease (PCR-RFLP). Detection of ‘AA’ and ‘AB’ genotypes in cattle breeds, ‘BB’ and ‘AB’ in buffalo and two alleles ‘A’ and ‘B’ in the studied breeds. Molecular selection for animals carrying the ‘B’ allele could impact breeding programs for dairy production in native cattle and buffalo breeds in Egypt. ast-language:AR-SA'>Simulated daily cycle of temperature was compared with data registered at six meteorological stations located in the cultivated floor of the semiarid Limari Valley (Chile, 31°S). Although in some cases the simulated temperature differs in about 2°C with the observed one, a good fit between model results and experimental data was observed. Using the simulated seasonal minimum and maximum mean temperature fields, maps of temperature differences with respect to a reference station were drawn. In order to observe the influence of the orography on the lapse rate around a station, the methodology was applied for two reference stations located in places with different orographic characteristics. Results for winter and summer seasons are shown. These generated maps can be used by farmers and agricultural planners to obtain information of seasonal minimum and maximum mean temperature from a station in any site of the cultivated area. This technique is a good alternative to obtain meteorological information at low costs, contributing to territorial planning for climate resilient agriculture sustainability.
Advantage of Using Allele-Specific Copy Numbers When Testing for Association in Regions with Common Copy Number Variants  [PDF]
Ga?lle Marenne, Stephen J. Chanock, Núria Malats, Emmanuelle Génin
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0075350
Abstract: Copy number variants (CNV) can be called from SNP-arrays; however, few studies have attempted to combine both CNV and SNP calls to test for association with complex diseases. Even when SNPs are located within CNVs, two separate association analyses are necessary, to compare the distribution of bi-allelic genotypes in cases and controls (referred to as SNP-only strategy) and the number of copies of a region (referred to as CNV-only strategy). However, when disease susceptibility is actually associated with allele specific copy-number states, the two strategies may not yield comparable results, raising a series of questions about the optimal analytical approach. We performed simulations of the performance of association testing under different scenarios that varied genotype frequencies and inheritance models. We show that the SNP-only strategy lacks power under most scenarios when the SNP is located within a CNV; frequently it is excluded from analysis as it does not pass quality control metrics either because of an increased rate of missing calls or a departure from fitness for Hardy-Weinberg proportion. The CNV-only strategy also lacks power because the association testing depends on the allele which copy number varies. The combined strategy performs well in most of the scenarios. Hence, we advocate the use of this combined strategy when testing for association with SNPs located within CNVs.
Variants of a Thermus aquaticus DNA Polymerase with Increased Selectivity for Applications in Allele- and Methylation-Specific Amplification  [PDF]
Matthias Drum, Ramon Kranaster, Christina Ewald, Rainer Blasczyk, Andreas Marx
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0096640
Abstract: The selectivity of DNA polymerases is crucial for many applications. For example, high discrimination between the extension of matched versus mismatched primer termini is desired for the detection of a single nucleotide variation at a particular locus within the genome. Here we describe the generation of thermostable mutants of the large fragment of Thermus aquaticus DNA polymerase (KlenTaq) with increased mismatch extension selectivity. In contrast to previously reported much less active KlenTaq mutants with mismatch discrimination abilities, many of the herein discovered mutants show conserved wild-type-like high activities. We demonstrate for one mutant containing the single amino acid exchange R660V the suitability for application in allele-specific amplifications directly from whole blood without prior sample purification. Also the suitability of the mutant for methylation specific amplification in the diagnostics of 5-methyl cytosines is demonstrated. Furthermore, the identified mutant supersedes other commercially available enzymes in human leukocyte antigen (HLA) analysis by sequence-specific primed polymerase chain reactions (PCRs).
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