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Sample records for haplotype analysis defined

  1. Haplotype Analysis Discriminates Genetic Risk for DR3-Associated Endocrine Autoimmunity and Helps Define Extreme Risk for Addison’s Disease

    Science.gov (United States)

    Baker, Peter R.; Baschal, Erin E.; Fain, Pam R.; Triolo, Taylor M.; Nanduri, Priyaanka; Siebert, Janet C.; Armstrong, Taylor K.; Babu, Sunanda R.; Rewers, Marian J.; Gottlieb, Peter A.; Barker, Jennifer M.; Eisenbarth, George S.

    2010-01-01

    Context: Multiple autoimmune disorders (e.g. Addison’s disease, type 1 diabetes, celiac disease) are associated with HLA-DR3, but it is likely that alleles of additional genes in linkage disequilibrium with HLA-DRB1 contribute to disease. Objective: The objective of the study was to characterize major histocompatability complex (MHC) haplotypes conferring extreme risk for autoimmune Addison’s disease (AD). Design, Setting, and Participants: Eighty-six 21-hydroxylase autoantibody-positive, nonautoimmune polyendocrine syndrome type 1, Caucasian individuals collected from 1992 to 2009 with clinical AD from 68 families (12 multiplex and 56 simplex) were genotyped for HLA-DRB1, HLA-DQB1, MICA, HLA-B, and HLA-A as well as high density MHC single-nucleotide polymorphism (SNP) analysis for 34. Main Outcome Measures: AD and genotype were measured. Result: Ninety-seven percent of the multiplex individuals had both HLA-DR3 and HLA-B8 vs. 60% of simplex AD patients (P = 9.72 × 10−4) and 13% of general population controls (P = 3.00 × 10−19). The genotype DR3/DR4 with B8 was present in 85% of AD multiplex patients, 24% of simplex patients, and 1.5% of control individuals (P = 4.92 × 10−191). The DR3-B8 haplotype of AD patients had HLA-A1 less often (47%) than controls (81%, P = 7.00 × 10−5) and type 1 diabetes patients (73%, P = 1.93 × 10−3). Analysis of 1228 SNPs across the MHC for individuals with AD revealed a shorter conserved haplotype (3.8) with the loss of the extended conserved 3.8.1 haplotype approximately halfway between HLA-B and HLA-A. Conclusion: Extreme risk for AD, especially in multiplex families, is associated with haplotypic DR3 variants, in particular a portion (3.8) but not all of the conserved 3.8.1 haplotype. PMID:20631027

  2. iHAP – integrated haplotype analysis pipeline for characterizing the haplotype structure of genes

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    Lim Yun Ping

    2006-12-01

    Full Text Available Abstract Background The advent of genotype data from large-scale efforts that catalog the genetic variants of different populations have given rise to new avenues for multifactorial disease association studies. Recent work shows that genotype data from the International HapMap Project have a high degree of transferability to the wider population. This implies that the design of genotyping studies on local populations may be facilitated through inferences drawn from information contained in HapMap populations. Results To facilitate analysis of HapMap data for characterizing the haplotype structure of genes or any chromosomal regions, we have developed an integrated web-based resource, iHAP. In addition to incorporating genotype and haplotype data from the International HapMap Project and gene information from the UCSC Genome Browser Database, iHAP also provides capabilities for inferring haplotype blocks and selecting tag SNPs that are representative of haplotype patterns. These include block partitioning algorithms, block definitions, tag SNP definitions, as well as SNPs to be "force included" as tags. Based on the parameters defined at the input stage, iHAP performs on-the-fly analysis and displays the result graphically as a webpage. To facilitate analysis, intermediate and final result files can be downloaded. Conclusion The iHAP resource, available at http://ihap.bii.a-star.edu.sg, provides a convenient yet flexible approach for the user community to analyze HapMap data and identify candidate targets for genotyping studies.

  3. Analysis of DR4 haplotypes in insulin dependent diabetes (IDD)

    International Nuclear Information System (INIS)

    Monos, D.S.; Radka, S.F.; Zmijewski, C.M.; Kamoun, M.

    1986-01-01

    Population studies indicate that HLA-DR4 is implicated in the susceptibility of IDD. However, biochemical characterization of the serologically defined DR4 haplotype from normal individuals revealed five DR4 and three DQW3 molecular forms. Hence, in this study, they investigated the heterogeneity of the DR4 haplotype, using B-lymphoblastoid cell lines (B-LCL) generated from patients with IDD and seropositive for DR4. Class II molecules, metabolically labeled with 35 S-methionine, were immunoprecipitated with monoclonal antibodies specific for DR(L243), DQ(N297), DQW3(IVD12) or DR and DQ(SG465) and analyzed by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE). The isoelectrofocusing (IEF) conditions employed in this study allow representation only of the DR4 haplotype from either DR3/4 or DR4/4 cell lines. The analysis of six different DR4 haplotypes from seven IDD patients, revealed the presence of two DR4 β and two DQW3 β chains. Three of the six DR4 β haplotypes analyzed shared the same DR4 β chain and three others shared a different one. Additionally five of the six haplotypes shared a different one. Additionally five of the six haplotypes shared the same DQW3 β chain and only one was carrying a different one. Different combinations of the two DR4 and two DQW3 β chains constitute three distinct patterns of DR4 haplotypes. These results suggest the prevalence of a DQW3 β chain in the small sample of IDD patients studied. Studies of a large number of patients should clarify whether IDD is associated with unique variants of DR4 or DQW3 β chains

  4. Deletion mutant defines DQ beta variants with DR4 positive DQw3 positive haplotypes

    International Nuclear Information System (INIS)

    Nepom, B.S.; Kim, S.J.; Nepom, G.T.

    1986-01-01

    We describe the production of an HLA deletion mutation by radiation mutagenesis of a DR4- and DQw3-homozygous, Dw4- and Dw14-heterozygous cell line designed to analyze polymorphisms associated with DR4 and DQw3. Southern blot analysis confirms a deletion of class I and class II genes on one haplotype. Variation in DQ beta alleles associated with DQw3 was previously described by characteristic RFLP patterns for a DQ beta bene. One pattern, which correlated precisely with A-10-83 monoclonal antibody reactivity (TA10), defined an allele which we call DQ''3.1''. The mutant cell line has lost the polymorphic bands on Southern blots corresponding to the DQ''3.1'' allele, while the intact Dw14 haplotype retains the alternate allele at DQ beta which is DQw-3 positive. TA10-negative. These data demonstrate the segregation of two DQw3 positive DQ beta allelic variants, both associated with DR4, which can be distinguished on the basis of both RFLP and monoclonal antibody reactivity

  5. Genome-wide haplotype analysis of cis expression quantitative trait loci in monocytes.

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    Sophie Garnier

    Full Text Available In order to assess whether gene expression variability could be influenced by several SNPs acting in cis, either through additive or more complex haplotype effects, a systematic genome-wide search for cis haplotype expression quantitative trait loci (eQTL was conducted in a sample of 758 individuals, part of the Cardiogenics Transcriptomic Study, for which genome-wide monocyte expression and GWAS data were available. 19,805 RNA probes were assessed for cis haplotypic regulation through investigation of ~2,1 × 10(9 haplotypic combinations. 2,650 probes demonstrated haplotypic p-values >10(4-fold smaller than the best single SNP p-value. Replication of significant haplotype effects were tested for 412 probes for which SNPs (or proxies that defined the detected haplotypes were available in the Gutenberg Health Study composed of 1,374 individuals. At the Bonferroni correction level of 1.2 × 10(-4 (~0.05/412, 193 haplotypic signals replicated. 1000 G imputation was then conducted, and 105 haplotypic signals still remained more informative than imputed SNPs. In-depth analysis of these 105 cis eQTL revealed that at 76 loci genetic associations were compatible with additive effects of several SNPs, while for the 29 remaining regions data could be compatible with a more complex haplotypic pattern. As 24 of the 105 cis eQTL have previously been reported to be disease-associated loci, this work highlights the need for conducting haplotype-based and 1000 G imputed cis eQTL analysis before commencing functional studies at disease-associated loci.

  6. Analysis of Multiallelic CNVs by Emulsion Haplotype Fusion PCR.

    Science.gov (United States)

    Tyson, Jess; Armour, John A L

    2017-01-01

    Emulsion-fusion PCR recovers long-range sequence information by combining products in cis from individual genomic DNA molecules. Emulsion droplets act as very numerous small reaction chambers in which different PCR products from a single genomic DNA molecule are condensed into short joint products, to unite sequences in cis from widely separated genomic sites. These products can therefore provide information about the arrangement of sequences and variants at a larger scale than established long-read sequencing methods. The method has been useful in defining the phase of variants in haplotypes, the typing of inversions, and determining the configuration of sequence variants in multiallelic CNVs. In this description we outline the rationale for the application of emulsion-fusion PCR methods to the analysis of multiallelic CNVs, and give practical details for our own implementation of the method in that context.

  7. Founder haplotype analysis of Fanconi anemia in the Korean population finds common ancestral haplotypes for a FANCG variant.

    Science.gov (United States)

    Park, Joonhong; Kim, Myungshin; Jang, Woori; Chae, Hyojin; Kim, Yonggoo; Chung, Nack-Gyun; Lee, Jae-Wook; Cho, Bin; Jeong, Dae-Chul; Park, In Yang; Park, Mi Sun

    2015-05-01

    A common ancestral haplotype is strongly suggested in the Korean and Japanese patients with Fanconi anemia (FA), because common mutations have been frequently found: c.2546delC and c.3720_3724delAAACA of FANCA; c.307+1G>C, c.1066C>T, and c.1589_1591delATA of FANCG. Our aim in this study was to investigate the origin of these common mutations of FANCA and FANCG. We genotyped 13 FA patients consisting of five FA-A patients and eight FA-G patients from the Korean FA population. Microsatellite markers used for haplotype analysis included four CA repeat markers which are closely linked with FANCA and eight CA repeat markers which are contiguous with FANCG. As a result, Korean FA-A patients carrying c.2546delC or c.3720_3724delAAACA did not share the same haplotypes. However, three unique haplotypes carrying c.307+1G>C, c.1066C > T, or c.1589_1591delATA, that consisted of eight polymorphic loci covering a flanking region were strongly associated with Korean FA-G, consistent with founder haplotypes reported previously in the Japanese FA-G population. Our finding confirmed the common ancestral haplotypes on the origins of the East Asian FA-G patients, which will improve our understanding of the molecular population genetics of FA-G. To the best of our knowledge, this is the first report on the association between disease-linked mutations and common ancestral haplotypes in the Korean FA population. © 2015 John Wiley & Sons Ltd/University College London.

  8. Haplotype association analysis of human disease traits using genotype data of unrelated individuals

    DEFF Research Database (Denmark)

    Tan, Qihua; Christiansen, Lene; Christensen, Kaare

    2005-01-01

    unphased multi-locus genotype data, ranging from the early approach by the simple gene-counting method to the recent work using the generalized linear model. However, these methods are either confined to case – control design or unable to yield unbiased point and interval estimates of haplotype effects....... Based on the popular logistic regression model, we present a new approach for haplotype association analysis of human disease traits. Using haplotype-based parameterization, our model infers the effects of specific haplotypes (point estimation) and constructs confidence interval for the risks...... on the well-known logistic regression model is a useful tool for haplotype association analysis of human disease traits....

  9. Haplotype analysis and linkage disequilibrium for DGAT1

    OpenAIRE

    Strucken, Eva M.; Rahmatalla, Siham; De Koning, Dirk-Jan; Brockmann, Gudrun A.

    2010-01-01

    This study focused on haplotype effects and linkage disequilibrium (LD) for the K232A locus and the promoter VNTR in the DGAT1 gene. Analyses were carried out in three German Holstein Frisian populations (including 492, 305, and 518 animals) for milk yield, milk fat and protein yield, and milk fat and protein content. We found that effects of the promoter VNTR were not significant and explain only a small amount of the variation of the QTL on BTA14. Haplotype effects were less significant tha...

  10. Mutation Analysis in Classical Phenylketonuria Patients Followed by Detecting Haplotypes Linked to Some PAH Mutations.

    Science.gov (United States)

    Dehghanian, Fatemeh; Silawi, Mohammad; Tabei, Seyed M B

    2017-02-01

    Deficiency of phenylalanine hydroxylase (PAH) enzyme and elevation of phenylalanine in body fluids cause phenylketonuria (PKU). The gold standard for confirming PKU and PAH deficiency is detecting causal mutations by direct sequencing of the coding exons and splicing involved sequences of the PAH gene. Furthermore, haplotype analysis could be considered as an auxiliary approach for detecting PKU causative mutations before direct sequencing of the PAH gene by making comparisons between prior detected mutation linked-haplotypes and new PKU case haplotypes with undetermined mutations. In this study, 13 unrelated classical PKU patients took part in the study detecting causative mutations. Mutations were identified by polymerase chain reaction (PCR) and direct sequencing in all patients. After that, haplotype analysis was performed by studying VNTR and PAHSTR markers (linked genetic markers of the PAH gene) through application of PCR and capillary electrophoresis (CE). Mutation analysis was performed successfully and the detected mutations were as follows: c.782G>A, c.754C>T, c.842C>G, c.113-115delTCT, c.688G>A, and c.696A>G. Additionally, PAHSTR/VNTR haplotypes were detected to discover haplotypes linked to each mutation. Mutation detection is the best approach for confirming PAH enzyme deficiency in PKU patients. Due to the relatively large size of the PAH gene and high cost of the direct sequencing in developing countries, haplotype analysis could be used before DNA sequencing and mutation detection for a faster and cheaper way via identifying probable mutated exons.

  11. Analysis of SNPs and haplotypes in vitamin D pathway genes and renal cancer risk.

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    Sara Karami

    2009-09-01

    Full Text Available In the kidney vitamin D is converted to its active form. Since vitamin D exerts its activity through binding to the nuclear vitamin D receptor (VDR, most genetic studies have primarily focused on variation within this gene. Therefore, analysis of genetic variation in VDR and other vitamin D pathway genes may provide insight into the role of vitamin D in renal cell carcinoma (RCC etiology. RCC cases (N = 777 and controls (N = 1,035 were genotyped to investigate the relationship between RCC risk and variation in eight target genes. Minimum-p-value permutation (Min-P tests were used to identify genes associated with risk. A three single nucleotide polymorphism (SNP sliding window was used to identify chromosomal regions with a False Discovery Rate of <10%, where subsequently, haplotype relative risks were computed in Haplostats. Min-P values showed that VDR (p-value = 0.02 and retinoid-X-receptor-alpha (RXRA (p-value = 0.10 were associated with RCC risk. Within VDR, three haplotypes across two chromosomal regions of interest were identified. The first region, located within intron 2, contained two haplotypes that increased RCC risk by approximately 25%. The second region included a haplotype (rs2239179, rs12717991 across intron 4 that increased risk among participants with the TC (OR = 1.31, 95% CI = 1.09-1.57 haplotype compared to participants with the common haplotype, TT. Across RXRA, one haplotype located 3' of the coding sequence (rs748964, rs3118523, increased RCC risk 35% among individuals with the variant haplotype compared to those with the most common haplotype. This study comprehensively evaluated genetic variation across eight vitamin D pathway genes in relation to RCC risk. We found increased risk associated with VDR and RXRA. Replication studies are warranted to confirm these findings.

  12. Cluster analysis of European Y-chromosomal STR haplotypes using the discrete Laplace method

    DEFF Research Database (Denmark)

    Andersen, Mikkel Meyer; Eriksen, Poul Svante; Morling, Niels

    2014-01-01

    The European Y-chromosomal short tandem repeat (STR) haplotype distribution has previously been analysed in various ways. Here, we introduce a new way of analysing population substructure using a new method based on clustering within the discrete Laplace exponential family that models the probabi......The European Y-chromosomal short tandem repeat (STR) haplotype distribution has previously been analysed in various ways. Here, we introduce a new way of analysing population substructure using a new method based on clustering within the discrete Laplace exponential family that models...... the probability distribution of the Y-STR haplotypes. Creating a consistent statistical model of the haplotypes enables us to perform a wide range of analyses. Previously, haplotype frequency estimation using the discrete Laplace method has been validated. In this paper we investigate how the discrete Laplace...... method can be used for cluster analysis to further validate the discrete Laplace method. A very important practical fact is that the calculations can be performed on a normal computer. We identified two sub-clusters of the Eastern and Western European Y-STR haplotypes similar to results of previous...

  13. Hemoglobin Constant Spring among Southeast Asian Populations: Haplotypic Heterogeneities and Phylogenetic Analysis.

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    Wittaya Jomoui

    Full Text Available Hemoglobin Constant Spring (Hb CS is an abnormal Hb caused by a mutation at the termination codon of α2-globin gene found commonly among Southeast Asian and Chinese people. Association of Hb CS with α°-thalassemia leads to a thalassemia intermedia syndrome commonly encountered in the region. We report chromosome background and addressed genetic origins of Hb CS observed in a large cohort of Hb CS among Southeast Asian populations.A study was done on 102 Vietnamese (aged 15-49 year-old and 40 Laotian (aged 18-39 year-old subjects with Hb CS and results compared with 120 Hb CS genes in Thailand. Hematological parameters were recorded and Hb analysis was performed using capillary electrophoresis. Hb CS mutation and thalassemia genotypes were defined by DNA analysis. Six DNA polymorphisms within α-globin gene cluster including 5'Xba I, Bgl I, Inter-zeta HVR, AccI, RsaI and αPstI 3', were determined using PCR-RFLP assay.Nine different genotypes of Hb CS were observed. In contrast to the Thai Hb CS alleles which are mostly linked to haplotype (+-S + + -, most of the Vietnamese and the Laotian Hb CS genes were associated with haplotype (+-M + + -, both of which are different from that of the European Hb CS.Hb CS is commonly found in combination with other thalassemias among Southeast Asian populations. Accurate genotyping of the cases requires both hematologic and DNA analyses. At least two independent origins are associated with the Hb CS gene which could indirectly explain the high prevalence of this Hb variant in the region.

  14. Analysis of Molecular Variance Inferred from Metric Distances among DNA Haplotypes: Application to Human Mitochondrial DNA Restriction Data

    OpenAIRE

    Excoffier, L.; Smouse, P. E.; Quattro, J. M.

    1992-01-01

    We present here a framework for the study of molecular variation within a single species. Information on DNA haplotype divergence is incorporated into an analysis of variance format, derived from a matrix of squared-distances among all pairs of haplotypes. This analysis of molecular variance (AMOVA) produces estimates of variance components and F-statistic analogs, designated here as φ-statistics, reflecting the correlation of haplotypic diversity at different levels of hierarchical subdivisi...

  15. Analysis of polymorphisms and haplotype structure of the human thymidylate synthase genetic region: a tool for pharmacogenetic studies.

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    Soma Ghosh

    Full Text Available 5-Fluorouracil (5FU, a widely used chemotherapeutic drug, inhibits the DNA replicative enzyme, thymidylate synthase (Tyms. Prior studies implicated a VNTR (variable numbers of tandem repeats polymorphism in the 5'-untranslated region (5'-UTR of the TYMS gene as a determinant of Tyms expression in tumors and normal tissues and proposed that these VNTR genotypes could help decide fluoropyrimidine dosing. Clinical associations between 5FU-related toxicity and the TYMS VNTR were reported, however, results were inconsistent, suggesting that additional genetic variation in the TYMS gene might influence Tyms expression. We thus conducted a detailed genetic analysis of this region, defining new polymorphisms in this gene including mononucleotide (poly A:T repeats and novel single nucleotide polymorphisms (SNPs flanking the VNTR in the TYMS genetic region. Our haplotype analysis of this region used data from both established and novel genetic variants and found nine SNP haplotypes accounting for more than 90% of the studied population. We observed non-exclusive relationships between the VNTR and adjacent SNP haplotypes, such that each type of VNTR commonly occurred on several haplotype backgrounds. Our results confirmed the expectation that the VNTR alleles exhibit homoplasy and lack the common ancestry required for a reliable marker of a linked adjacent locus that might govern toxicity. We propose that it may be necessary in a clinical trial to assay multiple types of genetic polymorphisms in the TYMS region to meaningfully model linkage of genetic markers to 5FU-related toxicity. The presence of multiple long (up to 26 nt, polymorphic monothymidine repeats in the promoter region of the sole human thymidylate synthetic enzyme is intriguing.

  16. Haplotyping, linkage mapping and expression analysis of barley genes regulated by terminal drought stress influencing seed quality

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    Wobus Ulrich

    2011-01-01

    Full Text Available Abstract Background The increasingly narrow genetic background characteristic of modern crop germplasm presents a challenge for the breeding of cultivars that require adaptation to the anticipated change in climate. Thus, high priority research aims at the identification of relevant allelic variation present both in the crop itself as well as in its progenitors. This study is based on the characterization of genetic variation in barley, with a view to enhancing its response to terminal drought stress. Results The expression patterns of drought regulated genes were monitored during plant ontogeny, mapped and the location of these genes was incorporated into a comprehensive barley SNP linkage map. Haplotypes within a set of 17 starch biosynthesis/degradation genes were defined, and a particularly high level of haplotype variation was uncovered in the genes encoding sucrose synthase (types I and II and starch synthase. The ability of a panel of 50 barley accessions to maintain grain starch content under terminal drought conditions was explored. Conclusion The linkage/expression map is an informative resource in the context of characterizing the response of barley to drought stress. The high level of haplotype variation among starch biosynthesis/degradation genes in the progenitors of cultivated barley shows that domestication and breeding have greatly eroded their allelic diversity in current elite cultivars. Prospective association analysis based on core drought-regulated genes may simplify the process of identifying favourable alleles, and help to understand the genetic basis of the response to terminal drought.

  17. Polymorphism screening and haplotype analysis of the tryptophan hydroxylase gene (TPH1 and association with bipolar affective disorder in Taiwan

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    Lin Yi-Mei J

    2005-03-01

    Full Text Available Abstract Background Disturbances in serotonin neurotransmission are implicated in the etiology of many psychiatric disorders, including bipolar affective disorder (BPD. The tryptophan hydroxylase gene (TPH, which codes for the enzyme catalyzing the rate-limiting step in serotonin biosynthetic pathway, is one of the leading candidate genes for psychiatric and behavioral disorders. In a preliminary study, we found that TPH1 intron7 A218C polymorphism was associated with BPD. This study was designed to investigate sequence variants of the TPH1 gene in Taiwanese and to test whether the TPH1 gene is a susceptibility factor for the BPD. Methods Using a systematic approach, we have searched the exons and promoter region of the TPH1 gene for sequence variants in Taiwanese Han and have identified five variants, A-1067G, G-347T, T3804A, C27224T, and A27237G. These five variants plus another five taken from the literature and a public database were examined for an association in 108 BPD patients and 103 controls; no association was detected for any of the 10 variants. Results Haplotype constructions using these 10 SNPs showed that the 3 most common haplotypes in both patients and controls were identical. One of the fourth common haplotype in the patient group (i.e. GGGAGACCCA was unique and showed a trend of significance with the disease (P = 0.028. However, the significance was abolished after Bonferroni correction thus suggesting the association is weak. In addition, three haplotype-tagged SNPs (htSNPs were selected to represent all haplotypes with frequencies larger than 2% in the Taiwanese Han population. The defined TPH1 htSNPs significantly reduce the marker number for haplotype analysis thus provides useful information for future association studies in our population. Conclusion Results of this study did not support the role of TPH1 gene in BPD etiology. As the current studies found the TPH1 gene under investigation belongs to the peripheral

  18. SNP and haplotype analysis reveal IGF2 variants associated with growth traits in Chinese Qinchuan cattle.

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    Huang, Yong-Zhen; Zhan, Zhao-Yang; Li, Xin-Yi; Wu, Sheng-Ru; Sun, Yu-Jia; Xue, Jing; Lan, Xian-Yong; Lei, Chu-Zhao; Zhang, Chun-Lei; Jia, Yu-Tang; Chen, Hong

    2014-02-01

    Insulin-like growth factor 2 (IGF2) is a potent cell growth and differentiation factor and is implicated in mammals' growth and development. The objective of this study was to evaluate the effects of the mutations in the bovine IGF2 with growth traits in Chinese Qinchuan cattle. Four single nucleotide polymorphisms (SNPs) were detected of the bovine IGF2 by DNA pool sequencing and forced polymerase chain reaction-restriction fragment length polymorphism (forced PCR-RFLP) methods. We also investigated haplotype structure and linkage disequilibrium (LD) coefficients for four SNPs in 817 individuals representing two main cattle breeds from China. The result of haplotype analysis showed eight different haplotypes and 27 combined genotypes within the study population. The statistical analyses indicated that the four SNPs, combined genotypes and haplotypes are associated with the withers height, body length, chest breadth, chest depth and body weight in Qinchuan cattle population (P growth traits; the heterozygote diplotype was associated with higher growth traits compared to wild-type homozygote. Our results provide evidence that polymorphisms in the IGF2 gene are associated with growth traits, and may be used for marker-assisted selection in beef cattle breeding program.

  19. The analysis of APOL1 genetic variation and haplotype diversity provided by 1000 Genomes project.

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    Peng, Ting; Wang, Li; Li, Guisen

    2017-08-11

    The APOL1 gene variants has been shown to be associated with an increased risk of multiple kinds of diseases, particularly in African Americans, but not in Caucasians and Asians. In this study, we explored the single nucleotide polymorphism (SNP) and haplotype diversity of APOL1 gene in different races provided by 1000 Genomes project. Variants of APOL1 gene in 1000 Genome Project were obtained and SNPs located in the regulatory region or coding region were selected for genetic variation analysis. Total 2504 individuals from 26 populations were classified as four groups that included Africa, Europe, Asia and Admixed populations. Tag SNPs were selected to evaluate the haplotype diversities in the four populations by HaploStats software. APOL1 gene was surrounded by some of the most polymorphic genes in the human genome, variation of APOL1 gene was common, with up to 613 SNP (1000 Genome Project reported) and 99 of them (16.2%) with MAF ≥ 1%. There were 79 SNPs in the URR and 92 SNPs in 3'UTR. Total 12 SNPs in URR and 24 SNPs in 3'UTR were considered as common variants with MAF ≥ 1%. It is worth noting that URR-1 was presents lower frequencies in European populations, while other three haplotypes taken an opposite pattern; 3'UTR presents several high-frequency variation sites in a short segment, and the differences of its haplotypes among different population were significant (P < 0.01), UTR-1 and UTR-5 presented much higher frequency in African population, while UTR-2, UTR-3 and UTR-4 were much lower. APOL1 coding region showed that two SNP of G1 with higher frequency are actually pull down the haplotype H-1 frequency when considering all populations pooled together, and the diversity among the four populations be widen by the G1 two mutation (P 1  = 3.33E-4 vs P 2  = 3.61E-30). The distributions of APOL1 gene variants and haplotypes were significantly different among the different populations, in either regulatory or coding regions. It could provide

  20. Analysis of Case-Control Association Studies: SNPs, Imputation and Haplotypes

    KAUST Repository

    Chatterjee, Nilanjan

    2009-11-01

    Although prospective logistic regression is the standard method of analysis for case-control data, it has been recently noted that in genetic epidemiologic studies one can use the "retrospective" likelihood to gain major power by incorporating various population genetics model assumptions such as Hardy-Weinberg-Equilibrium (HWE), gene-gene and gene-environment independence. In this article we review these modern methods and contrast them with the more classical approaches through two types of applications (i) association tests for typed and untyped single nucleotide polymorphisms (SNPs) and (ii) estimation of haplotype effects and haplotype-environment interactions in the presence of haplotype-phase ambiguity. We provide novel insights to existing methods by construction of various score-tests and pseudo-likelihoods. In addition, we describe a novel two-stage method for analysis of untyped SNPs that can use any flexible external algorithm for genotype imputation followed by a powerful association test based on the retrospective likelihood. We illustrate applications of the methods using simulated and real data. © Institute of Mathematical Statistics, 2009.

  1. Analysis of Case-Control Association Studies: SNPs, Imputation and Haplotypes

    KAUST Repository

    Chatterjee, Nilanjan; Chen, Yi-Hau; Luo, Sheng; Carroll, Raymond J.

    2009-01-01

    Although prospective logistic regression is the standard method of analysis for case-control data, it has been recently noted that in genetic epidemiologic studies one can use the "retrospective" likelihood to gain major power by incorporating various population genetics model assumptions such as Hardy-Weinberg-Equilibrium (HWE), gene-gene and gene-environment independence. In this article we review these modern methods and contrast them with the more classical approaches through two types of applications (i) association tests for typed and untyped single nucleotide polymorphisms (SNPs) and (ii) estimation of haplotype effects and haplotype-environment interactions in the presence of haplotype-phase ambiguity. We provide novel insights to existing methods by construction of various score-tests and pseudo-likelihoods. In addition, we describe a novel two-stage method for analysis of untyped SNPs that can use any flexible external algorithm for genotype imputation followed by a powerful association test based on the retrospective likelihood. We illustrate applications of the methods using simulated and real data. © Institute of Mathematical Statistics, 2009.

  2. Application of the Linux cluster for exhaustive window haplotype analysis using the FBAT and Unphased programs.

    Science.gov (United States)

    Mishima, Hiroyuki; Lidral, Andrew C; Ni, Jun

    2008-05-28

    Genetic association studies have been used to map disease-causing genes. A newly introduced statistical method, called exhaustive haplotype association study, analyzes genetic information consisting of different numbers and combinations of DNA sequence variations along a chromosome. Such studies involve a large number of statistical calculations and subsequently high computing power. It is possible to develop parallel algorithms and codes to perform the calculations on a high performance computing (HPC) system. However, most existing commonly-used statistic packages for genetic studies are non-parallel versions. Alternatively, one may use the cutting-edge technology of grid computing and its packages to conduct non-parallel genetic statistical packages on a centralized HPC system or distributed computing systems. In this paper, we report the utilization of a queuing scheduler built on the Grid Engine and run on a Rocks Linux cluster for our genetic statistical studies. Analysis of both consecutive and combinational window haplotypes was conducted by the FBAT (Laird et al., 2000) and Unphased (Dudbridge, 2003) programs. The dataset consisted of 26 loci from 277 extended families (1484 persons). Using the Rocks Linux cluster with 22 compute-nodes, FBAT jobs performed about 14.4-15.9 times faster, while Unphased jobs performed 1.1-18.6 times faster compared to the accumulated computation duration. Execution of exhaustive haplotype analysis using non-parallel software packages on a Linux-based system is an effective and efficient approach in terms of cost and performance.

  3. Spatial and temporal distribution of the neutral polymorphisms in the last ZFX intron: analysis of the haplotype structure and genealogy.

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    Jaruzelska, J; Zietkiewicz, E; Batzer, M; Cole, D E; Moisan, J P; Scozzari, R; Tavaré, S; Labuda, D

    1999-07-01

    With 10 segregating sites (simple nucleotide polymorphisms) in the last intron (1089 bp) of the ZFX gene we have observed 11 haplotypes in 336 chromosomes representing a worldwide array of 15 human populations. Two haplotypes representing 77% of all chromosomes were distributed almost evenly among four continents. Five of the remaining haplotypes were detected in Africa and 4 others were restricted to Eurasia and the Americas. Using the information about the ancestral state of the segregating positions (inferred from human-great ape comparisons), we applied coalescent analysis to estimate the age of the polymorphisms and the resulting haplotypes. The oldest haplotype, with the ancestral alleles at all the sites, was observed at low frequency only in two groups of African origin. Its estimated age of 740 to 1100 kyr corresponded to the time to the most recent common ancestor. The two most frequent worldwide distributed haplotypes were estimated at 550 to 840 and 260 to 400 kyr, respectively, while the age of the continentally restricted polymorphisms was 120 to 180 kyr and smaller. Comparison of spatial and temporal distribution of the ZFX haplotypes suggests that modern humans diverged from the common ancestral stock in the Middle Paleolithic era. Subsequent range expansion prevented substantial gene flow among continents, separating African groups from populations that colonized Eurasia and the New World.

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

    Science.gov (United States)

    Ma, Jennie Z; Beuten, Joke; Payne, Thomas J; Dupont, Randolph T; Elston, Robert C; Li, Ming D

    2005-06-15

    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.

  5. KIR And HLA Haplotype Analysis in a Family Lacking The KIR 2DL1-2DP1 Genes

    Directory of Open Access Journals (Sweden)

    Vojvodić Svetlana

    2015-06-01

    Full Text Available The killer cell immunoglobulin-like receptor (KIR gene cluster exhibits extensive allelic and haplotypic diversity that is observed as presence/absence of genes, resulting in expansion and contraction of KIR haplotypes and by allelic variation of individual KIR genes. We report a case of KIR pseudogene 2DP1 and 2DL1 gene absence in members of one family with the children suffering from acute myelogenous leukemia (AML. Killer cell immunoglo-bulin-like receptor low resolution genotyping was performed by the polymerase chain reaction (PCR-sequencespecific primers (SSP/sequence-specific oligonucleotide (SSO method and haplotype assignment was done by gene content analysis. Both parents and the maternal grandfather, shared the same Cen-B2 KIR haplotype, containing KIR 3DL3, -2DS2, -2DL2 and -3DP1 genes. The second haplotype in the KIR genotype of the mother and grandfather was Tel-A1 with KIR 2DL4 (normal and deleted variant, -3DL1, -22 bp deletion variant of the 2DS4 gene and -3DL2, while the second haplotype in the KIR genotype of the father was Tel-B1 with 2DL4 (normal variant, -3DS1, -2DL5, -2DS5, -2DS1 and 3DL2 genes. Haplotype analysis in all three offsprings revealed that the children inherited the Cen-B2 haplotype with the same gene content but two of the children inherited a deleted variant of the 2DL4 gene, while the third child inherited a normal one. The second haplotype of all three offspring contained KIR 2DL4, -2DL5, -2DS1, -2DS4 (del 22bp variant, -2DS5, -3DL1 and -3DL2 genes, which was the basis of the assumption that there is a hybrid haplotype and that the present 3DL1 gene is a variant of the 3DS1 gene. Due to consanguinity among the ancestors, the results of KIR segregation analysis showed the existence of a very rare KIR genotype in the offspring. The family who is the subject of this case is even more interesting because the father was 10/10 human leukocyte antigen (HLA-matched to his daughter, all members of the family have

  6. Haplotype Analysis of the Pre-harvest Sprouting Resistance Locus Phs-A1 Reveals a Causal Role of TaMKK3-A in Global Germplasm.

    Science.gov (United States)

    Shorinola, Oluwaseyi; Balcárková, Barbara; Hyles, Jessica; Tibbits, Josquin F G; Hayden, Matthew J; Holušova, Katarina; Valárik, Miroslav; Distelfeld, Assaf; Torada, Atsushi; Barrero, Jose M; Uauy, Cristobal

    2017-01-01

    Pre-harvest sprouting (PHS) is an important cause of quality loss in many cereal crops and is particularly prevalent and damaging in wheat. Resistance to PHS is therefore a valuable target trait in many breeding programs. The Phs-A1 locus on wheat chromosome arm 4AL has been consistently shown to account for a significant proportion of natural variation to PHS in diverse mapping populations. However, the deployment of sprouting resistance is confounded by the fact that different candidate genes, including the tandem duplicated Plasma Membrane 19 ( PM19 ) genes and the mitogen-activated protein kinase kinase 3 ( TaMKK3-A) gene, have been proposed to underlie Phs-A1 . To further define the Phs-A1 locus, we constructed a physical map across this interval in hexaploid and tetraploid wheat. We established close proximity of the proposed candidate genes which are located within a 1.2 Mb interval. Genetic characterization of diverse germplasm used in previous genetic mapping studies suggests that TaMKK3-A , and not PM19 , is the major gene underlying the Phs-A1 effect in European, North American, Australian and Asian germplasm. We identified the non-dormant TaMKK3-A allele at low frequencies within the A-genome diploid progenitor Triticum urartu genepool, and show an increase in the allele frequency in modern varieties. In United Kingdom varieties, the frequency of the dormant TaMKK3-A allele was significantly higher in bread-making quality varieties compared to feed and biscuit-making cultivars. Analysis of exome capture data from 58 diverse hexaploid wheat accessions identified fourteen haplotypes across the extended Phs-A1 locus and four haplotypes for TaMKK3-A . Analysis of these haplotypes in a collection of United Kingdom and Australian cultivars revealed distinct major dormant and non-dormant Phs-A1 haplotypes in each country, which were either rare or absent in the opposing germplasm set. The diagnostic markers and haplotype information reported in the study will

  7. Haplotype Analysis of the Pre-harvest Sprouting Resistance Locus Phs-A1 Reveals a Causal Role of TaMKK3-A in Global Germplasm

    Directory of Open Access Journals (Sweden)

    Oluwaseyi Shorinola

    2017-09-01

    Full Text Available Pre-harvest sprouting (PHS is an important cause of quality loss in many cereal crops and is particularly prevalent and damaging in wheat. Resistance to PHS is therefore a valuable target trait in many breeding programs. The Phs-A1 locus on wheat chromosome arm 4AL has been consistently shown to account for a significant proportion of natural variation to PHS in diverse mapping populations. However, the deployment of sprouting resistance is confounded by the fact that different candidate genes, including the tandem duplicated Plasma Membrane 19 (PM19 genes and the mitogen-activated protein kinase kinase 3 (TaMKK3-A gene, have been proposed to underlie Phs-A1. To further define the Phs-A1 locus, we constructed a physical map across this interval in hexaploid and tetraploid wheat. We established close proximity of the proposed candidate genes which are located within a 1.2 Mb interval. Genetic characterization of diverse germplasm used in previous genetic mapping studies suggests that TaMKK3-A, and not PM19, is the major gene underlying the Phs-A1 effect in European, North American, Australian and Asian germplasm. We identified the non-dormant TaMKK3-A allele at low frequencies within the A-genome diploid progenitor Triticum urartu genepool, and show an increase in the allele frequency in modern varieties. In United Kingdom varieties, the frequency of the dormant TaMKK3-A allele was significantly higher in bread-making quality varieties compared to feed and biscuit-making cultivars. Analysis of exome capture data from 58 diverse hexaploid wheat accessions identified fourteen haplotypes across the extended Phs-A1 locus and four haplotypes for TaMKK3-A. Analysis of these haplotypes in a collection of United Kingdom and Australian cultivars revealed distinct major dormant and non-dormant Phs-A1 haplotypes in each country, which were either rare or absent in the opposing germplasm set. The diagnostic markers and haplotype information reported in the

  8. Haplotype analysis of common variants in the BRCA1 gene and risk of sporadic breast cancer

    International Nuclear Information System (INIS)

    Cox, David G; Kraft, Peter; Hankinson, Susan E; Hunter, David J

    2005-01-01

    Truncation mutations in the BRCA1 gene cause a substantial increase in risk of breast cancer. However, these mutations are rare in the general population and account for little of the overall incidence of sporadic breast cancer. We used whole-gene resequencing data to select haplotype tagging single nucleotide polymorphisms, and examined the association between common haplotypes of BRCA1 and breast cancer in a nested case-control study in the Nurses' Health Study (1323 cases and 1910 controls). One haplotype was associated with a slight increase in risk (odds ratio 1.18, 95% confidence interval 1.02–1.37). A significant interaction (P = 0.05) was seen between this haplotype, positive family history of breast cancer, and breast cancer risk. Although not statistically significant, similar interactions were observed with age at diagnosis and with menopausal status at diagnosis; risk tended to be higher among younger, pre-menopausal women. We have described a haplotype in the BRCA1 gene that was associated with an approximately 20% increase in risk of sporadic breast cancer in the general population. However, the functional variant(s) responsible for the association are unclear

  9. Haplotype defined by the MLH1-93G/A polymorphism is associated with MLH1 promoter hypermethylation in sporadic colorectal cancers.

    Science.gov (United States)

    Miyakura, Yasuyuki; Tahara, Makiko; Lefor, Alan T; Yasuda, Yoshikazu; Sugano, Kokichi

    2014-11-24

    Methylation of the MLH1 promoter region has been suggested to be a major mechanism of gene inactivation in sporadic microsatellite instability-positive (MSI-H) colorectal cancers (CRCs). Recently, single-nucleotide polymorphism (SNP) in the MLH1 promoter region (MLH1-93G/A; rs1800734) has been proposed to be associated with MLH1 promoter methylation, loss of MLH1 protein expression and MSI-H tumors. We examined the association of MLH1-93G/A and six other SNPs surrounding MLH1-93G/A with the methylation status in 210 consecutive sporadic CRCs in Japanese patients. Methylation of the MLH1 promoter region was evaluated by Na-bisulfite polymerase chain reaction (PCR)/single-strand conformation polymorphism (SSCP) analysis. The genotype frequencies of SNPs located in the 54-kb region surrounding the MLH1-93G/A SNP were examined by SSCP analysis. Methylation of the MLH1 promoter region was observed in 28.6% (60/210) of sporadic CRCs. The proportions of MLH1-93G/A genotypes A/A, A/G and G/G were 26% (n=54), 51% (n=108) and 23% (n=48), respectively, and they were significantly associated with the methylation status (p=0.01). There were no significant associations between genotype frequency of the six other SNPs and methylation status. The A-allele of MLH1-93G/A was more common in cases with methylation than the G-allele (p=0.0094), especially in females (p=0.0067). In logistic regression, the A/A genotype of the MLH1-93G/A SNP was shown to be the most significant risk factor for methylation of the MLH1 promoter region (odds ratio 2.82, p=0.003). Furthermore, a haplotype of the A-allele of rs2276807 located -47 kb upstream from the MLH1-93G/A SNP and the A-allele of MLH1-93G/A SNP was significantly associated with MLH1 promoter methylation. These results indicate that individuals, and particularly females, carrying the A-allele at the MLH1-93G/A SNP, especially in association with the A-allele of rs2276807, may harbor an increased risk of methylation of the MLH1 promoter

  10. Structural insertion/deletion variation in IRF5 is associated with a risk haplotype and defines the precise IRF5 isoforms expressed in systemic lupus erythematosus

    DEFF Research Database (Denmark)

    Kozyrev, Sergey V; Lewén, Susanna; Reddy, Prasad M V Linga

    2007-01-01

    -alpha. The SNP most strongly associated with SLE was SNP no. rs2070197 (P=5.2x10(-11)), which is a proxy of the risk haplotype, but does not appear to be functional. CONCLUSION: None of the functional variants investigated in this study is strongly associated with SLE, with the exception of the exon 1B donor......OBJECTIVE: To determine whether specific isoforms of IRF5 are transcribed in patients with systemic lupus erythematosus (SLE) who have risk genotypes in the exon 1B donor splice site at single-nucleotide polymorphism (SNP) no. rs2004640. METHODS: Peripheral blood mononuclear cells were obtained...... interaction domain. The insertion segregates in the risk haplotype with the high expression allele of a poly(A) site SNP no. rs10954213 and the exon 1B donor splice allele of the 5'-UTR SNP no. rs2004640. The poly(A) polymorphism correlated with levels of IRF5 in cells stimulated with interferon...

  11. Deletion analysis of male sterility effects of t-haplotypes in the mouse.

    Science.gov (United States)

    Bennett, D; Artzt, K

    1990-01-01

    We present data on the effects of three chromosome 17 deletions on transmission ratio distortion (TRD) and sterility of several t-haplotypes. All three deletions have similar effects on male TRD: that is, Tdel/tcomplete genotypes all transmit their t-haplotype in very high proportion. However, each deletion has different effects on sterility of heterozygous males, with TOr/t being fertile, Thp/t less fertile, and TOrl/t still less fertile. These data suggest that wild-type genes on chromosomes homologous to t-haplotypes can be important regulators of both TRD and fertility in males, and that the wild-type genes concerned with TRD and fertility are at least to some extent different. The data also provide a rough map of the positions of these genes.

  12. Haplotype analysis and a novel allele-sharing method refines a chromosome 4p locus linked to bipolar affective disorder.

    Science.gov (United States)

    Le Hellard, Stephanie; Lee, Andrew J; Underwood, Sarah; Thomson, Pippa A; Morris, Stewart W; Torrance, Helen S; Anderson, Susan M; Adams, Richard R; Navarro, Pau; Christoforou, Andrea; Houlihan, Lorna M; Detera-Wadleigh, Sevilla; Owen, Michael J; Asherson, Philip; Muir, Walter J; Blackwood, Douglas H R; Wray, Naomi R; Porteous, David J; Evans, Kathryn L

    2007-03-15

    Bipolar affective disorder (BPAD) and schizophrenia (SCZ) are common conditions. Their causes are unknown, but they include a substantial genetic component. Previously, we described significant linkage of BPAD to a chromosome 4p locus within a large pedigree (F22). Others subsequently have found evidence for linkage of BPAD and SCZ to this region. We constructed high-resolution haplotypes for four linked families, calculated logarithm of the odds (LOD) scores, and developed a novel method to assess the extent of allele sharing within genes between the families. We describe an increase in the F22 LOD score for this region. Definition and comparison of the linked haplotypes allowed us to prioritize two subregions of 3.8 and 4.4 Mb. Analysis of the extent of allele sharing within these subregions identified 200 kb that shows increased allele sharing between families. Linkage of BPAD to chromosome 4p has been strengthened. Haplotype analysis in the additional linked families refined the 20-Mb linkage region. Development of a novel allele-sharing method allowed us to bridge the gap between conventional linkage and association studies. Description of a 200-kb region of increased allele sharing prioritizes this region, which contains two functional candidate genes for BPAD, SLC2A9, and WDR1, for subsequent studies.

  13. Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus.

    Directory of Open Access Journals (Sweden)

    Christopher G Bell

    2010-11-01

    Full Text Available Recent multi-dimensional approaches to the study of complex disease have revealed powerful insights into how genetic and epigenetic factors may underlie their aetiopathogenesis. We examined genotype-epigenotype interactions in the context of Type 2 Diabetes (T2D, focussing on known regions of genomic susceptibility. We assayed DNA methylation in 60 females, stratified according to disease susceptibility haplotype using previously identified association loci. CpG methylation was assessed using methylated DNA immunoprecipitation on a targeted array (MeDIP-chip and absolute methylation values were estimated using a Bayesian algorithm (BATMAN. Absolute methylation levels were quantified across LD blocks, and we identified increased DNA methylation on the FTO obesity susceptibility haplotype, tagged by the rs8050136 risk allele A (p = 9.40×10(-4, permutation p = 1.0×10(-3. Further analysis across the 46 kb LD block using sliding windows localised the most significant difference to be within a 7.7 kb region (p = 1.13×10(-7. Sequence level analysis, followed by pyrosequencing validation, revealed that the methylation difference was driven by the co-ordinated phase of CpG-creating SNPs across the risk haplotype. This 7.7 kb region of haplotype-specific methylation (HSM, encapsulates a Highly Conserved Non-Coding Element (HCNE that has previously been validated as a long-range enhancer, supported by the histone H3K4me1 enhancer signature. This study demonstrates that integration of Genome-Wide Association (GWA SNP and epigenomic DNA methylation data can identify potential novel genotype-epigenotype interactions within disease-associated loci, thus providing a novel route to aid unravelling common complex diseases.

  14. Haplotype analysis suggest that the MLH1 c.2059C > T mutation is a Swedish founder mutation.

    Science.gov (United States)

    von Salomé, Jenny; Liu, Tao; Keihäs, Markku; Morak, Moni; Holinski-Feder, Elke; Berry, Ian R; Moilanen, Jukka S; Baert-Desurmont, Stéphanie; Lindblom, Annika; Lagerstedt-Robinson, Kristina

    2017-12-29

    Lynch syndrome (LS) predisposes to a spectrum of cancers and increases the lifetime risk of developing colorectal- or endometrial cancer to over 50%. Lynch syndrome is dominantly inherited and is caused by defects in DNA mismatch-repair genes MLH1, MSH2, MSH6 or PMS2, with the vast majority detected in MLH1 and MSH2. Recurrent LS-associated variants observed in apparently unrelated individuals, have either arisen de novo in different families due to mutation hotspots, or are inherited from a founder (a common ancestor) that lived several generations back. There are variants that recur in some populations while also acting as founders in other ethnic groups. Testing for founder mutations can facilitate molecular diagnosis of Lynch Syndrome more efficiently and more cost effective than screening for all possible mutations. Here we report a study of the missense mutation MLH1 c.2059C > T (p.Arg687Trp), a potential founder mutation identified in eight Swedish families and one Finnish family with Swedish ancestors. Haplotype analysis confirmed that the Finnish and Swedish families shared a haplotype of between 0.9 and 2.8 Mb. While MLH1 c.2059C > T exists worldwide, the Swedish haplotype was not found among mutation carriers from Germany or France, which indicates a common founder in the Swedish population. The geographic distribution of MLH1 c.2059C > T in Sweden suggests a single, ancient mutational event in the northern part of Sweden.

  15. Major soybean maturity gene haplotypes revealed by SNPViz analysis of 72 sequenced soybean genomes.

    Directory of Open Access Journals (Sweden)

    Tiffany Langewisch

    Full Text Available In this Genomics Era, vast amounts of next-generation sequencing data have become publicly available for multiple genomes across hundreds of species. Analyses of these large-scale datasets can become cumbersome, especially when comparing nucleotide polymorphisms across many samples within a dataset and among different datasets or organisms. To facilitate the exploration of allelic variation and diversity, we have developed and deployed an in-house computer software to categorize and visualize these haplotypes. The SNPViz software enables users to analyze region-specific haplotypes from single nucleotide polymorphism (SNP datasets for different sequenced genomes. The examination of allelic variation and diversity of important soybean [Glycine max (L. Merr.] flowering time and maturity genes may provide additional insight into flowering time regulation and enhance researchers' ability to target soybean breeding for particular environments. For this study, we utilized two available soybean genomic datasets for a total of 72 soybean genotypes encompassing cultivars, landraces, and the wild species Glycine soja. The major soybean maturity genes E1, E2, E3, and E4 along with the Dt1 gene for plant growth architecture were analyzed in an effort to determine the number of major haplotypes for each gene, to evaluate the consistency of the haplotypes with characterized variant alleles, and to identify evidence of artificial selection. The results indicated classification of a small number of predominant haplogroups for each gene and important insights into possible allelic diversity for each gene within the context of known causative mutations. The software has both a stand-alone and web-based version and can be used to analyze other genes, examine additional soybean datasets, and view similar genome sequence and SNP datasets from other species.

  16. [The haplomatch program for comparing Y-chromosome STR-haplotypes and its application to the analysis of the origin of Don Cossacks].

    Science.gov (United States)

    Chukhryaeva, M I; Ivanov, I O; Frolova, S A; Koshel, S M; Utevska, O M; Skhalyakho, R A; Agdzhoyan, A T; Bogunov, Yu V; Balanovska, E V; Balanovsky, O P

    2016-05-01

    STR haplotypes of the Y chromosome are widely used as effective genetic markers in studies of human populations and in forensic DNA analysis. The task often arises to compare the spectrum of haplotypes in individuals or entire populations. Performing this task manually is too laborious and thus unrealistic. We propose an algorithm for counting similarity between STR haplotypes. This algorithm is suitable for massive analyses of samples. It is implemented in the computer program Haplomatch, which makes it possible to find haplotypes that differ from the target haplotype by 0, 1, 2, 3, or more mutational steps. The program may operate in two modes: comparison of individuals and comparison of populations. Flexibility of the program (the possibility of using any external database), its usability (MS Excel spreadsheets are used), and the capability of being applied to other chromosomes and other species could make this software a new useful tool in population genetics and forensic and genealogical studies. The Haplomatch software is freely available on our website www.genofond.ru. The program is applied to studying the gene pool of Cossacks. Experimental analysis of Y-chromosomal diversity in a representative set (N = 131) of Upper Don Cossacks is performed. Analysis of the STR haplotypes detects genetic proximity of Cossacks to East Slavic populations (in particular, to Southern and Central Russians, as well as to Ukrainians), which confirms the hypothesis of the origin of the Cossacks mainly due to immigration from Russia and Ukraine. Also, a small genetic influence of Turkicspeaking Nogais is found, probably caused by their occurrence in the Don Voisko as part of the Tatar layer. No similarities between haplotype spectra of Cossacks and Caucasus populations are found. This case study demonstrates the effectiveness of the Haplomatch software in analyzing large sets of STR haplotypes.

  17. Haplotyping Problem, A Clustering Approach

    International Nuclear Information System (INIS)

    Eslahchi, Changiz; Sadeghi, Mehdi; Pezeshk, Hamid; Kargar, Mehdi; Poormohammadi, Hadi

    2007-01-01

    Construction of two haplotypes from a set of Single Nucleotide Polymorphism (SNP) fragments is called haplotype reconstruction problem. One of the most popular computational model for this problem is Minimum Error Correction (MEC). Since MEC is an NP-hard problem, here we propose a novel heuristic algorithm based on clustering analysis in data mining for haplotype reconstruction problem. Based on hamming distance and similarity between two fragments, our iterative algorithm produces two clusters of fragments; then, in each iteration, the algorithm assigns a fragment to one of the clusters. Our results suggest that the algorithm has less reconstruction error rate in comparison with other algorithms

  18. Association analysis of calpain 10 gene variants/haplotypes with gestational diabetes mellitus among Mexican women.

    Science.gov (United States)

    Castro-Martínez, Anna Gabriela; Sánchez-Corona, José; Vázquez-Vargas, Adriana Patricia; García-Zapién, Alejandra Guadalupe; López-Quintero, Andres; Villalpando-Velazco, Héctor Javier; Flores-Martínez, Silvia Esperanza

    2018-02-28

    Gestational diabetes mellitus (GDM) is a metabolically complex disease with major genetic determinants. GDM has been associated with insulin resistance and dysfunction of pancreatic beta cells, so the GDM candidate genes are those that encode proteins modulating the function and secretion of insulin, such as that for calpain 10 (CAPN10). This study aimed to assess whether single nucleotide polymorphism (SNP)-43, SNP-44, SNP-63, and the indel-19 variant, and specific haplotypes of the CAPN10 gene were associated with gestational diabetes mellitus. We studied 116 patients with gestational diabetes mellitus and 83 women with normal glucose tolerance. Measurements of anthropometric and biochemical parameters were performed. SNP-43, SNP-44, and SNP-63 were identified by polymerase chain reaction (PCR)-restriction fragment length polymorphisms, while the indel-19 variant was detected by TaqMan qPCR assays.  The allele, genotype, and haplotype frequencies of the four variants did not differ significantly between women with gestational diabetes mellitus and controls. However, in women with gestational diabetes mellitus, glucose levels were significantly higher bearing the 3R/3R genotype than in carriers of the 3R/2R genotype of the indel-19 variant (p = 0.006). In conclusion, the 3R/3R genotype of the indel-19 variant of the CAPN-10 gene influenced increased glucose levels in these Mexican women with gestational diabetes mellitus.

  19. Analysis of 24 Y chromosomal STR haplotypes in a Chinese Han population sample from Henan Province, Central China.

    Science.gov (United States)

    Shi, Meisen; Liu, Yaju; Zhang, Juntao; Bai, Rufeng; Lv, Xiaojiao; Ma, Shuhua

    2015-07-01

    We analyzed haplotypes for 24 Y chromosomal STRs (Y-STRs), including 17 Yfiler loci (DYS19, DYS385a/b, DYS389I/II, DYS390, DYS391, DYS392, DYS393, DYS437, DY438, DYS439, DYS448, DYS456, DYS458, DYS635 and Y-GATA-H4) and 7 additional STRs (DYS388, DYS444, DYS447, DYS449, DYS522 and DYS527a/b) in 1100 unrelated Chinese Han individuals from Henan Province using AGCU Y24 STR kit systems. The calculated average gene diversity (GD) values ranged from 0.4105 to 0.9647 for the DYS388 and DYS385a/b loci, respectively. The discriminatory capacity (DC) was 72.91% with 802 observed haplotypes using 17 Yfiler loci, by the addition of 7 Y-STRs to the Yfiler system, the DC was increased to 79.09% while showing 870 observed haplotypes. Among the additional 7 Y-STRs, DYS449, DYS527a/b, DYS444 and DYS522 were major contributors to enhancing discrimination. In the analysis of molecular variance, the Henan Han population clustered with Han origin populations and showed significant differences from other Non-Han populations. In the present study, we report 24 Y-STR population data in Henan Han population, and we emphasize the need for adding additional markers to the commonly used 17 Yfiler loci to achieve more improved discriminatory capacity in a population with low genetic diversity. Copyright © 2015. Published by Elsevier Ireland Ltd.

  20. Mapping Haplotype-haplotype Interactions with Adaptive LASSO

    Directory of Open Access Journals (Sweden)

    Li Ming

    2010-08-01

    Full Text Available Abstract Background The genetic etiology of complex diseases in human has been commonly viewed as a complex process involving both genetic and environmental factors functioning in a complicated manner. Quite often the interactions among genetic variants play major roles in determining the susceptibility of an individual to a particular disease. Statistical methods for modeling interactions underlying complex diseases between single genetic variants (e.g. single nucleotide polymorphisms or SNPs have been extensively studied. Recently, haplotype-based analysis has gained its popularity among genetic association studies. When multiple sequence or haplotype interactions are involved in determining an individual's susceptibility to a disease, it presents daunting challenges in statistical modeling and testing of the interaction effects, largely due to the complicated higher order epistatic complexity. Results In this article, we propose a new strategy in modeling haplotype-haplotype interactions under the penalized logistic regression framework with adaptive L1-penalty. We consider interactions of sequence variants between haplotype blocks. The adaptive L1-penalty allows simultaneous effect estimation and variable selection in a single model. We propose a new parameter estimation method which estimates and selects parameters by the modified Gauss-Seidel method nested within the EM algorithm. Simulation studies show that it has low false positive rate and reasonable power in detecting haplotype interactions. The method is applied to test haplotype interactions involved in mother and offspring genome in a small for gestational age (SGA neonates data set, and significant interactions between different genomes are detected. Conclusions As demonstrated by the simulation studies and real data analysis, the approach developed provides an efficient tool for the modeling and testing of haplotype interactions. The implementation of the method in R codes can be

  1. Mapping of the Pim-1 oncogene in mouse t-haplotypes and its use to define the relative map positions of the tcl loci t0(t6) and tw12 and the marker tf (tufted).

    Science.gov (United States)

    Ark, B; Gummere, G; Bennett, D; Artzt, K

    1991-06-01

    Pim-1 is an oncogene activated in mouse T-cell lymphomas induced by Moloney and AKR mink cell focus (MCF) viruses. Pim-1 was previously mapped to chromosome 17 by somatic cell hybrids, and subsequently to the region between the hemoglobin alpha-chain pseudogene 4 (Hba-4ps) and the alpha-crystalline gene (Crya-1) by Southern blot analysis of DNA obtained from panels of recombinant inbred strains. We have now mapped Pim-1 more accurately in t-haplotypes by analysis of recombinant t-chromosomes. The recombinants were derived from Tts6tf/t12 parents backcrossed to + tf/ + tf, and scored for recombination between the loci of T and tf. For simplicity all t-complex lethal genes properly named tcl-tx are shortened to tx. The Pim-1 gene was localized 0.6 cM proximal to the tw12 lethal gene, thus placing the Pim-1 gene 5.2 cM distal to the H-2 region in t-haplotypes. Once mapped, the Pim-1 gene was used as a marker for further genetic analysis of t-haplotypes. tw12 is so close to tf that even with a large number of recombinants it was not possible to determine whether it is proximal or distal to tf. Southern blot analysis of DNA from T-tf recombinants with a separation of tw12 and tf indicated that tw12 is proximal to tf. The mapping of two allelic t-lethals, t0 and t6 with respect to tw12 and tf has also been a problem.(ABSTRACT TRUNCATED AT 250 WORDS)

  2. Canis mtDNA HV1 database: a web-based tool for collecting and surveying Canis mtDNA HV1 haplotype in public database.

    Science.gov (United States)

    Thai, Quan Ke; Chung, Dung Anh; Tran, Hoang-Dung

    2017-06-26

    Canine and wolf mitochondrial DNA haplotypes, which can be used for forensic or phylogenetic analyses, have been defined in various schemes depending on the region analyzed. In recent studies, the 582 bp fragment of the HV1 region is most commonly used. 317 different canine HV1 haplotypes have been reported in the rapidly growing public database GenBank. These reported haplotypes contain several inconsistencies in their haplotype information. To overcome this issue, we have developed a Canis mtDNA HV1 database. This database collects data on the HV1 582 bp region in dog mitochondrial DNA from the GenBank to screen and correct the inconsistencies. It also supports users in detection of new novel mutation profiles and assignment of new haplotypes. The Canis mtDNA HV1 database (CHD) contains 5567 nucleotide entries originating from 15 subspecies in the species Canis lupus. Of these entries, 3646 were haplotypes and grouped into 804 distinct sequences. 319 sequences were recognized as previously assigned haplotypes, while the remaining 485 sequences had new mutation profiles and were marked as new haplotype candidates awaiting further analysis for haplotype assignment. Of the 3646 nucleotide entries, only 414 were annotated with correct haplotype information, while 3232 had insufficient or lacked haplotype information and were corrected or modified before storing in the CHD. The CHD can be accessed at http://chd.vnbiology.com . It provides sequences, haplotype information, and a web-based tool for mtDNA HV1 haplotyping. The CHD is updated monthly and supplies all data for download. The Canis mtDNA HV1 database contains information about canine mitochondrial DNA HV1 sequences with reconciled annotation. It serves as a tool for detection of inconsistencies in GenBank and helps identifying new HV1 haplotypes. Thus, it supports the scientific community in naming new HV1 haplotypes and to reconcile existing annotation of HV1 582 bp sequences.

  3. Allelic variation of the inducible costimulator (ICOS) gene: detection of polymorphisms, analysis of the promoter region, and extended haplotype estimation

    DEFF Research Database (Denmark)

    Andersen, A.D.H.; Lange, Marianne; Lillevang, S.T.

    2003-01-01

    The human chromosome region 2q33 including the three costimulatory molecules CD28, CTLA-4 and ICOS, has been subject to much attention due to its linkage to a number of autoimmune diseases. The search for the causal relationship of this linkage has revealed several polymorphisms, but no variations...... in the amino acid sequences except for one polymorphism in, the leader sequence of CTLA-4. In the present study, we examined the ICOS gene of an unrelated group of healthy donors from the Danish population. We were able to report 16 intronic SNP, one intronic G-insert and two repeat regions in intron 4......, consistent with the [T](n) and the [GT](n) regions reported in a Japanese study. Putative haplotypes for the established SNP and repeat polymorphisms have been estimated by computational analysis. Sequencing of similar to3500 by of the upstream region of ICOS revealed an additional eight SNP of which two...

  4. Haplotype analysis of the HFE gene among populations of Northern Eurasia, in patients with metabolic disorders or stomach cancer, and in long-lived people.

    Science.gov (United States)

    Mikhailova, S V; Babenko, V N; Ivanoshchuk, D E; Gubina, M A; Maksimov, V N; Solovjova, I G; Voevoda, M I

    2016-06-17

    Previously, it was shown that the HFE gene (associated with human hereditary hemochromatosis) has several haplotypes of intronic polymorphisms. Some haplotype frequencies are race specific and hence can be used in phylogenetic analysis. We assumed that analysis of Caucasoid patients-living now in Western Siberia and having diseases associated with dietary habits and metabolic rate-will allow us to understand the processes of possible selection during settling of the northern part of Asia. Haplotype analysis of Northern Eurasian native and recently settled ethnic groups was performed on polymorphisms rs1799945, rs1800730, rs1800562, rs2071303, rs1800708, rs1572982, rs2794719, rs807209, and rs2032451 of this gene. The CCA haplotype of the rs2071303, rs1800708, and rs1572982 was found to be associated with HLA-A2 (39 %) in Asian populations. Haplotype analysis for the rs1799945, rs1800730, rs1800562, rs2071303, rs1800708, and rs1572982 was performed on Russian patients with some metabolic disorders or stomach cancer and among long-lived people. Decreased frequencies of the TTA haplotype (T in rs2071303, T in rs1800708, and A in rs1572982) were observed in the groups of patients with diseases associated with overweight (fatty liver disease, type 2 diabetes mellitus, or metabolic syndrome + arterial hypertension) as compared with the control sample. We detected significant differences in this haplotype's frequency between the patients with type 2 diabetes mellitus and Russian adolescents, elderly citizens, and long-lived people (χ(2) P value = 0.003, 0.010, and 0.015, respectively). No significant differences in frequencies of the alleles with mutations in coding regions of the HFE gene (C282Y, H63D, and S65C) were detected between the analyzed patients (with stomach cancer, metabolic syndrome, fatty liver disease, or type 2 diabetes mellitus) and the control Caucasoid sample. Monophyletic origin of H63D (rs1799945) was confirmed in Caucasoids and Northern

  5. Application of gene network analysis techniques identifies AXIN1/PDIA2 and endoglin haplotypes associated with bicuspid aortic valve.

    Directory of Open Access Journals (Sweden)

    Eric C Wooten

    2010-01-01

    Full Text Available Bicuspid Aortic Valve (BAV is a highly heritable congenital heart defect. The low frequency of BAV (1% of general population limits our ability to perform genome-wide association studies. We present the application of four a priori SNP selection techniques, reducing the multiple-testing penalty by restricting analysis to SNPs relevant to BAV in a genome-wide SNP dataset from a cohort of 68 BAV probands and 830 control subjects. Two knowledge-based approaches, CANDID and STRING, were used to systematically identify BAV genes, and their SNPs, from the published literature, microarray expression studies and a genome scan. We additionally tested Functionally Interpolating SNPs (fitSNPs present on the array; the fourth consisted of SNPs selected by Random Forests, a machine learning approach. These approaches reduced the multiple testing penalty by lowering the fraction of the genome probed to 0.19% of the total, while increasing the likelihood of studying SNPs within relevant BAV genes and pathways. Three loci were identified by CANDID, STRING, and fitSNPS. A haplotype within the AXIN1-PDIA2 locus (p-value of 2.926x10(-06 and a haplotype within the Endoglin gene (p-value of 5.881x10(-04 were found to be strongly associated with BAV. The Random Forests approach identified a SNP on chromosome 3 in association with BAV (p-value 5.061x10(-06. The results presented here support an important role for genetic variants in BAV and provide support for additional studies in well-powered cohorts. Further, these studies demonstrate that leveraging existing expression and genomic data in the context of GWAS studies can identify biologically relevant genes and pathways associated with a congenital heart defect.

  6. Meta-analysis reveals association between most common class II haplotype in full-heritage Native Americans and rheumatoid arthritis.

    Science.gov (United States)

    Williams, R C; Jacobsson, L T; Knowler, W C; del Puente, A; Kostyu, D; McAuley, J E; Bennett, P H; Pettitt, D J

    1995-01-01

    The association of RA with the alleles at the HLA system was tested among Pima and Tohono O'odham Indians (Pimans) of the Gila River Indian Community of Arizona. Serologic class I (HLA-A, -B, and -C) alleles were typed in 51 individuals with RA and in 302 without RA. Serologic class II (HLA-DR, DQ; DR52 DR53) alleles were typed in a subset of 47 with RA and 147 without RA. Molecular subtypes of DR3X6, DRB1*1402, and *1406 were determined in 29 individuals, 16 with RA and 13 without RA. Among the cases with RA, 46 of 47 had the serologic antigen HLA-DR3X6, as did 140 of 147 of those without the disease. However, this association was not statistically significant because of the high prevalence of the antigen in the controls. Data from Pimans were analyzed with similar results from the Tlingit and Yakima Indians. A meta-analysis employing the Mantel-Haenszel procedure, stratified by tribe, revealed a statistically significant association between the most common haplotype, DRB1*1402 DQA1*0501 DQB1*0301 DRB3*0101, and RA (summary odds ratio = 2.63, 95% confidence interval = 1.08, 6.46). There was also a statistically significant difference in the genotype distributions of one class I locus, HLA-C, between those with and without RA (chi 2 = 12.4, 5 df; p = 0.03). It is concluded that the association with the most common class II haplotype in full-heritage Native Americans might help explain their high prevalence of RA.

  7. Haplotype-based association analysis of general cognitive ability in Generation Scotland, the English Longitudinal Study of Ageing, and UK Biobank [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    David M. Howard

    2017-08-01

    Full Text Available Background: Cognitive ability is a heritable trait with a polygenic architecture, for which several associated variants have been identified using genotype-based and candidate gene approaches. Haplotype-based analyses are a complementary technique that take phased genotype data into account, and potentially provide greater statistical power to detect lower frequency variants. Methods: In the present analysis, three cohort studies (ntotal = 48,002 were utilised: Generation Scotland: Scottish Family Health Study (GS:SFHS, the English Longitudinal Study of Ageing (ELSA, and the UK Biobank. A genome-wide haplotype-based meta-analysis of cognitive ability was performed, as well as a targeted meta-analysis of several gene coding regions. Results: None of the assessed haplotypes provided evidence of a statistically significant association with cognitive ability in either the individual cohorts or the meta-analysis. Within the meta-analysis, the haplotype with the lowest observed P-value overlapped with the D-amino acid oxidase activator (DAOA gene coding region. This coding region has previously been associated with bipolar disorder, schizophrenia and Alzheimer’s disease, which have all been shown to impact upon cognitive ability. Another potentially interesting region highlighted within the current genome-wide association analysis (GS:SFHS: P = 4.09 x 10-7, was the butyrylcholinesterase (BCHE gene coding region. The protein encoded by BCHE has been shown to influence the progression of Alzheimer’s disease and its role in cognitive ability merits further investigation. Conclusions: Although no evidence was found for any haplotypes with a statistically significant association with cognitive ability, our results did provide further evidence that the genetic variants contributing to the variance of cognitive ability are likely to be of small effect.

  8. A Back Migration from Asia to Sub-Saharan Africa Is Supported by High-Resolution Analysis of Human Y-Chromosome Haplotypes

    Science.gov (United States)

    Cruciani, Fulvio; Santolamazza, Piero; Shen, Peidong; Macaulay, Vincent; Moral, Pedro; Olckers, Antonel; Modiano, David; Holmes, Susan; Destro-Bisol, Giovanni; Coia, Valentina; Wallace, Douglas C.; Oefner, Peter J.; Torroni, Antonio; Cavalli-Sforza, L. Luca; Scozzari, Rosaria; Underhill, Peter A.

    2002-01-01

    The variation of 77 biallelic sites located in the nonrecombining portion of the Y chromosome was examined in 608 male subjects from 22 African populations. This survey revealed a total of 37 binary haplotypes, which were combined with microsatellite polymorphism data to evaluate internal diversities and to estimate coalescence ages of the binary haplotypes. The majority of binary haplotypes showed a nonuniform distribution across the continent. Analysis of molecular variance detected a high level of interpopulation diversity (ΦST=0.342), which appears to be partially related to the geography (ΦCT=0.230). In sub-Saharan Africa, the recent spread of a set of haplotypes partially erased pre-existing diversity, but a high level of population (ΦST=0.332) and geographic (ΦCT=0.179) structuring persists. Correspondence analysis shows that three main clusters of populations can be identified: northern, eastern, and sub-Saharan Africans. Among the latter, the Khoisan, the Pygmies, and the northern Cameroonians are clearly distinct from a tight cluster formed by the Niger-Congo–speaking populations from western, central western, and southern Africa. Phylogeographic analyses suggest that a large component of the present Khoisan gene pool is eastern African in origin and that Asia was the source of a back migration to sub-Saharan Africa. Haplogroup IX Y chromosomes appear to have been involved in such a migration, the traces of which can now be observed mostly in northern Cameroon. PMID:11910562

  9. Haplotype Analysis of the Melanopsin Gene in Seasonal Affective Disorder and Controls

    Science.gov (United States)

    2007-06-19

    correlated with genetically estimated population membership and with cultural and environmental factors that could impact disease risk (Thomas & Witte, 2002...However, it is unlikely that culturally defined ethnicity completely reflects genetic differentiation, making self-reported race an incomplete...entire human genome using polymorphic data from four ethnically distinct populations; the Yoruba people in Nigeria (30 parent-child trios), Japanese

  10. Comparative sequence analysis of the potato cyst nematode resistance locus H1 reveals a major lack of co-linearity between three haplotypes in potato (Solanum tuberosum ssp.).

    Science.gov (United States)

    Finkers-Tomczak, Anna; Bakker, Erin; de Boer, Jan; van der Vossen, Edwin; Achenbach, Ute; Golas, Tomasz; Suryaningrat, Suwardi; Smant, Geert; Bakker, Jaap; Goverse, Aska

    2011-02-01

    The H1 locus confers resistance to the potato cyst nematode Globodera rostochiensis pathotypes 1 and 4. It is positioned at the distal end of chromosome V of the diploid Solanum tuberosum genotype SH83-92-488 (SH) on an introgression segment derived from S. tuberosum ssp. andigena. Markers from a high-resolution genetic map of the H1 locus (Bakker et al. in Theor Appl Genet 109:146-152, 2004) were used to screen a BAC library to construct a physical map covering a 341-kb region of the resistant haplotype coming from SH. For comparison, physical maps were also generated of the two haplotypes from the diploid susceptible genotype RH89-039-16 (S. tuberosum ssp. tuberosum/S. phureja), spanning syntenic regions of 700 and 319 kb. Gene predictions on the genomic segments resulted in the identification of a large cluster consisting of variable numbers of the CC-NB-LRR type of R genes for each haplotype. Furthermore, the regions were interspersed with numerous transposable elements and genes coding for an extensin-like protein and an amino acid transporter. Comparative analysis revealed a major lack of gene order conservation in the sequences of the three closely related haplotypes. Our data provide insight in the evolutionary mechanisms shaping the H1 locus and will facilitate the map-based cloning of the H1 resistance gene.

  11. Significant association between ERCC2 and MTHR polymorphisms and breast cancer susceptibility in Moroccan population: genotype and haplotype analysis in a case-control study.

    Science.gov (United States)

    Hardi, Hanaa; Melki, Rahma; Boughaleb, Zouhour; El Harroudi, Tijani; Aissaoui, Souria; Boukhatem, Noureddine

    2018-03-15

    Genetic determinants of breast cancer (BC) remained largely unknown in the majority of Moroccan patients. The purpose of this study was to explore the association of ERCC2 and MTHFR polymorphisms with genetic susceptibility to breast cancer in Moroccan population. We genotyped ERCC2 polymorphisms (rs1799793 (G934A) and rs13181 (A2251C)) and MTHFR polymorphisms (rs1801133 (C677T) and rs1801131 (A1298C)) using TaqMan SNP Genotyping Assays. Genotypes were compared in 151 BC cases and 156 population-matched controls. Allelic, genotypic and haplotype associations with the risk and clinicopathological features of BC were assessed using logistic regression analyses. ERCC2-rs1799793-AA genotype was associated with high risk of BC compared to wild type genotype (recessive model: OR: 2.90, 95% CI: 1.34-6.26, p = 0.0069) even after Bonferroni correction (p < 0,0125). MTHFR rs1801133-TT genotype was associated with increased risk of BC (recessive model, OR: 2.49, 95% CI: 1.17-5.29, p = 0.017) but the association turned insignificant after Bonferroni correction. For the rest of SNPs, no statistical associations to BC risk were detected. Significant association with clinical features was detected for MTHFR-rs1801133-TC genotype with early age at diagnosis and familial BC. Following Bonferroni correction, only association with familial BC remained significant. MTHFR-rs1801131-CC genotype was associated with sporadic BC. ERCC2-rs1799793-AA genotype correlated with ER+ and PR+ breast cancer. ERCC2-rs13181-CA genotype was significantly associated large tumors (T ≥ 3) in BC patients. None of these associations passed Bonferroni correction. Haplotype analysis showed that ERCC2 A-C haplotype was significantly associated with increased BC risk (OR: 3.71, 95% CI: 1.7-8.12, p = 0.0002 and p = 0.0008 before and after Bonferroni correction, respectively) and positive expression of ER and PR in BC patients. ERCC2 G-C haplotype was correlated with PR negative and

  12. Population haplotype analysis and evolutionary relations of the COL2A1 gene

    NARCIS (Netherlands)

    Meulenbelt, I.; Williams, G.J.; Koppele, J.M.T.E.; Giessen, G.C.D.E. van; Slagboom, P.E.

    1996-01-01

    We have determined the allele frequencies mad pairwise linkage disequilibria of restriction fragment length polymorphisms (RFLPs) distributed over the entire COL2A1 gene (spanning 23 · 6 kb) in a population of unrelated Dutch Caucasians. Pairwise linkage disequilibrium analysis of RFLP sites between

  13. Analysis of associations between major histocompatibility complex (BoLA) class I haplotypes and subclinical mastitis of dairy cows

    DEFF Research Database (Denmark)

    Aarestrup, Frank Møller; Jensen, N. E.; Østergård, H.

    1995-01-01

    The associations between BoLA class I haplotypes and subclinical mastitis were investigated using information on 333 cows from three different breeds and crossbreeds from 14 dairy herds in Denmark. Somatic cell count and bacteriological status were used as markers for subclinical mastitis....... Associations between BoLA class I haplotypes and IMI status were also determined. The association between BoLA class I haplotypes and subclinical mastitis was weak. The A10(W50), A11, A12(A30), A16, A19(A6), A21, A26, and A31(A30) alleles were associated with different markers of subclinical mastitis....... Susceptibility or resistance to the two bacteria categories was associated with different alleles. This study indicated that BoLA antigens may be involved in resistance to mastitis and that resistance may be specific for a particular pathogen....

  14. Different patterns of evolution in the centromeric and telomeric regions of group A and B haplotypes of the human killer cell Ig-like receptor locus.

    Directory of Open Access Journals (Sweden)

    Chul-Woo Pyo

    Full Text Available The fast evolving human KIR gene family encodes variable lymphocyte receptors specific for polymorphic HLA class I determinants. Nucleotide sequences for 24 representative human KIR haplotypes were determined. With three previously defined haplotypes, this gave a set of 12 group A and 15 group B haplotypes for assessment of KIR variation. The seven gene-content haplotypes are all combinations of four centromeric and two telomeric motifs. 2DL5, 2DS5 and 2DS3 can be present in centromeric and telomeric locations. With one exception, haplotypes having identical gene content differed in their combinations of KIR alleles. Sequence diversity varied between haplotype groups and between centromeric and telomeric halves of the KIR locus. The most variable A haplotype genes are in the telomeric half, whereas the most variable genes characterizing B haplotypes are in the centromeric half. Of the highly polymorphic genes, only the 3DL3 framework gene exhibits a similar diversity when carried by A and B haplotypes. Phylogenetic analysis and divergence time estimates, point to the centromeric gene-content motifs that distinguish A and B haplotypes having emerged ~6 million years ago, contemporaneously with the separation of human and chimpanzee ancestors. In contrast, the telomeric motifs that distinguish A and B haplotypes emerged more recently, ~1.7 million years ago, before the emergence of Homo sapiens. Thus the centromeric and telomeric motifs that typify A and B haplotypes have likely been present throughout human evolution. The results suggest the common ancestor of A and B haplotypes combined a B-like centromeric region with an A-like telomeric region.

  15. Haplotype analysis of TP53 polymorphisms, Arg72Pro and Ins16, in BRCA1 and BRCA2 mutation carriers of French Canadian descent

    International Nuclear Information System (INIS)

    Cavallone, Luca; Arcand, Suzanna L; Maugard, Christine; Ghadirian, Parviz; Mes-Masson, Anne-Marie; Provencher, Diane; Tonin, Patricia N

    2008-01-01

    small sample size did not permit analysis of all possible haplotypes, we observed that BRCA2 mutation carriers harboring the Ins16minus-72Arg haplotype had a significantly younger mean age of diagnosis of breast cancer. These observations suggest that investigations in a larger French Canadian sample are warranted to further elucidate the effects of TP53 variants on age of diagnosis of breast cancer among BRCA1 and BRCA2 mutation carriers

  16. Analysis of HLA-A, HLA-B, HLA-DRB1 allelic, genotypic, and haplotypic frequencies in colombian population

    OpenAIRE

    Yazmin Rocío Árias-Murillo; Miguel Ángel Castro-Jiménez; María Fernanda Ríos-Espinosa; Juan Javier López-Rivera; Sandra Johanna Echeverry-Coral; Oscar Martínez-Nieto

    2010-01-01

    Introduction: The high polymorphism of the HLA system allows its typification to be used as valuable tool in establishing association to various illnesses, immune and genetic profiles; it also provides a guide to identifying compatibility among donors and receptors of organs transplants. Objective: To establish HLA-A, HLA-B, and HLA.DRB1 allele, genotype and haplotype frequencies among patients treated at Clinica Colsanitas SA. Methods: 561 patients coming from different regions in Col...

  17. The roles of variants in human multidrug resistance (MDR1 gene and their haplotypes on antiepileptic drugs response: a meta-analysis of 57 studies.

    Directory of Open Access Journals (Sweden)

    Hui Li

    Full Text Available Previous studies reported the associations between the ATP-binding cassette sub-family B member 1 (ABCB1, also known as MDR1 polymorphisms and their haplotypes with risk of response to antiepileptic drugs in epilepsy, however, the results were inconclusive.The Pubmed, Embase, Web of Science, CNKI and Chinese Biomedicine databases were searched up to July 15, 2014. Pooled odds ratios (ORs and 95% confidence intervals (CIs were calculated using a fixed-effects or random-effects model based on heterogeneity tests. Meta-regression and Galbraith plot analysis were carried out to explore the possible heterogeneity.A total of 57 studies involving 12407 patients (6083 drug-resistant and 6324 drug-responsive patients with epilepsy were included in the pooled-analysis. For all three polymorphisms (C3435T, G2677T/A, and C1236T, we observed a wide spectrum of minor allele frequencies across different ethnicities. A significantly decreased risk of AEDs resistance was observed in Caucasian patients with T allele of C3435T variant, which was still significant after adjusted by multiple testing corrections (T vs C: OR=0.83, 95%CI=0.71-0.96, p=0.01. However, no significant association was observed between the other two variants and AEDs resistance. Of their haplotypes in ABCB1 gene (all studies were in Indians and Asians, no significant association was observed with AEDs resistance. Moreover, sensitivity and Cumulative analysis showed that the results of this meta-analysis were stable.In summary, this meta-analysis demonstrated that effect of C3435T variant on risk of AEDs resistance was ethnicity-dependent, which was significant in Caucasians. Additionally, further studies in different ethnic groups are warranted to clarify possible roles of haplotypes in ABCB1 gene in AEDs resistance, especially in Caucasians.

  18. Characterization of N-acetyltransferase 1 and 2 polymorphisms and haplotype analysis for inflammatory bowel disease and sporadic colorectal carcinoma

    Directory of Open Access Journals (Sweden)

    Cobbs Gary A

    2007-05-01

    Full Text Available Abstract Background N-acetyltransferase 1 (NAT1 and 2 (NAT2 are polymorphic isoenzymes responsible for the metabolism of numerous drugs and carcinogens. Acetylation catalyzed by NAT1 and NAT2 are important in metabolic activation of arylamines to electrophilic intermediates that initiate carcinogenesis. Inflammatory bowel diseases (IBD consist of Crohn's disease (CD and ulcerative colitis (UC, both are associated with increased colorectal cancer (CRC risk. We hypothesized that NAT1 and/or NAT2 polymorphisms contribute to the increased cancer evident in IBD. Methods A case control study was performed with 729 Caucasian participants, 123 CRC, 201 CD, 167 UC, 15 IBD dysplasia/cancer and 223 controls. NAT1 and NAT2 genotyping were performed using Taqman based techniques. Eight single nucleotide polymorphisms (SNPs were characterized for NAT1 and 7 SNPs for NAT2. Haplotype frequencies were estimated using an Expectation-Maximization (EM method. Disease groups were compared to a control group for the frequencies at each individual SNP separately. The same groups were compared for the frequencies of NAT1 and NAT2 haplotypes and deduced NAT2 phenotypes. Results No statistically significant differences were found for any comparison. Strong linkage disequilibrium was present among both the NAT1 SNPs and the NAT2 SNPs. Conclusion This study did not demonstrate an association between NAT1 and NAT2 polymorphisms and IBD or sporadic CRC, although power calculations indicate this study had sufficient sample size to detect differences in frequency as small as 0.05 to 0.15 depending on SNP or haplotype.

  19. Post-mortem analysis of suicide victims shows ABCB1 haplotype 1236T-2677T-3435T as a candidate predisposing factor behind adverse drug reactions in females.

    Science.gov (United States)

    Rahikainen, Anna-Liina; Palo, Jukka U; Haukka, Jari; Sajantila, Antti

    2018-04-01

    Genetic variation in efflux transporter, permeability glycoprotein (P-gp), has recently been associated with completed violent suicides and also violent suicide attempts. As depression is known to be a risk factor for suicide and many antidepressants are P-gp substrates, it has been speculated that inadequate antidepressant treatment response or adverse side effects could be involved. The aim of this study was to investigate whether there is an association between the P-gp coding ABCB1 gene and completed suicides in citalopram users. Also, the effect of sex and suicide method used (violent vs. non-violent) was evaluated. All cases included in the study population, 349 completed suicide victims and 284 controls, were shown to be positive for antidepressant citalopram in a post-mortem toxicological drug screen. ABCB1 1236C>T, 2677G>T/A and 3435C>T polymorphisms were determined by TaqMan genotyping assays. Haplotypes were constructed from genotype data using the PHASE software. The association between the manner of death and the ABCB1 haplotype was tested with logistic regression analysis. No statistically significant differences were observed in the ABCB1 allele or genotype frequencies between the suicide and control groups. However, the ABCB1 1236T-2677T-3435T haplotype was associated with completed suicides of female citalopram users (odds ratio: 2.23; 95% confidence interval: 1.22-4.07; P=0.009). After stratification by the method used for suicide, the association emerged in fatal intoxications (odds ratio: 2.51; 95% confidence interval: 1.29-4.87; P=0.007). In other groups, no statistically significant associations were observed. Our results suggest that female citalopram users with ABCB1 1236T-2677T-3435T are more vulnerable to adverse effects of the drugs as this haplotype was enriched in non-violent suicides of female citalopram users. Even though the biological mechanism behind this observation is unknown, the results provide another example of the importance

  20. Image Chunking: Defining Spatial Building Blocks for Scene Analysis.

    Science.gov (United States)

    1987-04-01

    mumgs0.USmusa 7.AUWOJO 4. CIUTAC Rm6ANT Wuugme*j James V/. Mlahoney DACA? 6-85-C-00 10 NOQ 1 4-85-K-O 124 Artificial Inteligence Laboratory US USS 545...0197 672 IMAGE CHUWING: DEINING SPATIAL UILDING PLOCKS FOR 142 SCENE ANRLYSIS(U) MASSACHUSETTS INST OF TECH CAIIAIDGE ARTIFICIAL INTELLIGENCE LAO J...Technical Report 980 F-Image Chunking: Defining Spatial Building Blocks for Scene DTm -Analysis S ELECTED James V. Mahoney’ MIT Artificial Intelligence

  1. Identification of rheumatoid arthritis biomarkers based on single nucleotide polymorphisms and haplotype blocks: A systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Mohamed N. Saad

    2016-01-01

    Full Text Available Genetics of autoimmune diseases represent a growing domain with surpassing biomarker results with rapid progress. The exact cause of Rheumatoid Arthritis (RA is unknown, but it is thought to have both a genetic and an environmental bases. Genetic biomarkers are capable of changing the supervision of RA by allowing not only the detection of susceptible individuals, but also early diagnosis, evaluation of disease severity, selection of therapy, and monitoring of response to therapy. This review is concerned with not only the genetic biomarkers of RA but also the methods of identifying them. Many of the identified genetic biomarkers of RA were identified in populations of European and Asian ancestries. The study of additional human populations may yield novel results. Most of the researchers in the field of identifying RA biomarkers use single nucleotide polymorphism (SNP approaches to express the significance of their results. Although, haplotype block methods are expected to play a complementary role in the future of that field.

  2. FMR1 CGG repeat expansion mutation detection and linked haplotype analysis for reliable and accurate preimplantation genetic diagnosis of fragile X syndrome.

    Science.gov (United States)

    Rajan-Babu, Indhu-Shree; Lian, Mulias; Cheah, Felicia S H; Chen, Min; Tan, Arnold S C; Prasath, Ethiraj B; Loh, Seong Feei; Chong, Samuel S

    2017-07-19

    Fragile X mental retardation 1 (FMR1) full-mutation expansion causes fragile X syndrome. Trans-generational fragile X syndrome transmission can be avoided by preimplantation genetic diagnosis (PGD). We describe a robust PGD strategy that can be applied to virtually any couple at risk of transmitting fragile X syndrome. This novel strategy utilises whole-genome amplification, followed by triplet-primed polymerase chain reaction (TP-PCR) for robust detection of expanded FMR1 alleles, in parallel with linked multi-marker haplotype analysis of 13 highly polymorphic microsatellite markers located within 1 Mb of the FMR1 CGG repeat, and the AMELX/Y dimorphism for gender identification. The assay was optimised and validated on single lymphoblasts isolated from fragile X reference cell lines, and applied to a simulated PGD case and a clinical in vitro fertilisation (IVF)-PGD case. In the simulated PGD case, definitive diagnosis of the expected results was achieved for all 'embryos'. In the clinical IVF-PGD case, delivery of a healthy baby girl was achieved after transfer of an expansion-negative blastocyst. FMR1 TP-PCR reliably detects presence of expansion mutations and obviates reliance on informative normal alleles for determining expansion status in female embryos. Together with multi-marker haplotyping and gender determination, misdiagnosis and diagnostic ambiguity due to allele dropout is minimised, and couple-specific assay customisation can be avoided.

  3. Defining Smart City. A Conceptual Framework Based on Keyword Analysis

    Directory of Open Access Journals (Sweden)

    Farnaz Mosannenzadeh

    2014-05-01

    Full Text Available “Smart city” is a concept that has been the subject of increasing attention in urban planning and governance during recent years. The first step to create Smart Cities is to understand its concept. However, a brief review of literature shows that the concept of Smart City is the subject of controversy. Thus, the main purpose of this paper is to provide a conceptual framework to define Smart City. To this aim, an extensive literature review was done. Then, a keyword analysis on literature was held against main research questions (why, what, who, when, where, how and based on three main domains involved in the policy decision making process and Smart City plan development: Academic, Industrial and Governmental. This resulted in a conceptual framework for Smart City. The result clarifies the definition of Smart City, while providing a framework to define Smart City’s each sub-system. Moreover, urban authorities can apply this framework in Smart City initiatives in order to recognize their main goals, main components, and key stakeholders.

  4. Stability analysis of an implicitly defined labor market model

    Science.gov (United States)

    Mendes, Diana A.; Mendes, Vivaldo M.

    2008-06-01

    Until very recently, the pervasive existence of models exhibiting well-defined backward dynamics but ill-defined forward dynamics in economics and finance has apparently posed no serious obstacles to the analysis of their dynamics and stability, despite the problems that may arise from possible erroneous conclusions regarding theoretical considerations and policy prescriptions from such models. A large number of papers have dealt with this problem in the past by assuming the existence of symmetry between forward and backward dynamics, even in the case when the map cannot be invertible either forward or backwards. However, this procedure has been seriously questioned over the last few years in a series of papers dealing with implicit difference equations and inverse limit spaces. This paper explores the search and matching labor market model developed by Bhattacharya and Bunzel [J. Bhattacharya, H. Bunzel, Chaotic Planning Solution in the Textbook Model of Equilibrium Labor Market Search and Matching, Mimeo, Iowa State University, 2002; J. Bhattacharya, H. Bunzel, Economics Bulletin 5 (19) (2003) 1-10], with the following objectives in mind: (i) to show that chaotic dynamics may still be present in the model for acceptable parameter values, (ii) to clarify some open questions related with the admissible dynamics in the forward looking setting, by providing a rigorous proof of the existence of cyclic and chaotic dynamics through the application of tools from symbolic dynamics and inverse limit theory.

  5. A Phospholipidomic Analysis of All Defined Human Plasma Lipoproteins

    Science.gov (United States)

    Dashti, Monireh; Kulik, Willem; Hoek, Frans; Veerman, Enno C.; Peppelenbosch, Maikel P.; Rezaee, Farhad

    2011-01-01

    Since plasma lipoproteins contain both protein and phospholipid components, either may be involved in processes such as atherosclerosis. In this study the identification of plasma lipoprotein-associated phospholipids, which is essential for understanding these processes at the molecular level, are performed. LC-ESI/MS, LC-ESI-MS/MS and High Performance Thin Layer Chromatography (HPTLC) analysis of different lipoprotein fractions collected from pooled plasma revealed the presence of phosphatidylethanolamine (PE), phosphatidylinositol (PI), and sphingomyeline (SM) only on lipoproteins and phosphatidylcholine (PC), Lyso-PC on both lipoproteins and plasma lipoprotein free fraction (PLFF). Cardiolipin, phosphatidylglycerol (PG) and Phosphatidylserine (PS) were observed neither in the lipoprotein fractions nor in PLFF. All three approaches led to the same results regarding phospholipids occurrence in plasma lipoproteins and PLFF. A high abundancy of PE and SM was observed in VLDL and LDL fractions respectively. This study provides for the first time the knowledge about the phospholipid composition of all defined plasma lipoproteins. PMID:22355656

  6. Green turtles (Chelonia mydas foraging at Arvoredo Island in Southern Brazil: genetic characterization and mixed stock analysis through mtDNA control region haplotypes

    Directory of Open Access Journals (Sweden)

    Maíra Carneiro Proietti

    2009-01-01

    Full Text Available We analyzed mtDNA control region sequences of green turtles (Chelonia mydas from Arvoredo Island, a foraging ground in southern Brazil, and identified eight haplotypes. Of these, CM-A8 (64% and CM-A5 (22% were dominant, the remainder presenting low frequencies ( 0.05. Mixed Stock Analysis, incorporating eleven Atlantic and one Mediterranean rookery as possible sources of individuals, indicated Ascension and Aves islands as the main contributing stocks to the Arvoredo aggregation (68.01% and 22.96%, respectively. These results demonstrate the extensive relationships between Arvoredo Island and other Atlantic foraging and breeding areas. Such an understanding provides a framework for establishing adequate management and conservation strategies for this endangered species.

  7. Tracking human migrations by the analysis of the distribution of HLA alleles, lineages and haplotypes in closed and open populations

    Science.gov (United States)

    Vina, Marcelo A. Fernandez; Hollenbach, Jill A.; Lyke, Kirsten E.; Sztein, Marcelo B.; Maiers, Martin; Klitz, William; Cano, Pedro; Mack, Steven; Single, Richard; Brautbar, Chaim; Israel, Shosahna; Raimondi, Eduardo; Khoriaty, Evelyne; Inati, Adlette; Andreani, Marco; Testi, Manuela; Moraes, Maria Elisa; Thomson, Glenys; Stastny, Peter; Cao, Kai

    2012-01-01

    The human leucocyte antigen (HLA) system shows extensive variation in the number and function of loci and the number of alleles present at any one locus. Allele distribution has been analysed in many populations through the course of several decades, and the implementation of molecular typing has significantly increased the level of diversity revealing that many serotypes have multiple functional variants. While the degree of diversity in many populations is equivalent and may result from functional polymorphism(s) in peptide presentation, homogeneous and heterogeneous populations present contrasting numbers of alleles and lineages at the loci with high-density expression products. In spite of these differences, the homozygosity levels are comparable in almost all of them. The balanced distribution of HLA alleles is consistent with overdominant selection. The genetic distances between outbred populations correlate with their geographical locations; the formal genetic distance measurements are larger than expected between inbred populations in the same region. The latter present many unique alleles grouped in a few lineages consistent with limited founder polymorphism in which any novel allele may have been positively selected to enlarge the communal peptide-binding repertoire of a given population. On the other hand, it has been observed that some alleles are found in multiple populations with distinctive haplotypic associations suggesting that convergent evolution events may have taken place as well. It appears that the HLA system has been under strong selection, probably owing to its fundamental role in varying immune responses. Therefore, allelic diversity in HLA should be analysed in conjunction with other genetic markers to accurately track the migrations of modern humans. PMID:22312049

  8. Using Bayesian Population Viability Analysis to Define Relevant Conservation Objectives.

    Directory of Open Access Journals (Sweden)

    Adam W Green

    Full Text Available Adaptive management provides a useful framework for managing natural resources in the face of uncertainty. An important component of adaptive management is identifying clear, measurable conservation objectives that reflect the desired outcomes of stakeholders. A common objective is to have a sustainable population, or metapopulation, but it can be difficult to quantify a threshold above which such a population is likely to persist. We performed a Bayesian metapopulation viability analysis (BMPVA using a dynamic occupancy model to quantify the characteristics of two wood frog (Lithobates sylvatica metapopulations resulting in sustainable populations, and we demonstrate how the results could be used to define meaningful objectives that serve as the basis of adaptive management. We explored scenarios involving metapopulations with different numbers of patches (pools using estimates of breeding occurrence and successful metamorphosis from two study areas to estimate the probability of quasi-extinction and calculate the proportion of vernal pools producing metamorphs. Our results suggest that ≥50 pools are required to ensure long-term persistence with approximately 16% of pools producing metamorphs in stable metapopulations. We demonstrate one way to incorporate the BMPVA results into a utility function that balances the trade-offs between ecological and financial objectives, which can be used in an adaptive management framework to make optimal, transparent decisions. Our approach provides a framework for using a standard method (i.e., PVA and available information to inform a formal decision process to determine optimal and timely management policies.

  9. Differentiation analysis for estimating individual ancestry from the Tibetan Plateau by an archaic altitude adaptation EPAS1 haplotype among East Asian populations.

    Science.gov (United States)

    Jiang, Li; Peng, Jianxiong; Huang, Meisha; Liu, Jing; Wang, Ling; Ma, Quan; Zhao, Hui; Yang, Xin; Ji, Anquan; Li, Caixia

    2018-02-10

    Tibetans have adapted to the extreme environment of high altitude for hundreds of generations. A highly differentiated 5-SNP (Single Nucleotide Polymorphism) haplotype motif (AGGAA) on a hypoxic pathway gene, EPAS1, is observed in Tibetans and lowlanders. To evaluate the potential usage of the 5-SNP haplotype in ancestry inference for Tibetan or Tibetan-related populations, we analyzed this haplotype in 1053 individuals of 12 Chinese populations residing on the Tibetan Plateau, peripheral regions of Tibet, and plain regions. These data were integrated with the genotypes from the 1000 Genome populations and populations in a previously reported paper for population structure analyses. We found that populations representing highland and lowland groups have different dominant ancestry components. The core Denisovan haplotype (AGGAA) was observed at a frequency of 72.32% in the Tibetan Plateau, with a frequency range from 9.48 to 21.05% in the peripheral regions and Tibetan Plateau carried the archaic haplotype, while < 5% of the Chinese Han people carried the haplotype. Our findings indicate that the 5-SNP haplotype has a special distribution pattern in populations of Tibet and peripheral regions and could be integrated into AISNP (Ancestry Informative Single Nucleotide Polymorphism) panels to enhance ancestry resolution.

  10. Multi-channel software defined radio experimental evaluation and analysis

    CSIR Research Space (South Africa)

    Van der Merwe, JR

    2014-09-01

    Full Text Available Multi-channel software-defined radios (SDRs) can be utilised as inexpensive prototyping platforms for transceiver arrays. The application for multi-channel prototyping is discussed and measured results of coherent channels for both receiver...

  11. Haplotype analysis of the genes encoding glutamine synthetase plastic isoforms and their association with nitrogen-use- and yield-related traits in bread wheat.

    Science.gov (United States)

    Li, Xin-Peng; Zhao, Xue-Qiang; He, Xue; Zhao, Guang-Yao; Li, Bin; Liu, Dong-Cheng; Zhang, Ai-Min; Zhang, Xue-Yong; Tong, Yi-Ping; Li, Zhen-Sheng

    2011-01-01

    Glutamine synthetase (GS) plays a key role in the growth, nitrogen (N) use and yield potential of cereal crops. Investigating the haplotype variation of GS genes and its association with agronomic traits may provide useful information for improving wheat N-use efficiency and yield. We isolated the promoter and coding region sequences of the plastic glutamine synthetase isoform (GS2) genes located on chromosomes 2A, 2B and 2D in bread wheat. By analyzing nucleotide sequence variations of the coding region, two, six and two haplotypes were distinguished for TaGS2-A1 (a and b), TaGS2-B1 (a-f) and TaGS2-D1 (a and b), respectively. By analyzing the frequency data of different haplotypes and their association with N use and agronomic traits, four major and favorable TaGS2 haplotypes (A1b, B1a, B1b, D1a) were revealed. These favorable haplotypes may confer better seedling growth, better agronomic performance, and improved N uptake during vegetative growth or grain N concentration. Our data suggest that certain TaGS2 haplotypes may be valuable in breeding wheat varieties with improved agronomic performance and N-use efficiency. © The Authors (2010). Journal compilation © New Phytologist Trust (2010).

  12. Stability analysis of switched linear systems defined by graphs

    OpenAIRE

    Athanasopoulos, Nikolaos; Lazar, Mircea

    2015-01-01

    We present necessary and sufficient conditions for global exponential stability for switched discrete-time linear systems, under arbitrary switching, which is constrained within a set of admissible transitions. The class of systems studied includes the family of systems under arbitrary switching, periodic systems, and systems with minimum and maximum dwell time specifications. To reach the result, we describe the set of rules that define the admissible transitions with a weighted directed gra...

  13. SLC22A1-ABCB1 haplotype profiles predict imatinib pharmacokinetics in Asian patients with chronic myeloid leukemia.

    Directory of Open Access Journals (Sweden)

    Onkar Singh

    Full Text Available OBJECTIVE: This study aimed to explore the influence of SLC22A1, PXR, ABCG2, ABCB1 and CYP3A5 3 genetic polymorphisms on imatinib mesylate (IM pharmacokinetics in Asian patients with chronic myeloid leukemia (CML. PATIENTS AND METHODS: Healthy subjects belonging to three Asian populations (Chinese, Malay, Indian; n = 70 each and CML patients (n = 38 were enrolled in a prospective pharmacogenetics study. Imatinib trough (C(0h and clearance (CL were determined in the patients at steady state. Haplowalk method was applied to infer the haplotypes and generalized linear model (GLM to estimate haplotypic effects on IM pharmacokinetics. Association of haplotype copy numbers with IM pharmacokinetics was defined by Mann-Whitney U test. RESULTS: Global haplotype score statistics revealed a SLC22A1 sub-haplotypic region encompassing three polymorphisms (rs3798168, rs628031 and IVS7+850C>T, to be significantly associated with IM clearance (p = 0.013. Haplotype-specific GLM estimated that the haplotypes AGT and CGC were both associated with 22% decrease in clearance compared to CAC [CL (10(-2 L/hr/mg: CAC vs AGT: 4.03 vs 3.16, p = 0.017; CAC vs CGC: 4.03 vs 3.15, p = 0.017]. Patients harboring 2 copies of AGT or CGC haplotypes had 33.4% lower clearance and 50% higher C(0h than patients carrying 0 or 1 copy [CL (10(-2 L/hr/mg: 2.19 vs 3.29, p = 0.026; C(0h (10(-6 1/ml: 4.76 vs 3.17, p = 0.013, respectively]. Further subgroup analysis revealed SLC22A1 and ABCB1 haplotypic combinations to be significantly associated with clearance and C(0h (p = 0.002 and 0.009, respectively. CONCLUSION: This exploratory study suggests that SLC22A1-ABCB1 haplotypes may influence IM pharmacokinetics in Asian CML patients.

  14. Work program analysis - defining the capability/risk plan

    International Nuclear Information System (INIS)

    Hrinivich, W.A.

    2004-01-01

    Bruce Power has developed and implemented an analysis methodology (Work Program Analysis) to assess and address corporate business risk associated with work group capability. Work Program Analysis is proving to be an excellent tool for identifying and supporting key business decisions facing the line and senior management at Bruce Power. The following describes the methodology, its application and the results achieved. (author)

  15. Association analysis of the dopamine D{sub 2} receptor gene in Tourette`s syndrome using the haplotype relative risk method

    Energy Technology Data Exchange (ETDEWEB)

    Noethen, M.M.; Cichon, S.; Propping, P. [Univ. of Bonn (Germany)] [and others

    1994-09-15

    Comings et al. have recently reported a highly significant association between Tourette`s syndrome (TS) and a restriction fragment length polymorphism (RFLP) of the dopamine D{sub 2} receptor gene (DRD2) locus. The A1 allele of the DRD2 Taq I RFLP was present in 45% of the Tourette patients compared with 25% of controls. We tried to replicate this finding by using the haplotype relative risk (HRR) method for association analysis. This method overcomes a major problem of conventional case-control studies, where undetected ethnic differences between patients and controls may result in a false-positive finding, by using parental alleles not inherited by the proband as control alleles. Sixty-one nuclear families encompassing an affected child and parents were typed for the DRD2 Taq I polymorphism. No significant differences in DRD2 A1 allele frequency were observed between TS probands, sub-populations of probands classified according to tic severity, or parental control alleles. Our data do not support the hypothesis that the DRD2 locus may act as a modifying gene in the expression of the disorder in TS probands. 40 refs., 1 tab.

  16. Are molecular haplotypes worth the time and expense? A cost-effective method for applying molecular haplotypes.

    Directory of Open Access Journals (Sweden)

    Mark A Levenstien

    2006-08-01

    Full Text Available Because current molecular haplotyping methods are expensive and not amenable to automation, many researchers rely on statistical methods to infer haplotype pairs from multilocus genotypes, and subsequently treat these inferred haplotype pairs as observations. These procedures are prone to haplotype misclassification. We examine the effect of these misclassification errors on the false-positive rate and power for two association tests. These tests include the standard likelihood ratio test (LRTstd and a likelihood ratio test that employs a double-sampling approach to allow for the misclassification inherent in the haplotype inference procedure (LRTae. We aim to determine the cost-benefit relationship of increasing the proportion of individuals with molecular haplotype measurements in addition to genotypes to raise the power gain of the LRTae over the LRTstd. This analysis should provide a guideline for determining the minimum number of molecular haplotypes required for desired power. Our simulations under the null hypothesis of equal haplotype frequencies in cases and controls indicate that (1 for each statistic, permutation methods maintain the correct type I error; (2 specific multilocus genotypes that are misclassified as the incorrect haplotype pair are consistently misclassified throughout each entire dataset; and (3 our simulations under the alternative hypothesis showed a significant power gain for the LRTae over the LRTstd for a subset of the parameter settings. Permutation methods should be used exclusively to determine significance for each statistic. For fixed cost, the power gain of the LRTae over the LRTstd varied depending on the relative costs of genotyping, molecular haplotyping, and phenotyping. The LRTae showed the greatest benefit over the LRTstd when the cost of phenotyping was very high relative to the cost of genotyping. This situation is likely to occur in a replication study as opposed to a whole-genome association study.

  17. Defining Business decline, failure and turnaround: A content analysis

    Directory of Open Access Journals (Sweden)

    Marius Pretorius

    2009-12-01

    Full Text Available In the past, researchers have often defined failure to suit their data. This has led to a lack of comparability in research outputs. The overriding objective of this paper is to propose a universal definition for the failure phenomenon. Clear definitions are a prerequisite for exploring major constructs, their relationship to failure and the context and processes involved. The study reports on the core definitions of the failure phenomenon and identifies core criteria for distinguishing between them. It places decline, failure and turnaround in perspective and highlights level of distress and turnaround as key moderating elements. It distinguishes the failure phenomenon from controversial synonyms such as closure, accidental bankruptcy and closure for alternative motives. Key words and phrases: business decline, failure, turnaround, level of distress

  18. Transcriptome analysis reveals the same 17 S-locus F-box genes in two haplotypes of the self-incompatibility locus of Petunia inflata.

    Science.gov (United States)

    Williams, Justin S; Der, Joshua P; dePamphilis, Claude W; Kao, Teh-Hui

    2014-07-01

    Petunia possesses self-incompatibility, by which pistils reject self-pollen but accept non-self-pollen for fertilization. Self-/non-self-recognition between pollen and pistil is regulated by the pistil-specific S-RNase gene and by multiple pollen-specific S-locus F-box (SLF) genes. To date, 10 SLF genes have been identified by various methods, and seven have been shown to be involved in pollen specificity. For a given S-haplotype, each SLF interacts with a subset of its non-self S-RNases, and an as yet unknown number of SLFs are thought to collectively mediate ubiquitination and degradation of all non-self S-RNases to allow cross-compatible pollination. To identify a complete suite of SLF genes of P. inflata, we used a de novo RNA-seq approach to analyze the pollen transcriptomes of S2-haplotype and S3-haplotype, as well as the leaf transcriptome of the S3S3 genotype. We searched for genes that fit several criteria established from the properties of the known SLF genes and identified the same seven new SLF genes in S2-haplotype and S3-haplotype, suggesting that a total of 17 SLF genes constitute pollen specificity in each S-haplotype. This finding lays the foundation for understanding how multiple SLF genes evolved and the biochemical basis for differential interactions between SLF proteins and S-RNases. © 2014 American Society of Plant Biologists. All rights reserved.

  19. Defining Antimicrobial Textile Requirements for Military Applications - A Gap Analysis

    Science.gov (United States)

    2016-05-09

    yard of fabric for the ACU. The antimicrobial added to the Fire - Resistant Environmental Ensemble (FREE) socks increased cost about $2 per pair...There were also very little conclusive laboratory and field test data on the effectiveness, risks, and potential for bacterial resistance of use of...RISK ANALYSIS LABORATORY TESTS TEST AND EVALUATION FABRICS BODY ODOR REQUIREMENTS FUNGAL INFECTIONS

  20. Five novel glucose-6-phosphate dehydrogenase deficiency haplotypes correlating with disease severity

    Directory of Open Access Journals (Sweden)

    Dallol Ashraf

    2012-09-01

    Full Text Available Abstract Background Glucose-6-phosphate dehydrogenase (G6PD, EC 1.1.1.49 deficiency is caused by one or more mutations in the G6PD gene on chromosome X. An association between enzyme levels and gene haplotypes remains to be established. Methods In this study, we determined G6PD enzyme levels and sequenced the coding region, including the intron-exon boundaries, in a group of individuals (163 males and 86 females who were referred to the clinic with suspected G6PD deficiency. The sequence data were analysed by physical linkage analysis and PHASE haplotype reconstruction. Results All previously reported G6PD missense changes, including the AURES, MEDITERRANEAN, A-, SIBARI, VIANGCHAN and ANANT, were identified in our cohort. The AURES mutation (p.Ile48Thr was the most common variant in the cohort (30% in males patients followed by the Mediterranean variant (p.Ser188Phe detectable in 17.79% in male patients. Variant forms of the A- mutation (p.Val68Met, p.Asn126Asp or a combination of both were detectable in 15.33% of the male patients. However, unique to this study, several of such mutations co-existed in the same patient as shown by physical linkage in males or PHASE haplotype reconstruction in females. Based on 6 non-synonymous variants of G6PD, 13 different haplotypes (13 in males, 8 in females were identified. Five of these were previously unreported (Jeddah A, B, C, D and E and were defined by previously unreported combinations of extant mutations where patients harbouring these haplotypes exhibited severe G6PD deficiency. Conclusions Our findings will help design a focused population screening approach and provide better management for G6PD deficiency patients.

  1. Mutation profile of all 49 exons of the human myosin VIIA gene, and haplotype analysis, in Usher 1B families from diverse origins.

    Science.gov (United States)

    Adato, A; Weil, D; Kalinski, H; Pel-Or, Y; Ayadi, H; Petit, C; Korostishevsky, M; Bonne-Tamir, B

    1997-10-01

    Usher syndrome types I (USH1A-USH1E) are a group of autosomal recessive diseases characterized by profound congenital hearing loss, vestibular areflexia, and progressive visual loss due to retinitis pigmentosa. The human myosin VIIA gene, located on 11q14, has been shown to be responsible for Usher syndrome type 1B (USH1B). Haplotypes were constructed in 28 USH1 families by use of the following polymorphic markers spanning the USH1B locus: D11S787, D11S527, D11S1789, D11S906, D11S4186, and OMP. Affected individuals and members of their families from 12 different ethnic origins were screened for the presence of mutations in all 49 exons of the myosin VIIA gene. In 15 families myosin VIIA mutations were detected, verifying their classification as USH1B. All these mutations are novel, including three missense mutations, one premature stop codon, two splicing mutations, one frameshift, and one deletion of >2 kb comprising exons 47 and 48, a part of exon 49, and the introns between them. Three mutations were shared by more than one family, consistent with haplotype similarities. Altogether, 16 USH1B haplotypes were observed in the 15 families; most haplotypes were population specific. Several exonic and intronic polymorphisms were also detected. None of the 20 known USH1B mutations reported so far in other world populations were identified in our families.

  2. Numerical analysis on pool boiling using user defined function

    Energy Technology Data Exchange (ETDEWEB)

    Ryu, Sung Uk; Jeon, Byong Guk; Kim, Seok; Euh, Dong-Jin [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2015-10-15

    PAFS (passive auxiliary feedwater system) adopted in the APR+ (Advanced Power Reactor Plus) of Korea is one such application. When PAFS is activated with an actuation signal, steam from the steam generator passes through heat exchanger tubes submerged in a water tank of the PAFS. Outside these heat exchanger tubes, nucleate boiling phenomena appears. In the present work, a numerical study is reported on three-dimensional transient state pool boiling of water having an immersed heat source. The velocity vector fields during the decrease in the water level are numerically investigated in a pool, and the accuracy of the results is checked by comparing the experimental results conducted using the PIV techniques by Kim et al. These numerical results can be used as basic research data for an analysis and prediction of the natural circulation phenomena in the cooling tank of the passive safety system in a nuclear power plant.

  3. Analysis of HLA class II haplotypes in the Cayapa indians of ecuador: A novel DRBI allele reveals evidence for convergent evolution and balancing selection at position 86

    Energy Technology Data Exchange (ETDEWEB)

    Titus-Trachtenberg, E.A.; Erlich, H. (Roche Molecular Systems, Alameda, CA (United States)); Rickards, O.; De Stefano, G.F. (Universita di Roma, Rome (Italy))

    1994-07-01

    PCR amplification, oligonucleotide probe typing, and sequencing were used to analyze the HLA class II loci (DRB1, DQA1, DAB1, and DPB1) of an isolated South Amerindian tribe. Here the authors report HLA class II variation, including the identification of a new DRB1 allele, several novel DR/DQ haplotypes, and an unusual distribution of DPB1 alleles, among the Cayapa Indians (N=100) of Ecuador. A general reduction of HLA class II allelic variation in the Cayapa is consistent with a population bottleneck during the colonization of the Americas. The new Cayapa DRB1 allele, DRB1[sup *]08042, which arose by a G[yields]T point mutation in the parental DRB1[sup *]0802, contains a novel Val codon (GTT) at position 86. The generation of DRB1[sup *]08042 (Val-86) from DRB1[sup *]0802 (Gly-86) in the Cayapa, by a different mechanism than the (GT[yields]TG) change in the creation of DRB1[sub *]08041 (Val-86) from DRB1[sup *]0802 in Africa, implicates selection in the convergent evolution of position 86 DR[beta] variants. The DRB1[sup *]08042 allele has not been found in >1,800 Amerindian haplotypes and thus presumably arose after the Cayapa separated from other South American Amerindians. Selection pressure for increased haplotype diversity can be inferred in the generation and maintenance of three new DRB1[sup *]08042 haplotypes and several novel DR/DQ haplotypes in this population. The DPB1 allelic distribution in the Cayapa is also extraordinary, with two alleles, DPB1[sup *]1401, a very rare allele in North American Amerindian populations, and DPB1[sup *]0402, the most common Amerindian DPB1 allele, constituting 89% of the Cayapa DPB1. These data are consistent with the postulated rapid rate of evolution as noted for the class I HLA-B locus of other South American Indians. 34 refs., 2 figs., 2 tabs.

  4. De novo assembly of a haplotype-resolved human genome.

    Science.gov (United States)

    Cao, Hongzhi; Wu, Honglong; Luo, Ruibang; Huang, Shujia; Sun, Yuhui; Tong, Xin; Xie, Yinlong; Liu, Binghang; Yang, Hailong; Zheng, Hancheng; Li, Jian; Li, Bo; Wang, Yu; Yang, Fang; Sun, Peng; Liu, Siyang; Gao, Peng; Huang, Haodong; Sun, Jing; Chen, Dan; He, Guangzhu; Huang, Weihua; Huang, Zheng; Li, Yue; Tellier, Laurent C A M; Liu, Xiao; Feng, Qiang; Xu, Xun; Zhang, Xiuqing; Bolund, Lars; Krogh, Anders; Kristiansen, Karsten; Drmanac, Radoje; Drmanac, Snezana; Nielsen, Rasmus; Li, Songgang; Wang, Jian; Yang, Huanming; Li, Yingrui; Wong, Gane Ka-Shu; Wang, Jun

    2015-06-01

    The human genome is diploid, and knowledge of the variants on each chromosome is important for the interpretation of genomic information. Here we report the assembly of a haplotype-resolved diploid genome without using a reference genome. Our pipeline relies on fosmid pooling together with whole-genome shotgun strategies, based solely on next-generation sequencing and hierarchical assembly methods. We applied our sequencing method to the genome of an Asian individual and generated a 5.15-Gb assembled genome with a haplotype N50 of 484 kb. Our analysis identified previously undetected indels and 7.49 Mb of novel coding sequences that could not be aligned to the human reference genome, which include at least six predicted genes. This haplotype-resolved genome represents the most complete de novo human genome assembly to date. Application of our approach to identify individual haplotype differences should aid in translating genotypes to phenotypes for the development of personalized medicine.

  5. In Vivo Characterization of Human APOA5 Haplotypes

    Energy Technology Data Exchange (ETDEWEB)

    Ahituv, Nadav; Akiyama, Jennifer; Chapman-Helleboid, Audrey; Fruchart, Jamila; Pennacchio, Len A.

    2006-10-01

    Increased plasma triglycerides concentrations are an independent risk factor for cardiovascular disease. Numerous studies support a reproducible genetic association between two minor haplotypes in the human apolipoprotein A5 gene (APOA5) and increased plasma triglyceride concentrations. We thus sought to investigate the effect of these minor haplotypes (APOA5*2 and APOA5*3) on ApoAV plasma levels through the precise insertion of single-copy intact APOA5 haplotypes at a targeted location in the mouse genome. While we found no difference in the amount of human plasma ApoAV in mice containing the common APOA5*1 and minor APOA5*2 haplotype, the introduction of the single APOA5*3 defining allele (19W) resulted in 3-fold lower ApoAV plasma levels consistent with existing genetic association studies. These results indicate that S19W polymorphism is likely to be functional and explain the strong association of this variant with plasma triglycerides supporting the value of sensitive in vivo assays to define the functional nature of human haplotypes.

  6. An Integrated Gait and Balance Analysis System to Define Human Locomotor Control

    Science.gov (United States)

    2016-04-29

    test hypotheses they developed about how people walk. An Integrated Gait and Balance Analysis System to define Human Locomotor Control W911NF-14-R-0009...An Integrated Gait and Balance Analysis System to Define Human Locomotor Control Walking is a complicated task that requires the motor coordination...Gait and Balance Analysis System to Define Human Locomotor Control Report Title Walking is a complicated task that requires the motor coordination across

  7. The iSelect 9 K SNP analysis revealed polyploidization induced revolutionary changes and intense human selection causing strong haplotype blocks in wheat.

    Science.gov (United States)

    Hao, Chenyang; Wang, Yuquan; Chao, Shiaoman; Li, Tian; Liu, Hongxia; Wang, Lanfen; Zhang, Xueyong

    2017-01-30

    A Chinese wheat mini core collection was genotyped using the wheat 9 K iSelect SNP array. Total 2420 and 2396 polymorphic SNPs were detected on the A and the B genome chromosomes, which formed 878 haplotype blocks. There were more blocks in the B genome, but the average block size was significantly (P polyploidization of wheat (both tetraploidization and hexaploidization) induced revolutionary changes in both the A and the B genomes, with a greater increase of gene diversity compared to their diploid ancestors. Modern breeding has dramatically increased diversity in the gene coding regions, though obvious blocks were formed on most of the chromosomes in both tetraploid and hexaploid wheats. Tag-SNP markers identified in this study can be used for marker assisted selection using haplotype blocks as a wheat breeding strategy. This strategy can also be employed to facilitate genome selection in other self-pollinating crop species.

  8. Designing and conducting in silico analysis for identifying of Echinococcus spp. with discrimination of novel haplotypes: an approach to better understanding of parasite taxonomic.

    Science.gov (United States)

    Spotin, Adel; Gholami, Shirzad; Nasab, Abbas Najafi; Fallah, Esmaeil; Oskouei, Mahmoud Mahami; Semnani, Vahid; Shariatzadeh, Seyyed Ali; Shahbazi, Abbas

    2015-04-01

    The definitive identification of Echinococcus species is currently carried out by sequencing and phylogenetic strategies. However, the application of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) patterns is not broadly used as a result of heterogeneity traits of Echinococcus genome in different regions of the world. Therefore, designing and conducting a standardized pattern should indigenously be considered in under-studied areas. In this investigation, an in silico mapping was designed and developed for eight Echinococcus spp. on the basis of regional sequences in Iran and the world. The numbers of 60 Echinococcus isolates were collected from the liver and lungs of 15 human, 15 sheep, 15 cattle, and 15 camel cases in Semnan province, Central Iran. DNA samples were extracted and examined by polymerase chain reaction of ribosomal DNA (rDNA) internal transcribed spacer 1 (ITS1) and PCR-RFLP via Rsa1 endonuclease enzyme. Moreover, 15 amplicons of cytochrome oxidase 1 (Cox1) were directly sequenced in order to identify the strains/haplotypes. PCR-RFLP and phylogenetic analyses revealed firmly the presence of the G1 and G6 genotypes with heterogeneity (three novel haplotypes) of Cox1 gene although no other expected genotypes were found in the region. Finding shows that the identification of novel haplotypes along with discrimination of Echinococcus spp. through regional patterns can unambiguously illustrate the real taxonomic status of parasite in Central Iran.

  9. Approximation properties of haplotype tagging

    Directory of Open Access Journals (Sweden)

    Dreiseitl Stephan

    2006-01-01

    Full Text Available Abstract Background Single nucleotide polymorphisms (SNPs are locations at which the genomic sequences of population members differ. Since these differences are known to follow patterns, disease association studies are facilitated by identifying SNPs that allow the unique identification of such patterns. This process, known as haplotype tagging, is formulated as a combinatorial optimization problem and analyzed in terms of complexity and approximation properties. Results It is shown that the tagging problem is NP-hard but approximable within 1 + ln((n2 - n/2 for n haplotypes but not approximable within (1 - ε ln(n/2 for any ε > 0 unless NP ⊂ DTIME(nlog log n. A simple, very easily implementable algorithm that exhibits the above upper bound on solution quality is presented. This algorithm has running time O((2m - p + 1 ≤ O(m(n2 - n/2 where p ≤ min(n, m for n haplotypes of size m. As we show that the approximation bound is asymptotically tight, the algorithm presented is optimal with respect to this asymptotic bound. Conclusion The haplotype tagging problem is hard, but approachable with a fast, practical, and surprisingly simple algorithm that cannot be significantly improved upon on a single processor machine. Hence, significant improvement in computatational efforts expended can only be expected if the computational effort is distributed and done in parallel.

  10. Pathways to injury in chronic pancreatitis: decoding the role of the high-risk SPINK1 N34S haplotype using meta-analysis.

    Directory of Open Access Journals (Sweden)

    Elie Aoun

    2008-04-01

    Full Text Available The complex interactions between recurrent trypsin-mediated pancreatic injury, alcohol-associated pancreatic injury and SPINK1 polymorphisms in chronic pancreatitis (CP are undefined. We hypothesize that CP occurs as a result of multiple pathological mechanisms (pathways that are initiated by different metabolic or environmental factors (etiologies and may be influenced differentially by downstream genetic risk factors. We tested this hypothesis by evaluating the differences in effect size of the high risk SPINK1 N34S haplotype on CP from multiple etiologies after combining clinical reports of SPINK1 N34S frequency using meta-analysis.The Pubmed and the Embase databases were reviewed. We studied 24 reports of SPINK1 N34S in CP (2,421 cases, 4,857 controls using reported etiological factors as surrogates for pathways and multiple meta-analyses to determine the differential effects of SPINK1 N34S between alcoholic and non-alcoholic etiologies. Using estimates of between-study heterogeneity, we sub-classified our 24 studies into four specific clusters. We found that SPINK1 N34S is strongly associated with CP overall (OR 11.00; 95% CI: 7.59-15.93, but the effect of SPINK1 N34S in alcoholic CP (OR 4.98, 95% CI: 3.16-7.85 was significantly smaller than in idiopathic CP (OR 14.97, 95% C.I. = 9.09-24.67 or tropical CP (OR 19.15, 95% C.I. = 8.83-41.56. Studies analyzing familial CP showed very high heterogeneity suggestive of a complex etiology with an I(2 = 80.95%.The small effect of SPINK1 N34S in alcoholic subjects suggests that CP is driven through a different pathway that is largely trypsin-independent. The results also suggest that large effect sizes of SPINK1 N34S in small candidate gene studies in CP may be related to a mixture of multiple etiologic pathways leading to the same clinical endpoint.

  11. Detecting structure of haplotypes and local ancestry

    Science.gov (United States)

    We present a two-layer hidden Markov model to detect the structure of haplotypes for unrelated individuals. This allows us to model two scales of linkage disequilibrium (one within a group of haplotypes and one between groups), thereby taking advantage of rich haplotype information to infer local an...

  12. Prion gene haplotypes of U.S. cattle

    Directory of Open Access Journals (Sweden)

    Harhay Gregory P

    2006-11-01

    Full Text Available Abstract Background Bovine spongiform encephalopathy (BSE is a fatal neurological disorder characterized by abnormal deposits of a protease-resistant isoform of the prion protein. Characterizing linkage disequilibrium (LD and haplotype networks within the bovine prion gene (PRNP is important for 1 testing rare or common PRNP variation for an association with BSE and 2 interpreting any association of PRNP alleles with BSE susceptibility. The objective of this study was to identify polymorphisms and haplotypes within PRNP from the promoter region through the 3'UTR in a diverse sample of U.S. cattle genomes. Results A 25.2-kb genomic region containing PRNP was sequenced from 192 diverse U.S. beef and dairy cattle. Sequence analyses identified 388 total polymorphisms, of which 287 have not previously been reported. The polymorphism alleles define PRNP by regions of high and low LD. High LD is present between alleles in the promoter region through exon 2 (6.7 kb. PRNP alleles within the majority of intron 2, the entire coding sequence and the untranslated region of exon 3 are in low LD (18.0 kb. Two haplotype networks, one representing the region of high LD and the other the region of low LD yielded nineteen different combinations that represent haplotypes spanning PRNP. The haplotype combinations are tagged by 19 polymorphisms (htSNPS which characterize variation within and across PRNP. Conclusion The number of polymorphisms in the prion gene region of U.S. cattle is nearly four times greater than previously described. These polymorphisms define PRNP haplotypes that may influence BSE susceptibility in cattle.

  13. Updated listing of haplotypes at the human phenylalanine hydroxylase (PAH) locus

    Energy Technology Data Exchange (ETDEWEB)

    Eisensmith, R.C.; Woo, S.L.C. (Baylor College of Medicine, Houston, TX (United States))

    1992-12-01

    Analysis of mutant PAH chromosomes has identified approximately 60 different single-base substitutions and deletions within the PAH locus. Nearly all of these molecular lesions are in strong linkage disequilibrium with specific RFLP haplotypes in different ethnic populations. Thus, haplotype analysis is not only useful for diagnostic purposes but is proving to be a valuable tool in population genetic studies of the origin and spread of phenylketonuria alleles in human populations. PCR-based methods have been developed to detect six of the eight polymorphic restriction sites used for determination of RFLP haplotypes at the PAH locus. A table of the proposed expanded haplotypes is given.

  14. Haplotype Analysis of the Pre-harvest Sprouting Resistance Locus Phs-A1 Reveals a Causal Role of TaMKK3-A in Global Germplasm

    Czech Academy of Sciences Publication Activity Database

    Shorinola, O.; Balcárková, Barbora; Hyles, J.; Tibbits, J. F. G.; Hayden, M. J.; Holušová, Kateřina; Valárik, Miroslav; Distelfeld, A.; Torada, A.; Barrero, R. A.; Uauy, C.

    2017-01-01

    Roč. 8, SEP 13 (2017), č. článku 1555. ISSN 1664-462X R&D Projects: GA MŠk(CZ) LO1204; GA ČR(CZ) GA14-07164S Institutional support: RVO:61389030 Keywords : triticum-aestivum l. * controlling seed dormancy * white-grained wheat * pcr-based markers * chromosome 4a * winter-wheat * major qtl * abscisic-acid * bread wheat * genes * dormancy * seed * pm19 * TaMKK3-A * pre-harvest sprouting * Triticum aestivum * haplotype Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Plant sciences, botany Impact factor: 4.298, year: 2016

  15. A new mathematical modeling for pure parsimony haplotyping problem.

    Science.gov (United States)

    Feizabadi, R; Bagherian, M; Vaziri, H R; Salahi, M

    2016-11-01

    Pure parsimony haplotyping (PPH) problem is important in bioinformatics because rational haplotyping inference plays important roles in analysis of genetic data, mapping complex genetic diseases such as Alzheimer's disease, heart disorders and etc. Haplotypes and genotypes are m-length sequences. Although several integer programing models have already been presented for PPH problem, its NP-hardness characteristic resulted in ineffectiveness of those models facing the real instances especially instances with many heterozygous sites. In this paper, we assign a corresponding number to each haplotype and genotype and based on those numbers, we set a mixed integer programing model. Using numbers, instead of sequences, would lead to less complexity of the new model in comparison with previous models in a way that there are neither constraints nor variables corresponding to heterozygous nucleotide sites in it. Experimental results approve the efficiency of the new model in producing better solution in comparison to two state-of-the art haplotyping approaches. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Defining disease beyond conceptual analysis: an analysis of conceptual analysis in philosophy of medicine.

    Science.gov (United States)

    Lemoine, Maël

    2013-08-01

    Conceptual analysis of health and disease is portrayed as consisting in the confrontation of a set of criteria--a "definition"--with a set of cases, called instances of either "health" or "disease." Apart from logical counter-arguments, there is no other way to refute an opponent's definition than by providing counter-cases. As resorting to intensional stipulation (stipulation of meaning) is not forbidden, several contenders can therefore be deemed to have succeeded. This implies that conceptual analysis alone is not likely to decide between naturalism and normativism. An alternative to this approach would be to examine whether the concept of disease can be naturalized.

  17. Common ataxia telangiectasia mutated haplotypes and risk of breast cancer: a nested case–control study

    International Nuclear Information System (INIS)

    Tamimi, Rulla M; Hankinson, Susan E; Spiegelman, Donna; Kraft, Peter; Colditz, Graham A; Hunter, David J

    2004-01-01

    The ataxia telangiectasia mutated (ATM) gene is a tumor suppressor gene with functions in cell cycle arrest, apoptosis, and repair of DNA double-strand breaks. Based on family studies, women heterozygous for mutations in the ATM gene are reported to have a fourfold to fivefold increased risk of breast cancer compared with noncarriers of the mutations, although not all studies have confirmed this association. Haplotype analysis has been suggested as an efficient method for investigating the role of common variation in the ATM gene and breast cancer. Five biallelic haplotype tagging single nucleotide polymorphisms are estimated to capture 99% of the haplotype diversity in Caucasian populations. We conducted a nested case–control study of breast cancer within the Nurses' Health Study cohort to address the role of common ATM haplotypes and breast cancer. Cases and controls were genotyped for five haplotype tagging single nucleotide polymorphisms. Haplotypes were predicted for 1309 cases and 1761 controls for which genotype information was available. Six unique haplotypes were predicted in this study, five of which occur at a frequency of 5% or greater. The overall distribution of haplotypes was not significantly different between cases and controls (χ 2 = 3.43, five degrees of freedom, P = 0.63). There was no evidence that common haplotypes of ATM are associated with breast cancer risk. Extensive single nucleotide polymorphism detection using the entire genomic sequence of ATM will be necessary to rule out less common variation in ATM and sporadic breast cancer risk

  18. ADAGE signature analysis: differential expression analysis with data-defined gene sets.

    Science.gov (United States)

    Tan, Jie; Huyck, Matthew; Hu, Dongbo; Zelaya, René A; Hogan, Deborah A; Greene, Casey S

    2017-11-22

    ADAGE signature analysis to perform gene set analysis using data-defined functional gene signatures. This approach addresses an important gap for biologists studying non-traditional model organisms and those without extensive curated resources available. We built both an R package and web server to provide ADAGE signature analysis to the community.

  19. MGMT DNA repair gene promoter/enhancer haplotypes alter transcription factor binding and gene expression.

    Science.gov (United States)

    Xu, Meixiang; Cross, Courtney E; Speidel, Jordan T; Abdel-Rahman, Sherif Z

    2016-10-01

    The O 6 -methylguanine-DNA methyltransferase (MGMT) protein removes O 6 -alkyl-guanine adducts from DNA. MGMT expression can thus alter the sensitivity of cells and tissues to environmental and chemotherapeutic alkylating agents. Previously, we defined the haplotype structure encompassing single nucleotide polymorphisms (SNPs) in the MGMT promoter/enhancer (P/E) region and found that haplotypes, rather than individual SNPs, alter MGMT promoter activity. The exact mechanism(s) by which these haplotypes exert their effect on MGMT promoter activity is currently unknown, but we noted that many of the SNPs comprising the MGMT P/E haplotypes are located within or in close proximity to putative transcription factor binding sites. Thus, these haplotypes could potentially affect transcription factor binding and, subsequently, alter MGMT promoter activity. In this study, we test the hypothesis that MGMT P/E haplotypes affect MGMT promoter activity by altering transcription factor (TF) binding to the P/E region. We used a promoter binding TF profiling array and a reporter assay to evaluate the effect of different P/E haplotypes on TF binding and MGMT expression, respectively. Our data revealed a significant difference in TF binding profiles between the different haplotypes evaluated. We identified TFs that consistently showed significant haplotype-dependent binding alterations (p ≤ 0.01) and revealed their role in regulating MGMT expression using siRNAs and a dual-luciferase reporter assay system. The data generated support our hypothesis that promoter haplotypes alter the binding of TFs to the MGMT P/E and, subsequently, affect their regulatory function on MGMT promoter activity and expression level.

  20. A haplotype regression approach for genetic evaluation using sequences from the 1000 bull genomes Project

    International Nuclear Information System (INIS)

    Lakhssassi, K.; González-Recio, O.

    2017-01-01

    Haplotypes from sequencing data may improve the prediction accuracy in genomic evaluations as haplotypes are in stronger linkage disequilibrium with quantitative trait loci than markers from SNP chips. This study focuses first, on the creation of haplotypes in a population sample of 450 Holstein animals, with full-sequence data from the 1000 bull genomes project; and second, on incorporating them into the whole genome prediction model. In total, 38,319,258 SNPs (and indels) from Next Generation Sequencing were included in the analysis. After filtering variants with minor allele frequency (MAF< 0.025) 13,912,326 SNPs were available for the haplotypes extraction with findhap.f90. The number of SNPs in the haploblocks was on average 924 SNP (166,552 bp). Unique haplotypes were around 97% in all chromosomes and were ignored leaving 153,428 haplotypes. Estimated haplotypes had a large contribution to the total variance of genomic estimated breeding values for kilogram of protein, Global Type Index, Somatic Cell Score and Days Open (between 32 and 99.9%). Haploblocks containing haplotypes with large effects were selected by filtering for each trait, haplotypes whose effect was larger/lower than the mean plus/minus 3 times the standard deviation (SD) and 1 SD above the mean of the haplotypes effect distribution. Results showed that filtering by 3 SD would not be enough to capture a large proportion of genetic variance, whereas filtering by 1 SD could be useful but model convergence should be considered. Additionally, sequence haplotypes were able to capture additional genetic variance to the polygenic effect for traits undergoing lower selection intensity like fertility and health traits.

  1. A haplotype regression approach for genetic evaluation using sequences from the 1000 bull genomes Project

    Energy Technology Data Exchange (ETDEWEB)

    Lakhssassi, K.; González-Recio, O.

    2017-07-01

    Haplotypes from sequencing data may improve the prediction accuracy in genomic evaluations as haplotypes are in stronger linkage disequilibrium with quantitative trait loci than markers from SNP chips. This study focuses first, on the creation of haplotypes in a population sample of 450 Holstein animals, with full-sequence data from the 1000 bull genomes project; and second, on incorporating them into the whole genome prediction model. In total, 38,319,258 SNPs (and indels) from Next Generation Sequencing were included in the analysis. After filtering variants with minor allele frequency (MAF< 0.025) 13,912,326 SNPs were available for the haplotypes extraction with findhap.f90. The number of SNPs in the haploblocks was on average 924 SNP (166,552 bp). Unique haplotypes were around 97% in all chromosomes and were ignored leaving 153,428 haplotypes. Estimated haplotypes had a large contribution to the total variance of genomic estimated breeding values for kilogram of protein, Global Type Index, Somatic Cell Score and Days Open (between 32 and 99.9%). Haploblocks containing haplotypes with large effects were selected by filtering for each trait, haplotypes whose effect was larger/lower than the mean plus/minus 3 times the standard deviation (SD) and 1 SD above the mean of the haplotypes effect distribution. Results showed that filtering by 3 SD would not be enough to capture a large proportion of genetic variance, whereas filtering by 1 SD could be useful but model convergence should be considered. Additionally, sequence haplotypes were able to capture additional genetic variance to the polygenic effect for traits undergoing lower selection intensity like fertility and health traits.

  2. Chronic inflammatory state in sickle cell anemia patients is associated with HBB(*)S haplotype.

    Science.gov (United States)

    Bandeira, Izabel C J; Rocha, Lillianne B S; Barbosa, Maritza C; Elias, Darcielle B D; Querioz, José A N; Freitas, Max Vitor Carioca; Gonçalves, Romélia P

    2014-02-01

    The chronic inflammatory state in sickle cell anemia (SCA) is associated with several factors such as the following: endothelial damage; increased production of reactive oxygen species; hemolysis; increased expression of adhesion molecules by leukocytes, erythrocytes, and platelets; and increased production of proinflammatory cytokines. Genetic characteristics affecting the clinical severity of SCA include variations in the hemoglobin F (HbF) level, coexistence of alpha-thalassemia, and the haplotype associated with the HbS gene. The different haplotypes of SCA are Bantu, Benin, Senegal, Cameroon, and Arab-Indian. These haplotypes are associated with ethnic groups and also based on the geographical origin. Studies have shown that the Bantu haplotype is associated with higher incidence of clinical complications than the other haplotypes and is therefore considered to have the worst prognosis. This study aimed to evaluate the profile of the proinflammatory cytokines interleukin-6, tumor necrosis factor-α, and interleukin-17 in patients with SCA and also to assess the haplotypes associated with beta globin cluster S (HBB(*)S). We analyzed a total of 62 patients who had SCA and had been treated with hydroxyurea; they had received a dose ranging between 15 and 25 (20.0±0.6)mg/kg/day for 6-60 (18±3.4)months; their data were compared with those for 30 normal individuals. The presence of HbS was detected and the haplotypes of the beta S gene cluster were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Our study demonstrated that SCA patients have increased inflammatory profile when compared to the healthy individuals. Further, analysis of the association between the haplotypes and inflammatory profile showed that the levels of IL-6 and TNF-α were greater in subjects with the Bantu/Bantu haplotype than in subjects with the Benin/Benin haplotype. The Bantu/Benin haplotype individuals had lower levels of cytokines than those with

  3. Estimating haplotype effects for survival data

    DEFF Research Database (Denmark)

    Scheike, Thomas; Martinussen, Torben; Silver, J

    2010-01-01

    Genetic association studies often investigate the effect of haplotypes on an outcome of interest. Haplotypes are not observed directly, and this complicates the inclusion of such effects in survival models. We describe a new estimating equations approach for Cox's regression model to assess haplo...

  4. Haplotype-Based Genotyping in Polyploids

    Directory of Open Access Journals (Sweden)

    Josh P. Clevenger

    2018-04-01

    Full Text Available Accurate identification of polymorphisms from sequence data is crucial to unlocking the potential of high throughput sequencing for genomics. Single nucleotide polymorphisms (SNPs are difficult to accurately identify in polyploid crops due to the duplicative nature of polyploid genomes leading to low confidence in the true alignment of short reads. Implementing a haplotype-based method in contrasting subgenome-specific sequences leads to higher accuracy of SNP identification in polyploids. To test this method, a large-scale 48K SNP array (Axiom Arachis2 was developed for Arachis hypogaea (peanut, an allotetraploid, in which 1,674 haplotype-based SNPs were included. Results of the array show that 74% of the haplotype-based SNP markers could be validated, which is considerably higher than previous methods used for peanut. The haplotype method has been implemented in a standalone program, HAPLOSWEEP, which takes as input bam files and a vcf file and identifies haplotype-based markers. Haplotype discovery can be made within single reads or span paired reads, and can leverage long read technology by targeting any length of haplotype. Haplotype-based genotyping is applicable in all allopolyploid genomes and provides confidence in marker identification and in silico-based genotyping for polyploid genomics.

  5. Defining critical success factors in TOD implementation using rough set analysis

    NARCIS (Netherlands)

    Thomas, R.; Bertolini, L.

    2017-01-01

    This paper defines critical success conditions in transit-oriented development (TOD), evaluating the impact of practices, policies, and governance models on implementation. As part of a meta-analysis of 11 international case studies, 16 critical success factors were developed and validated using

  6. A Network Analysis of the American Library Association: Defining a Profession

    Science.gov (United States)

    Battleson, Brenda L.

    2010-01-01

    The term "librarianship" is a generic one, suggesting one overarching discipline despite the numerous specializations and areas of research within the profession. While many disciplines use bibliometric analysis of their literature to define subfields of study within, such methods are not appropriate to librarianship due to the nature of…

  7. Organelle DNA haplotypes reflect crop-use characteristics and geographic origins of Cannabis sativa.

    Science.gov (United States)

    Gilmore, Simon; Peakall, Rod; Robertson, James

    2007-10-25

    Comparative sequencing of cannabis individuals across 12 chloroplast and mitochondrial DNA loci revealed 7 polymorphic sites, including 5 length variable regions and 2 single nucleotide polymorphisms. Simple PCR assays were developed to assay these polymorphisms, and organelle DNA haplotypes were obtained for 188 cannabis individuals from 76 separate populations, including drug-type, fibre-type and wild populations. The haplotype data were analysed using parsimony, UPGMA and neighbour joining methods. Three haplotype groups were recovered by each analysis method, and these groups are suggestive of the crop-use characteristics and geographical origin of the populations, although not strictly diagnostic. We discuss the relationship between our haplotype data and taxonomic opinions of cannabis, and the implications of organelle DNA haplotyping to forensic investigations of cannabis.

  8. The putative oncogene Pim-1 in the mouse: its linkage and variation among t haplotypes.

    Science.gov (United States)

    Nadeau, J H; Phillips, S J

    1987-11-01

    Pim-1, a putative oncogene involved in T-cell lymphomagenesis, was mapped between the pseudo-alpha globin gene Hba-4ps and the alpha-crystallin gene Crya-1 on mouse chromosome 17 and therefore within the t complex. Pim-1 restriction fragment variants were identified among t haplotypes. Analysis of restriction fragment sizes obtained with 12 endonucleases demonstrated that the Pim-1 genes in some t haplotypes were indistinguishable from the sizes for the Pim-1b allele in BALB/c inbred mice. There are now three genes, Pim-1, Crya-1 and H-2 I-E, that vary among independently derived t haplotypes and that have indistinguishable alleles in t haplotypes and inbred strains. These genes are closely linked within the distal inversion of the t complex. Because it is unlikely that these variants arose independently in t haplotypes and their wild-type homologues, we propose that an exchange of chromosomal segments, probably through double crossingover, was responsible for indistinguishable Pim-1 genes shared by certain t haplotypes and their wild-type homologues. There was, however, no apparent association between variant alleles of these three genes among t haplotypes as would be expected if a single exchange introduced these alleles into t haplotypes. If these variant alleles can be shown to be identical to the wild-type allele, then lack of association suggests that multiple exchanges have occurred during the evolution of the t complex.

  9. The integration of expert-defined importance factors to enrich Bayesian Fault Tree Analysis

    International Nuclear Information System (INIS)

    Darwish, Molham; Almouahed, Shaban; Lamotte, Florent de

    2017-01-01

    This paper proposes an analysis of a hybrid Bayesian-Importance model for system designers to improve the quality of services related to Active Assisted Living Systems. The proposed model is based on two factors: failure probability measure of different service components and, an expert defined degree of importance that each component holds for the success of the corresponding service. The proposed approach advocates the integration of expert-defined importance factors to enrich the Bayesian Fault Tree Analysis (FTA) approach. The evaluation of the proposed approach is conducted using the Fault Tree Analysis formalism where the undesired state of a system is analyzed using Boolean logic mechanisms to combine a series of lower-level events.

  10. Molecular analysis of childhood primitive neuroectodermal tumors defines markers associated with poor outcome

    DEFF Research Database (Denmark)

    Scheurlen, W G; Schwabe, G C; Joos, S

    1998-01-01

    PURPOSE: The diagnostic and prognostic significance of well-defined molecular markers was investigated in childhood primitive neuroectodermal tumors (PNET). MATERIALS AND METHODS: Using microsatellite analysis, Southern blot analysis, and fluorescence in situ hybridization (FISH), 30 primary tumors......: In our study, amplification of c-myc was a poor-prognosis marker in PNET. LOH of chromosome 17p was associated with metastatic disease. Molecular analysis of primary tumors using these markers may be useful for stratification of children with PNET in future prospective studies. The other aberrations...... investigated were not of significant prognostic value, but may provide an entry point for future large-scale molecular studies....

  11. User Defined Data in the New Analysis Model of the BaBar Experiment

    Energy Technology Data Exchange (ETDEWEB)

    De Nardo, G.

    2005-04-06

    The BaBar experiment has recently revised its Analysis Model. One of the key ingredient of BaBar new Analysis Model is the support of the capability to add to the Event Store user defined data, which can be the output of complex computations performed at an advanced stage of a physics analysis, and are associated to analysis objects. In order to provide flexibility and extensibility with respect to object types, template generic programming has been adopted. In this way the model is non-intrusive with respect to reconstruction and analysis objects it manages, not requiring changes in their interfaces and implementations. Technological details are hidden as much as possible to the user, providing a simple interface. In this paper we present some of the limitations of the old model and how they are addressed by the new Analysis Model.

  12. Influence of promoter/enhancer region haplotypes on MGMT transcriptional regulation: a potential biomarker for human sensitivity to alkylating agents.

    Science.gov (United States)

    Xu, Meixiang; Nekhayeva, Ilona; Cross, Courtney E; Rondelli, Catherine M; Wickliffe, Jeffrey K; Abdel-Rahman, Sherif Z

    2014-03-01

    The O6-methylguanine-DNA methyltransferase gene (MGMT) encodes the direct reversal DNA repair protein that removes alkyl adducts from the O6 position of guanine. Several single-nucleotide polymorphisms (SNPs) exist in the MGMT promoter/enhancer (P/E) region. However, the haplotype structure encompassing these SNPs and their functional/biological significance are currently unknown. We hypothesized that MGMT P/E haplotypes, rather than individual SNPs, alter MGMT transcription and can thus alter human sensitivity to alkylating agents. To identify the haplotype structure encompassing the MGMT P/E region SNPs, we sequenced 104 DNA samples from healthy individuals and inferred the haplotypes using the data generated. We identified eight SNPs in this region, namely T7C (rs180989103), T135G (rs1711646), G290A (rs61859810), C485A (rs1625649), C575A (rs113813075), G666A (rs34180180), C777A (rs34138162) and C1099T (rs16906252). Phylogenetics and Sequence Evolution analysis predicted 21 potential haplotypes that encompass these SNPs ranging in frequencies from 0.000048 to 0.39. Of these, 10 were identified in our study population as 20 paired haplotype combinations. To determine the functional significance of these haplotypes, luciferase reporter constructs representing these haplotypes were transfected into glioblastoma cells and their effect on MGMT promoter activity was determined. Compared with the most common (reference) haplotype 1, seven haplotypes significantly upregulated MGMT promoter activity (18-119% increase; P alkylating agents.

  13. Factor IX gene haplotypes in Amerindians.

    Science.gov (United States)

    Franco, R F; Araújo, A G; Zago, M A; Guerreiro, J F; Figueiredo, M S

    1997-02-01

    We have determined the haplotypes of the factor IX gene for 95 Indians from 5 Brazilian Amazon tribes: Wayampí, Wayana-Apalaí, Kayapó, Arára, and Yanomámi. Eight polymorphisms linked to the factor IX gene were investigated: MseI (at 5', nt -698), BamHI (at 5', nt -561), DdeI (intron 1), BamHI (intron 2), XmnI (intron 3), TaqI (intron 4), MspI (intron 4), and HhaI (at 3', approximately 8 kb). The results of the haplotype distribution and the allele frequencies for each of the factor IX gene polymorphisms in Amerindians were similar to the results reported for Asian populations but differed from results for other ethnic groups. Only five haplotypes were identified within the entire Amerindian study population, and the haplotype distribution was significantly different among the five tribes, with one (Arára) to four (Wayampí) haplotypes being found per tribe. These findings indicate a significant heterogeneity among the Indian tribes and contrast with the homogeneous distribution of the beta-globin gene cluster haplotypes but agree with our recent findings on the distribution of alpha-globin gene cluster haplotypes and the allele frequencies for six VNTRs in the same Amerindian tribes. Our data represent the first study of factor IX-associated polymorphisms in Amerindian populations and emphasizes the applicability of these genetic markers for population and human evolution studies.

  14. Polymorphism at Expressed DQ and DR Loci in Five Common Equine MHC Haplotypes

    Science.gov (United States)

    Miller, Donald; Tallmadge, Rebecca L.; Binns, Matthew; Zhu, Baoli; Mohamoud, Yasmin Ali; Ahmed, Ayeda; Brooks, Samantha A.; Antczak, Douglas F.

    2016-01-01

    The polymorphism of Major Histocompatibility Complex (MHC) class II DQ and DR genes in five common Equine Leukocyte Antigen (ELA) haplotypes was determined through sequencing of mRNA transcripts isolated from lymphocytes of eight ELA homozygous horses. Ten expressed MHC class II genes were detected in horses of the ELA-A3 haplotype carried by the donor horses of the equine Bacterial Artificial Chromosome (BAC) library and the reference genome sequence: four DR genes and six DQ genes. The other four ELA haplotypes contained at least eight expressed polymorphic MHC class II loci. Next Generation Sequencing (NGS) of genomic DNA of these four MHC haplotypes revealed stop codons in the DQA3 gene in the ELA-A2, ELA-A5, and ELA-A9 haplotypes. Few NGS reads were obtained for the other MHC class II genes that were not amplified in these horses. The amino acid sequences across haplotypes contained locus-specific residues, and the locus clusters produced by phylogenetic analysis were well supported. The MHC class II alleles within the five tested haplotypes were largely non-overlapping between haplotypes. The complement of equine MHC class II DQ and DR genes appears to be well conserved between haplotypes, in contrast to the recently described variation in class I gene loci between equine MHC haplotypes. The identification of allelic series of equine MHC class II loci will aid comparative studies of mammalian MHC conservation and evolution and may also help to interpret associations between the equine MHC class II region and diseases of the horse. PMID:27889800

  15. Haplotype phasing and inheritance of copy number variants in nuclear families.

    Science.gov (United States)

    Palta, Priit; Kaplinski, Lauris; Nagirnaja, Liina; Veidenberg, Andres; Möls, Märt; Nelis, Mari; Esko, Tõnu; Metspalu, Andres; Laan, Maris; Remm, Maido

    2015-01-01

    DNA copy number variants (CNVs) that alter the copy number of a particular DNA segment in the genome play an important role in human phenotypic variability and disease susceptibility. A number of CNVs overlapping with genes have been shown to confer risk to a variety of human diseases thus highlighting the relevance of addressing the variability of CNVs at a higher resolution. So far, it has not been possible to deterministically infer the allelic composition of different haplotypes present within the CNV regions. We have developed a novel computational method, called PiCNV, which enables to resolve the haplotype sequence composition within CNV regions in nuclear families based on SNP genotyping microarray data. The algorithm allows to i) phase normal and CNV-carrying haplotypes in the copy number variable regions, ii) resolve the allelic copies of rearranged DNA sequence within the haplotypes and iii) infer the heritability of identified haplotypes in trios or larger nuclear families. To our knowledge this is the first program available that can deterministically phase null, mono-, di-, tri- and tetraploid genotypes in CNV loci. We applied our method to study the composition and inheritance of haplotypes in CNV regions of 30 HapMap Yoruban trios and 34 Estonian families. For 93.6% of the CNV loci, PiCNV enabled to unambiguously phase normal and CNV-carrying haplotypes and follow their transmission in the corresponding families. Furthermore, allelic composition analysis identified the co-occurrence of alternative allelic copies within 66.7% of haplotypes carrying copy number gains. We also observed less frequent transmission of CNV-carrying haplotypes from parents to children compared to normal haplotypes and identified an emergence of several de novo deletions and duplications in the offspring.

  16. Haplotype phasing and inheritance of copy number variants in nuclear families.

    Directory of Open Access Journals (Sweden)

    Priit Palta

    Full Text Available DNA copy number variants (CNVs that alter the copy number of a particular DNA segment in the genome play an important role in human phenotypic variability and disease susceptibility. A number of CNVs overlapping with genes have been shown to confer risk to a variety of human diseases thus highlighting the relevance of addressing the variability of CNVs at a higher resolution. So far, it has not been possible to deterministically infer the allelic composition of different haplotypes present within the CNV regions. We have developed a novel computational method, called PiCNV, which enables to resolve the haplotype sequence composition within CNV regions in nuclear families based on SNP genotyping microarray data. The algorithm allows to i phase normal and CNV-carrying haplotypes in the copy number variable regions, ii resolve the allelic copies of rearranged DNA sequence within the haplotypes and iii infer the heritability of identified haplotypes in trios or larger nuclear families. To our knowledge this is the first program available that can deterministically phase null, mono-, di-, tri- and tetraploid genotypes in CNV loci. We applied our method to study the composition and inheritance of haplotypes in CNV regions of 30 HapMap Yoruban trios and 34 Estonian families. For 93.6% of the CNV loci, PiCNV enabled to unambiguously phase normal and CNV-carrying haplotypes and follow their transmission in the corresponding families. Furthermore, allelic composition analysis identified the co-occurrence of alternative allelic copies within 66.7% of haplotypes carrying copy number gains. We also observed less frequent transmission of CNV-carrying haplotypes from parents to children compared to normal haplotypes and identified an emergence of several de novo deletions and duplications in the offspring.

  17. OpenMSI Arrayed Analysis Toolkit: Analyzing Spatially Defined Samples Using Mass Spectrometry Imaging

    Energy Technology Data Exchange (ETDEWEB)

    de Raad, Markus [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); de Rond, Tristan [Univ. of California, Berkeley, CA (United States); Rübel, Oliver [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Keasling, Jay D. [Univ. of California, Berkeley, CA (United States); Joint BioEnergy Inst. (JBEI), Emeryville, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Technical Univ. of Denmark, Lyngby (Denmark); Northen, Trent R. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States); Bowen, Benjamin P. [Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); USDOE Joint Genome Institute (JGI), Walnut Creek, CA (United States)

    2017-05-03

    Mass spectrometry imaging (MSI) has primarily been applied in localizing biomolecules within biological matrices. Although well-suited, the application of MSI for comparing thousands of spatially defined spotted samples has been limited. One reason for this is a lack of suitable and accessible data processing tools for the analysis of large arrayed MSI sample sets. In this paper, the OpenMSI Arrayed Analysis Toolkit (OMAAT) is a software package that addresses the challenges of analyzing spatially defined samples in MSI data sets. OMAAT is written in Python and is integrated with OpenMSI (http://openmsi.nersc.gov), a platform for storing, sharing, and analyzing MSI data. By using a web-based python notebook (Jupyter), OMAAT is accessible to anyone without programming experience yet allows experienced users to leverage all features. OMAAT was evaluated by analyzing an MSI data set of a high-throughput glycoside hydrolase activity screen comprising 384 samples arrayed onto a NIMS surface at a 450 μm spacing, decreasing analysis time >100-fold while maintaining robust spot-finding. The utility of OMAAT was demonstrated for screening metabolic activities of different sized soil particles, including hydrolysis of sugars, revealing a pattern of size dependent activities. Finally, these results introduce OMAAT as an effective toolkit for analyzing spatially defined samples in MSI. OMAAT runs on all major operating systems, and the source code can be obtained from the following GitHub repository: https://github.com/biorack/omaat.

  18. Mice, humans and haplotypes--the hunt for disease genes in SLE.

    Science.gov (United States)

    Rigby, R J; Fernando, M M A; Vyse, T J

    2006-09-01

    Defining the polymorphisms that contribute to the development of complex genetic disease traits is a challenging, although increasingly tractable problem. Historically, the technical difficulties in conducting association studies across the entire human genome are such that murine models have been used to generate candidate genes for analysis in human complex diseases, such as SLE. In this article we discuss the advantages and disadvantages of this approach and specifically address some assumptions made in the transition from studying one species to another, using lupus as an example. These issues include differences in genetic structure and genetic organisation which are a reflection on the population history. Clearly there are major differences in the histories of the human population and inbred laboratory strains of mice. Both human and murine genomes do exhibit structure at the genetic level. That is to say, they comprise haplotypes which are genomic regions that carry runs of polymorphisms that are not independently inherited. Haplotypes therefore reduce the number of combinations of the polymorphisms in the DNA in that region and facilitate the identification of disease susceptibility genes in both mice and humans. There are now novel means of generating candidate genes in SLE using mutagenesis (with ENU) in mice and identifying mice that generate antinuclear autoimmunity. In addition, murine models still provide a valuable means of exploring the functional consequences of genetic variation. However, advances in technology are such that human geneticists can now screen large fractions of the human genome for disease associations using microchip technologies that provide information on upwards of 100,000 different polymorphisms. These approaches are aimed at identifying haplotypes that carry disease susceptibility mutations and rely less on the generation of candidate genes.

  19. OpenMSI Arrayed Analysis Toolkit: Analyzing Spatially Defined Samples Using Mass Spectrometry Imaging

    DEFF Research Database (Denmark)

    de Raad, Markus; de Rond, Tristan; Rübel, Oliver

    2017-01-01

    ://openmsinersc.gov), a platform for storing, sharing, and analyzing MSI data. By using a web-based python notebook (Jupyter), OMAAT is accessible to anyone without programming experience yet allows experienced users to leverage all features. OMAAT was :evaluated by analyzing an MSI data set of a high-throughput glycoside...... processing tools for the analysis of large arrayed MSI sample sets. The OpenMSI Arrayed Analysis Toolkit (OMAAT) is a software package that addresses the challenges of analyzing spatially defined samples in MSI data sets. OMAAT is written in Python and is integrated with OpenMSI (http...

  20. Y-chromosome STR haplotypes in Somalis

    DEFF Research Database (Denmark)

    Hallenberg, Charlotte; Simonsen, Bo; Sanchez Sanchez, Juan Jose

    2005-01-01

    A total of 201 males from Somalia were typed for the Y-chromosome STRs DYS19, DYS385a/b, DYS389-I, DYS389-II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438 and DYS439 with the PowerPlex Y kit (Promega). A total of 96 different haplotypes were observed and the haplotype diversity was 0.9715. The ......A total of 201 males from Somalia were typed for the Y-chromosome STRs DYS19, DYS385a/b, DYS389-I, DYS389-II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438 and DYS439 with the PowerPlex Y kit (Promega). A total of 96 different haplotypes were observed and the haplotype diversity was 0...

  1. Defining, illustrating and reflecting on logic analysis with an example from a professional development program.

    Science.gov (United States)

    Tremblay, Marie-Claude; Brousselle, Astrid; Richard, Lucie; Beaudet, Nicole

    2013-10-01

    Program designers and evaluators should make a point of testing the validity of a program's intervention theory before investing either in implementation or in any type of evaluation. In this context, logic analysis can be a particularly useful option, since it can be used to test the plausibility of a program's intervention theory using scientific knowledge. Professional development in public health is one field among several that would truly benefit from logic analysis, as it appears to be generally lacking in theorization and evaluation. This article presents the application of this analysis method to an innovative public health professional development program, the Health Promotion Laboratory. More specifically, this paper aims to (1) define the logic analysis approach and differentiate it from similar evaluative methods; (2) illustrate the application of this method by a concrete example (logic analysis of a professional development program); and (3) reflect on the requirements of each phase of logic analysis, as well as on the advantages and disadvantages of such an evaluation method. Using logic analysis to evaluate the Health Promotion Laboratory showed that, generally speaking, the program's intervention theory appeared to have been well designed. By testing and critically discussing logic analysis, this article also contributes to further improving and clarifying the method. Copyright © 2013 Elsevier Ltd. All rights reserved.

  2. Two families from New England with usher syndrome type IC with distinct haplotypes.

    Science.gov (United States)

    DeAngelis, M M; McGee, T L; Keats, B J; Slim, R; Berson, E L; Dryja, T P

    2001-03-01

    To search for patients with Usher syndrome type IC among those with Usher syndrome type I who reside in New England. Genotype analysis of microsatellite markers closely linked to the USH1C locus was done using the polymerase chain reaction. We compared the haplotype of our patients who were homozygous in the USH1C region with the haplotypes found in previously reported USH1C Acadian families who reside in southwestern Louisiana and from a single family residing in Lebanon. Of 46 unrelated cases of Usher syndrome type I residing in New England, two were homozygous at genetic markers in the USH1C region. Of these, one carried the Acadian USH1C haplotype and had Acadian ancestors (that is, from Nova Scotia) who did not participate in the 1755 migration of Acadians to Louisiana. The second family had a haplotype that proved to be the same as that of a family with USH1C residing in Lebanon. Each of the two families had haplotypes distinct from the other. This is the first report that some patients residing in New England have Usher syndrome type IC. Patients with Usher syndrome type IC can have the Acadian haplotype or the Lebanese haplotype compatible with the idea that at least two independently arising pathogenic mutations have occurred in the yet-to-be identified USH1C gene.

  3. RFLP's for the human pepsinogen A haplotypes (PGA)

    Energy Technology Data Exchange (ETDEWEB)

    Taggart, R T; Boudi, F B; Bell, G I

    1988-10-11

    PGA 101 is a 1340 bp cDNA clone containing exons 1-9 of the predicted human pepsinogen A coding sequence. Two distinct polymorphisms are detected with EcoRI and Bg1 II. Analysis with these enzymes provides for discrimination of the PGA haplotypes A, B, and C containing three, two and one PGA genes respectively. The PGA complex is located at 11q13. Mendelian inheritance was demonstrated in 20 families.

  4. Analysis of radiation and chemical factors which define the ecological situation of environment

    International Nuclear Information System (INIS)

    Trofimenko, A.P.

    1996-01-01

    A new method of large information set statistical analysis is proposed. It permits to define the main directions of work in a given field in the world or in a particular country, to find the most important investigated problems and to evaluate the role each of them quantitatively, as well as to study the dynamics of work development in time, the methods of research used, the centres in which this research is mostly developed, authors of publications etc. Statistical analysis may be supplemented with subject analysis of selected publications. Main factors which influence on different environment components and on public health are presented as an example of this method use, and the role of radiation and chemical factors is evaluated. 18 refs., 6 tab

  5. β-globin haplotypes in normal and hemoglobinopathic individuals from Reconcavo Baiano, State of Bahia, Brazil

    Directory of Open Access Journals (Sweden)

    Wellington dos Santos Silva

    2010-01-01

    Full Text Available Five restriction site polymorphisms in the β-globin gene cluster (HincII-5'ε, HindIII-Gγ, HindIII-ªγ, HincII-'ψβ1 and HincII-3''ψβ1 were analyzed in three populations (n = 114 from Reconcavo Baiano, State of Bahia, Brazil. The groups included two urban populations from the towns of Cachoeira and Maragojipe and one rural Afro-descendant population, known as the "quilombo community", from Cachoeira municipality. The number of haplotypes found in the populations ranged from 10 to 13, which indicated higher diversity than in the parental populations. The haplotypes 2 (+----,3(----+,4(-+--+and6(-++-+onthe βA chromosomes were the most common, and two haplotypes, 9 (-++++and 14 (++--+, were found exclusively in the Maragojipe population. The other haplotypes (1, 5, 9, 11, 12, 13, 14 and 16 had lower frequencies. Restriction site analysis and the derived haplotypes indicated homogeneity among the populations. Thirty-two individuals with hemoglobinopathies (17 sickle cell disease, 12 HbSC disease and 3 HbCC disease were also analyzed. The haplotype frequencies of these patients differed significantly from those of the general population. In the sickle cell disease subgroup, the predominant haplotypes were BEN (Benin and CAR (Central African Republic, with frequencies of 52.9% and 32.4%, respectively. The high frequency of the BEN haplotype agreed with the historical origin of the afro-descendant population in the state of Bahia. However, this frequency differed from that of Salvador, the state capital, where the CAR and BEN haplotypes have similar frequencies, probably as a consequence of domestic slave trade and subsequent internal migrations to other regions of Brazil.

  6. A unified framework for haplotype inference in nuclear families.

    Science.gov (United States)

    Iliadis, Alexandros; Anastassiou, Dimitris; Wang, Xiaodong

    2012-07-01

    Many large genome-wide association studies include nuclear families with more than one child (trio families), allowing for analysis of differences between siblings (sib pair analysis). Statistical power can be increased when haplotypes are used instead of genotypes. Currently, haplotype inference in families with more than one child can be performed either using the familial information or statistical information derived from the population samples but not both. Building on our recently proposed tree-based deterministic framework (TDS) for trio families, we augment its applicability to general nuclear families. We impose a minimum recombinant approach locally and independently on each multiple children family, while resorting to the population-derived information to solve the remaining ambiguities. Thus our framework incorporates all available information (familial and population) in a given study. We demonstrate that using all the constraints in our approach we can have gains in the accuracy as opposed to breaking the multiple children families to separate trios and resorting to a trio inference algorithm or phasing each family in isolation. We believe that our proposed framework could be the method of choice for haplotype inference in studies that include nuclear families with multiple children. Our software (tds2.0) is downloadable from www.ee.columbia.edu/∼anastas/tds. © 2012 The Authors Annals of Human Genetics © 2012 Blackwell Publishing Ltd/University College London.

  7. Per-operative vibration analysis: a valuable tool for defining correct stem insertion: preliminary report.

    Science.gov (United States)

    Mulier, Michiel; Pastrav, Cesar; Van der Perre, Georges

    2008-01-01

    Defining the stem insertion end point during total hip replacement still relies on the surgeon's feeling. When a custom-made stem prosthesis with an optimal fit into the femoral canal is used, the risk of per-operative fractures is even greater than with standard prostheses. Vibration analysis is used in other clinical settings and has been tested as a means to detect optimal stem insertion in the laboratory. The first per-operative use of vibration analysis during non-cemented custom-made stem insertion in 30 patients is reported here. Thirty patients eligible for total hip replacement with uncemented stem prosthesis were included. The neck of the stem was connected with a shaker that emitted white noise as excitation signal and an impedance head that measured the frequency response. The response signal was sent to a computer that analyzed the frequency response function after each insertion phase. A technician present in the operating theatre but outside the laminated airflow provided feed-back to the surgeon. The correlation index between the frequency response function measured during the last two insertion hammering sessions was >0.99 in 86.7% of the cases. In four cases the surgeon stopped the insertion procedure because of a perceived risk of fracture. Two special cases illustrating the potential benefit of per-operative vibration analysis are described. The results of intra-operative vibration analysis indicate that this technique may be a useful tool assisting the orthopaedic surgeon in defining the insertion endpoint of the stem. The development of a more user-friendly device is therefore warranted.

  8. Endothelial Nitric Oxide Synthase Haplotypes Are Associated with Preeclampsia in Maya Mestizo Women

    Science.gov (United States)

    Díaz-Olguín, Lizbeth; Coral-Vázquez, Ramón Mauricio; Canto-Cetina, Thelma; Canizales-Quinteros, Samuel; Ramírez Regalado, Belem; Fernández, Genny; Canto, Patricia

    2011-01-01

    Preeclampsia is a specific disease of pregnancy and believed to have a genetic component. The aim of this study was to investigate if three polymorphisms in eNOS or their haplotypes are associated with preeclampsia in Maya mestizo women. A case-control study was performed where 127 preeclamptic patients and 263 controls were included. Genotyped and haplotypes for the -768T→C, intron 4 variants, Glu298Asp of eNOS were determined by PCR and real-time PCR allelic discrimination. Logistic regression analysis with adjustment for age and body mass index (BMI) was used to test for associations between genotype and preeclampsia under recessive, codominant and dominant models. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated by direct correlation r2, and haplotype analysis was conducted. Women homozygous for the Asp298 allele showed an association of preeclampsia. In addition, analysis of the haplotype frequencies revealed that the -786C-4b-Asp298 haplotype was significantly more frequent in preeclamptic patients than in controls (0.143 vs. 0.041, respectively; OR = 3.01; 95% CI = 1.74–5.23; P = 2.9 × 10−4). Despite the Asp298 genotype in a recessive model associated with the presence of preeclampsia in Maya mestizo women, we believe that in this population the -786C-4b-Asp298 haplotype is a better genetic marker. PMID:21897002

  9. Haplotype-based stratification of Huntington's disease.

    Science.gov (United States)

    Chao, Michael J; Gillis, Tammy; Atwal, Ranjit S; Mysore, Jayalakshmi Srinidhi; Arjomand, Jamshid; Harold, Denise; Holmans, Peter; Jones, Lesley; Orth, Michael; Myers, Richard H; Kwak, Seung; Wheeler, Vanessa C; MacDonald, Marcy E; Gusella, James F; Lee, Jong-Min

    2017-11-01

    Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by expansion of a CAG trinucleotide repeat in HTT, resulting in an extended polyglutamine tract in huntingtin. We and others have previously determined that the HD-causing expansion occurs on multiple different haplotype backbones, reflecting more than one ancestral origin of the same type of mutation. In view of the therapeutic potential of mutant allele-specific gene silencing, we have compared and integrated two major systems of HTT haplotype definition, combining data from 74 sequence variants to identify the most frequent disease-associated and control chromosome backbones and revealing that there is potential for additional resolution of HD haplotypes. We have used the large collection of 4078 heterozygous HD subjects analyzed in our recent genome-wide association study of HD age at onset to estimate the frequency of these haplotypes in European subjects, finding that common genetic variation at HTT can distinguish the normal and CAG-expanded chromosomes for more than 95% of European HD individuals. As a resource for the HD research community, we have also determined the haplotypes present in a series of publicly available HD subject-derived fibroblasts, induced pluripotent cells, and embryonic stem cells in order to facilitate efforts to develop inclusive methods of allele-specific HTT silencing applicable to most HD patients. Our data providing genetic guidance for therapeutic gene-based targeting will significantly contribute to the developments of rational treatments and implementation of precision medicine in HD.

  10. Estimating haplotype effects for survival data.

    Science.gov (United States)

    Scheike, Thomas H; Martinussen, Torben; Silver, Jeremy D

    2010-09-01

    Genetic association studies often investigate the effect of haplotypes on an outcome of interest. Haplotypes are not observed directly, and this complicates the inclusion of such effects in survival models. We describe a new estimating equations approach for Cox's regression model to assess haplotype effects for survival data. These estimating equations are simple to implement and avoid the use of the EM algorithm, which may be slow in the context of the semiparametric Cox model with incomplete covariate information. These estimating equations also lead to easily computable, direct estimators of standard errors, and thus overcome some of the difficulty in obtaining variance estimators based on the EM algorithm in this setting. We also develop an easily implemented goodness-of-fit procedure for Cox's regression model including haplotype effects. Finally, we apply the procedures presented in this article to investigate possible haplotype effects of the PAF-receptor on cardiovascular events in patients with coronary artery disease, and compare our results to those based on the EM algorithm. © 2009, The International Biometric Society.

  11. Mitochondrial Haplotype Diversity in Zambian Lions: Bridging a Gap in the Biogeography of an Iconic Species.

    Science.gov (United States)

    Curry, Caitlin J; White, Paula A; Derr, James N

    2015-01-01

    Analysis of DNA sequence diversity at the 12S to 16S mitochondrial genes of 165 African lions (Panthera leo) from five main areas in Zambia has uncovered haplotypes which link Southern Africa with East Africa. Phylogenetic analysis suggests Zambia may serve as a bridge connecting the lion populations in southern Africa to eastern Africa, supporting earlier hypotheses that eastern-southern Africa may represent the evolutionary cradle for the species. Overall gene diversity throughout the Zambian lion population was 0.7319 +/- 0.0174 with eight haplotypes found; three haplotypes previously described and the remaining five novel. The addition of these five novel haplotypes, so far only found within Zambia, nearly doubles the number of haplotypes previously reported for any given geographic location of wild lions. However, based on an AMOVA analysis of these haplotypes, there is little to no matrilineal gene flow (Fst = 0.47) when the eastern and western regions of Zambia are considered as two regional sub-populations. Crossover haplotypes (H9, H11, and Z1) appear in both populations as rare in one but common in the other. This pattern is a possible result of the lion mating system in which predominately males disperse, as all individuals with crossover haplotypes were male. The determination and characterization of lion sub-populations, such as done in this study for Zambia, represent a higher-resolution of knowledge regarding both the genetic health and connectivity of lion populations, which can serve to inform conservation and management of this iconic species.

  12. Mitochondrial Haplotype Diversity in Zambian Lions: Bridging a Gap in the Biogeography of an Iconic Species.

    Directory of Open Access Journals (Sweden)

    Caitlin J Curry

    Full Text Available Analysis of DNA sequence diversity at the 12S to 16S mitochondrial genes of 165 African lions (Panthera leo from five main areas in Zambia has uncovered haplotypes which link Southern Africa with East Africa. Phylogenetic analysis suggests Zambia may serve as a bridge connecting the lion populations in southern Africa to eastern Africa, supporting earlier hypotheses that eastern-southern Africa may represent the evolutionary cradle for the species. Overall gene diversity throughout the Zambian lion population was 0.7319 +/- 0.0174 with eight haplotypes found; three haplotypes previously described and the remaining five novel. The addition of these five novel haplotypes, so far only found within Zambia, nearly doubles the number of haplotypes previously reported for any given geographic location of wild lions. However, based on an AMOVA analysis of these haplotypes, there is little to no matrilineal gene flow (Fst = 0.47 when the eastern and western regions of Zambia are considered as two regional sub-populations. Crossover haplotypes (H9, H11, and Z1 appear in both populations as rare in one but common in the other. This pattern is a possible result of the lion mating system in which predominately males disperse, as all individuals with crossover haplotypes were male. The determination and characterization of lion sub-populations, such as done in this study for Zambia, represent a higher-resolution of knowledge regarding both the genetic health and connectivity of lion populations, which can serve to inform conservation and management of this iconic species.

  13. Extended HLA-D region haplotype associated with celiac disease

    International Nuclear Information System (INIS)

    Howell, M.D.; Smith, J.R.; Austin, R.K.; Kelleher, D.; Nepom, G.T.; Volk, B.; Kagnoff, M.F.

    1988-01-01

    Celiac disease has one of the strongest associations with HLA (human leukocyte antigen) class II markers of the known HLA-linked diseases. This association is primarily with the class II serologic specificities HLA-DR3 and -DQw2. The authors previously described a restriction fragment length polymorphism (RFLP) characterized by the presence of a 4.0-kilobase Rsa I fragment derived from an HLA class II β-chain gene, which distinguishes the class II HLA haplotype of celiac disease patients from those of many serologically matched controls. They now report the isolation of this β-chain gene from a bacteriophage genomic library constructed from the DNA of a celiac disease patient. Based on restriction mapping and differential hybridization with class II cDNA and oligonucleotide probes, this gene was identified as one encoding an HLA-DP β-chain. This celiac disease-associated HLA-DP β-chain gene was flanked by HLA-DP α-chain genes and, therefore, was probably in its normal chromosomal location. The HLA-DPα-chain genes of celiac disease patients also were studied by RFLP analysis. Celiac disease is associated with a subset of HLA-DR3, -DQw2 haplotypes characterized by HLA-DP α- and β-chain gene RFLPs. Within the celiac-disease patient population, the joint segregation of these HLA-DP genes with those encoding the serologic specificities HLA-DR3 and -DQw2 indicates: (i) that the class II HLA haplotype associated with celiac disease is extended throughout the entire HLA-D region, and (ii) that celiac-disease susceptibility genes may reside as far centromeric on this haplotype as the HLA-DP subregion

  14. Extended HLA-D region haplotype associated with celiac disease

    Energy Technology Data Exchange (ETDEWEB)

    Howell, M.D.; Smith, J.R.; Austin, R.K.; Kelleher, D.; Nepom, G.T.; Volk, B.; Kagnoff, M.F.

    1988-01-01

    Celiac disease has one of the strongest associations with HLA (human leukocyte antigen) class II markers of the known HLA-linked diseases. This association is primarily with the class II serologic specificities HLA-DR3 and -DQw2. The authors previously described a restriction fragment length polymorphism (RFLP) characterized by the presence of a 4.0-kilobase Rsa I fragment derived from an HLA class II ..beta..-chain gene, which distinguishes the class II HLA haplotype of celiac disease patients from those of many serologically matched controls. They now report the isolation of this ..beta..-chain gene from a bacteriophage genomic library constructed from the DNA of a celiac disease patient. Based on restriction mapping and differential hybridization with class II cDNA and oligonucleotide probes, this gene was identified as one encoding an HLA-DP ..beta..-chain. This celiac disease-associated HLA-DP ..beta..-chain gene was flanked by HLA-DP ..cap alpha..-chain genes and, therefore, was probably in its normal chromosomal location. The HLA-DP..cap alpha..-chain genes of celiac disease patients also were studied by RFLP analysis. Celiac disease is associated with a subset of HLA-DR3, -DQw2 haplotypes characterized by HLA-DP ..cap alpha..- and ..beta..-chain gene RFLPs. Within the celiac-disease patient population, the joint segregation of these HLA-DP genes with those encoding the serologic specificities HLA-DR3 and -DQw2 indicates: (i) that the class II HLA haplotype associated with celiac disease is extended throughout the entire HLA-D region, and (ii) that celiac-disease susceptibility genes may reside as far centromeric on this haplotype as the HLA-DP subregion.

  15. Phylogenetic analysis to define feline immunodeficiency virus subtypes in 31 domestic cats in South Africa

    Directory of Open Access Journals (Sweden)

    R. Kann

    2006-06-01

    Full Text Available Feline immunodeficiency virus (FIV, a lentivirus, is an important pathogen of domestic cats around the world and has many similarities to human immunodeficiency virus (HIV. A characteristic of these lentiviruses is their extensive genetic diversity, which has been an obstacle in the development of successful vaccines. Of the FIV genes, the envelope gene is the most variable and sequence differences in a portion of this gene have been used to define 5 FIV subtypes (A, B, C, D and E. In this study, the proviral DNA sequence of the V3-V5 region of the envelope gene was determined in blood samples from 31 FIV positive cats from 4 different regions of South Africa. Phylogenetic analysis demonstrated the presence of both subtypes A and C, with subtype A predominating. These findings contribute to the understanding of the genetic diversity of FIV.

  16. Association between β2-adrenoceptor (ADRB2) haplotypes and insulin resistance in PCOS.

    Science.gov (United States)

    Tellechea, Mariana L; Muzzio, Damián O; Iglesias Molli, Andrea E; Belli, Susana H; Graffigna, Mabel N; Levalle, Oscar A; Frechtel, Gustavo D; Cerrone, Gloria E

    2013-04-01

    The aim of this study was to explore β2-adrenoceptor (ADRB2) haplotype associations with phenotypes and quantitative traits related to insulin resistance (IR) and the metabolic syndrome (MS) in a polycystic ovary syndrome (PCOS) population. A secondary purpose was to assess the association between ADRB2 haplotype and PCOS. Genetic polymorphism analysis. Cross-sectional case-control association study. Medical University Hospital and research laboratory. One hundred and sixty-five unrelated women with PCOS and 116 unrelated women without PCOS (control sample). Clinical and biochemical measurements, and ADRB2 genotyping in PCOS patients and control subjects. ADRB2 haplotypes (comprising rs1042711, rs1801704, rs1042713 and rs1042714 in that order), genotyping and statistical analysis to evaluate associations with continuous variables and traits related to IR and MS in a PCOS population. Associations between ADRB2 haplotypes and PCOS were also assessed. We observed an age-adjusted association between ADRB2 haplotype CCGG and lower insulin (P = 0·018) and HOMA (P = 0·008) in the PCOS sample. Interestingly, the expected differences in surrogate measures of IR between cases and controls were not significant in CCGG/CCGG carriers. In the case-control study, genotype CCGG/CCGG was associated with a 14% decrease in PCOS risk (P = 0·043), taking into account confounding variables. Haplotype I (CCGG) has a protective role for IR and MS in PCOS. © 2012 Blackwell Publishing Ltd.

  17. Crouch gait patterns defined using k-means cluster analysis are related to underlying clinical pathology.

    Science.gov (United States)

    Rozumalski, Adam; Schwartz, Michael H

    2009-08-01

    In this study a gait classification method was developed and applied to subjects with Cerebral palsy who walk with excessive knee flexion at initial contact. Sagittal plane gait data, simplified using the gait features method, is used as input into a k-means cluster analysis to determine homogeneous groups. Several clinical domains were explored to determine if the clusters are related to underlying pathology. These domains included age, joint range-of-motion, strength, selective motor control, and spasticity. Principal component analysis is used to determine one overall score for each of the multi-joint domains (strength, selective motor control, and spasticity). The current study shows that there are five clusters among children with excessive knee flexion at initial contact. These clusters were labeled, in order of increasing gait pathology: (1) mild crouch with mild equinus, (2) moderate crouch, (3) moderate crouch with anterior pelvic tilt, (4) moderate crouch with equinus, and (5) severe crouch. Further analysis showed that age, range-of-motion, strength, selective motor control, and spasticity were significantly different between the clusters (p<0.001). The general tendency was for the clinical domains to worsen as gait pathology increased. This new classification tool can be used to define homogeneous groups of subjects in crouch gait, which can help guide treatment decisions and outcomes assessment.

  18. Quantitative Analysis of the Security of Software-Defined Network Controller Using Threat/Effort Model

    Directory of Open Access Journals (Sweden)

    Zehui Wu

    2017-01-01

    Full Text Available SDN-based controller, which is responsible for the configuration and management of the network, is the core of Software-Defined Networks. Current methods, which focus on the secure mechanism, use qualitative analysis to estimate the security of controllers, leading to inaccurate results frequently. In this paper, we employ a quantitative approach to overcome the above shortage. Under the analysis of the controller threat model we give the formal model results of the APIs, the protocol interfaces, and the data items of controller and further provide our Threat/Effort quantitative calculation model. With the help of Threat/Effort model, we are able to compare not only the security of different versions of the same kind controller but also different kinds of controllers and provide a basis for controller selection and secure development. We evaluated our approach in four widely used SDN-based controllers which are POX, OpenDaylight, Floodlight, and Ryu. The test, which shows the similarity outcomes with the traditional qualitative analysis, demonstrates that with our approach we are able to get the specific security values of different controllers and presents more accurate results.

  19. [Haplotype Analysis of Coagulation Factor VII Gene in a Patient with Congenital Coagulation Factor VII Deficiency with Heterozygous p.Arg337Cys Mutation and o.Aro413Gin Polymorphism..

    Science.gov (United States)

    Suzuki, Keijiro; Yoshioka, Tomoko; Obara, Takehiro; Suwabe, Akira

    2016-05-01

    Congenital coagulation factor VII (FVII) deficiency is a rare hemorrhagic disease with an autosomal reces- sive inheritance pattern. We analyzed coagulation factor VII gene (F7) of a patient with FVII deficiency and used expression studies to investigate the effect of a missense mutation on FVII secretion. The proband, a 69-year-old Japanese woman, had a history of postpartum bleeding and excessive bleeding after dental extrac- tion. She was found to have mildly increased PT-INR (1.17) before an ophthalmic operation. FVII activity and antigen were reduced (29.0% and 32.8%). Suspecting that the proband was FVII deficient, we analyzed F7 of the patient. Sequence analysis revealed that the patient was heterozygous for a point mutation (p.Arg337Cys) in the catalytic domain and polymorphisms: the decanucleotide insertion at the promoter re- gion, dimorphism (c.525C >T) in exon 5, and p.Arg413Gln in exon 8. Haplotype analysis clarified that p.Arg337Cys was located on the p.Arg413 allele (Ml allele). The other allele had the p.Arg413Gln polymor- phism(M2 allele) which is known to produce less FVII. Expression studies revealed that p.Arg337Cys causes impairment of FVII secretion. Insufficient secretion of FVII arising from both the p.Arg337Cys/M1 allele and the p.Arg337/M2 allele might lower the FVII level of this patient(<50%). The FVII level in a heterozygous FVII deficient patient might be influenced by F7 polymorphisms on the normal allele. There- fore, genetic analyses are important for the diagnosis of heterozygous FVII deficiency.

  20. Meta-analysis of gene expression signatures defining the epithelial to mesenchymal transition during cancer progression.

    Directory of Open Access Journals (Sweden)

    Christian J Gröger

    Full Text Available The epithelial to mesenchymal transition (EMT represents a crucial event during cancer progression and dissemination. EMT is the conversion of carcinoma cells from an epithelial to a mesenchymal phenotype that associates with a higher cell motility as well as enhanced chemoresistance and cancer stemness. Notably, EMT has been increasingly recognized as an early event of metastasis. Numerous gene expression studies (GES have been conducted to obtain transcriptome signatures and marker genes to understand the regulatory mechanisms underlying EMT. Yet, no meta-analysis considering the multitude of GES of EMT has been performed to comprehensively elaborate the core genes in this process. Here we report the meta-analysis of 18 independent and published GES of EMT which focused on different cell types and treatment modalities. Computational analysis revealed clustering of GES according to the type of treatment rather than to cell type. GES of EMT induced via transforming growth factor-β and tumor necrosis factor-α treatment yielded uniformly defined clusters while GES of models with alternative EMT induction clustered in a more complex fashion. In addition, we identified those up- and downregulated genes which were shared between the multitude of GES. This core gene list includes well known EMT markers as well as novel genes so far not described in this process. Furthermore, several genes of the EMT-core gene list significantly correlated with impaired pathological complete response in breast cancer patients. In conclusion, this meta-analysis provides a comprehensive survey of available EMT expression signatures and shows fundamental insights into the mechanisms that are governing carcinoma progression.

  1. Application of a latent class analysis to empirically define eating disorder phenotypes.

    Science.gov (United States)

    Keel, Pamela K; Fichter, Manfred; Quadflieg, Norbert; Bulik, Cynthia M; Baxter, Mark G; Thornton, Laura; Halmi, Katherine A; Kaplan, Allan S; Strober, Michael; Woodside, D Blake; Crow, Scott J; Mitchell, James E; Rotondo, Alessandro; Mauri, Mauro; Cassano, Giovanni; Treasure, Janet; Goldman, David; Berrettini, Wade H; Kaye, Walter H

    2004-02-01

    Diagnostic criteria for eating disorders influence how we recognize, research, and treat eating disorders, and empirically valid phenotypes are required for revealing their genetic bases. To empirically define eating disorder phenotypes. Data regarding eating disorder symptoms and features from 1179 individuals with clinically significant eating disorders were submitted to a latent class analysis. The resulting latent classes were compared on non-eating disorder variables in a series of validation analyses. Multinational, collaborative study with cases ascertained through diverse clinical settings (inpatient, outpatient, and community). Members of affected relative pairs recruited for participation in genetic studies of eating disorders in which probands met DSM-IV-TR criteria for anorexia nervosa (AN) or bulimia nervosa and had at least 1 biological relative with a clinically significant eating disorder. Main Outcome Measure Number and clinical characterization of latent classes. A 4-class solution provided the best fit. Latent class 1 (LC1) resembled restricting AN; LC2, AN and bulimia nervosa with the use of multiple methods of purging; LC3, restricting AN without obsessive-compulsive features; and LC4, bulimia nervosa with self-induced vomiting as the sole form of purging. Biological relatives were significantly likely to belong to the same latent class. Across validation analyses, LC2 demonstrated the highest levels of psychological disturbance, and LC3 demonstrated the lowest. The presence of obsessive-compulsive features differentiates among individuals with restricting AN. Similarly, the combination of low weight and multiple methods of purging distinguishes among individuals with binge eating and purging behaviors. These results support some of the distinctions drawn within the DSM-IV-TR among eating disorder subtypes, while introducing new features to define phenotypes.

  2. Unique haplotypes of cacao trees as revealed by trnH-psbA chloroplast DNA

    Directory of Open Access Journals (Sweden)

    Nidia Gutiérrez-López

    2016-04-01

    Full Text Available Cacao trees have been cultivated in Mesoamerica for at least 4,000 years. In this study, we analyzed sequence variation in the chloroplast DNA trnH-psbA intergenic spacer from 28 cacao trees from different farms in the Soconusco region in southern Mexico. Genetic relationships were established by two analysis approaches based on geographic origin (five populations and genetic origin (based on a previous study. We identified six polymorphic sites, including five insertion/deletion (indels types and one transversion. The overall nucleotide diversity was low for both approaches (geographic = 0.0032 and genetic = 0.0038. Conversely, we obtained moderate to high haplotype diversity (0.66 and 0.80 with 10 and 12 haplotypes, respectively. The common haplotype (H1 for both networks included cacao trees from all geographic locations (geographic approach and four genetic groups (genetic approach. This common haplotype (ancient derived a set of intermediate haplotypes and singletons interconnected by one or two mutational steps, which suggested directional selection and event purification from the expansion of narrow populations. Cacao trees from Soconusco region were grouped into one cluster without any evidence of subclustering based on AMOVA (FST = 0 and SAMOVA (FST = 0.04393 results. One population (Mazatán showed a high haplotype frequency; thus, this population could be considered an important reservoir of genetic material. The indels located in the trnH-psbA intergenic spacer of cacao trees could be useful as markers for the development of DNA barcoding.

  3. VNTR alleles associated with the {alpha}-globin locus are haplotype and population related

    Energy Technology Data Exchange (ETDEWEB)

    Martinson, J.J.; Clegg, J.B.; Boyce, A.J. [Univ. of Oxford (United Kingdom)

    1994-09-01

    The human {alpha}-globin complex contains several polymorphic restriction-enzyme sites (i.e., RFLPs) linked to form haplotypes and is flanked by two hypervariable VNTR loci, the 5{prime} hypervariable region (HVR) and the more highly polymorphic 3{prime}HVR. Using a combination of RFLP analysis and PCR, the authors have characterized the 5{prime}HVR and 3{prime}HVR alleles associated with the {alpha}-globin haplotypes of 133 chromosomes, and they here show that specific {alpha}-globin haplotypes are each associated with discrete subsets of the alleles observed at these two VNTR loci. This statistically highly significant association is observed over a region spanning {approximately} 100 kb. With the exception of closely related haplotypes, different haplotypes do not share identically sized 3{prime}HVR alleles. Earlier studies have shown that {alpha}-globin haplotype distributions differ between populations; the current findings also reveal extensive population substructure in the repertoire of {alpha}-globin VNTRs. If similar features are characteristic of other VNTR loci, this will have important implications for forensic and anthropological studies. 42 refs., 5 figs., 5 tabs.

  4. Inheritance of the 8.1 ancestral haplotype in recurrent pregnancy loss

    DEFF Research Database (Denmark)

    Kolte, Astrid M; Nielsen, Henriette S; Steffensen, Rudi

    2015-01-01

    . The objective was to test the gestational drive theory for the 8.1AH in women with RPL and their live born children. METHODOLOGY: We investigated the inheritance of the 8.1AH from 82 heterozygous RPL women to 110 live born children. All participants were genotyped for HLA-A, -B and -DRB1 in DNA from EDTA...... pleiotropy. It has also been proposed that the survival of long, conserved haplotypes may be due to gestational drive, i.e. selective miscarriage of fetuses who have not inherited the haplotype from a heterozygous mother. Recurrent pregnancy loss (RPL) is defined as three or more consecutive pregnancy losses...

  5. Congruence as a measurement of extended haplotype structure across the genome

    Science.gov (United States)

    2012-01-01

    Background Historically, extended haplotypes have been defined using only a few data points, such as alleles for several HLA genes in the MHC. High-density SNP data, and the increasing affordability of whole genome SNP typing, creates the opportunity to define higher resolution extended haplotypes. This drives the need for new tools that support quantification and visualization of extended haplotypes as defined by as many as 2000 SNPs. Confronted with high-density SNP data across the major histocompatibility complex (MHC) for 2,300 complete families, compiled by the Type 1 Diabetes Genetics Consortium (T1DGC), we developed software for studying extended haplotypes. Methods The software, called ExHap (Extended Haplotype), uses a similarity measurement we term congruence to identify and quantify long-range allele identity. Using ExHap, we analyzed congruence in both the T1DGC data and family-phased data from the International HapMap Project. Results Congruent chromosomes from the T1DGC data have between 96.5% and 99.9% allele identity over 1,818 SNPs spanning 2.64 megabases of the MHC (HLA-DRB1 to HLA-A). Thirty-three of 132 DQ-DR-B-A defined haplotype groups have > 50% congruent chromosomes in this region. For example, 92% of chromosomes within the DR3-B8-A1 haplotype are congruent from HLA-DRB1 to HLA-A (99.8% allele identity). We also applied ExHap to all 22 autosomes for both CEU and YRI cohorts from the International HapMap Project, identifying multiple candidate extended haplotypes. Conclusions Long-range congruence is not unique to the MHC region. Patterns of allele identity on phased chromosomes provide a simple, straightforward approach to visually and quantitatively inspect complex long-range structural patterns in the genome. Such patterns aid the biologist in appreciating genetic similarities and differences across cohorts, and can lead to hypothesis generation for subsequent studies. PMID:22369243

  6. MCP1 haplotypes associated with protection from pulmonary tuberculosis

    Directory of Open Access Journals (Sweden)

    Owusu-Dabo Ellis

    2011-04-01

    Full Text Available Abstract Background The monocyte chemoattractant protein 1 (MCP-1 is involved in the recruitment of lymphocytes and monocytes and their migration to sites of injury and cellular immune reactions. In a Ghanaian tuberculosis (TB case-control study group, associations of the MCP1 -362C and the MCP1 -2581G alleles with resistance to TB were recently described. The latter association was in contrast to genetic effects previously described in study groups originating from Mexico, Korea, Peru and Zambia. This inconsistency prompted us to further investigate the MCP1 gene in order to determine causal variants or haplotypes genetically and functionally. Results A 14 base-pair deletion in the first MCP1 intron, int1del554-567, was strongly associated with protection against pulmonary TB (OR = 0.84, CI 0.77-0.92, Pcorrected = 0.00098. Compared to the wildtype combination, a haplotype comprising the -2581G and -362C promoter variants and the intronic deletion conferred an even stronger protection than did the -362C variant alone (OR = 0.78, CI 0.69-0.87, Pnominal = 0.00002; adjusted Pglobal = 0.0028. In a luciferase reporter gene assay, a significant reduction of luciferase gene expression was observed in the two constructs carrying the MCP1 mutations -2581 A or G plus the combination -362C and int1del554-567 compared to the wildtype haplotype (P = 0.02 and P = 0.006. The associated variants, in particular the haplotypes composed of these latter variants, result in decreased MCP-1 expression and a decreased risk of pulmonary TB. Conclusions In addition to the results of the previous study of the Ghanaian TB case-control sample, we have now identified the haplotype combination -2581G/-362C/int1del554-567 that mediates considerably stronger protection than does the MCP1 -362C allele alone (OR = 0.78, CI 0.69-0.87 vs OR = 0.83, CI 0.76-0.91. Our findings in both the genetic analysis and the reporter gene study further indicate a largely negligible role of the

  7. Association mapping and haplotype analysis of a 3.1-Mb genomic region involved in Fusarium head blight resistance on wheat chromosome 3BS.

    Directory of Open Access Journals (Sweden)

    Chenyang Hao

    Full Text Available A previous study provided an in-depth understanding of molecular population genetics of European and Asian wheat gene pools using a sequenced 3.1-Mb contig (ctg954 on chromosome 3BS. This region is believed to carry the Fhb1 gene for response to Fusarium head blight. In this study, 266 wheat accessions were evaluated in three environments for Type II FHB response based on the single floret inoculation method. Hierarchical clustering (UPGMA based on a Manhattan dissimilarity matrix divided the accessions into eight groups according to five FHB-related traits which have a high correlation between them; Group VIII comprised six accessions with FHB response levels similar to variety Sumai 3. Based on the compressed mixed linear model (MLM, association analysis between five FHB-related traits and 42 molecular markers along the 3.1-Mb region revealed 12 significant association signals at a threshold of P0.1 and P0.05 within each HapB at r(2>0.1 and P<0.001 showed significant differences between the Hap carried by FHB resistant resources, such as Sumai 3 and Wangshuibai, and susceptible genotypes in HapB3 and HapB6. These results suggest that Fhb1 is located within HapB6, with the possibility that another gene is located at or near HapB3. SSR markers and Haps detected in this study will be helpful in further understanding the genetic basis of FHB resistance, and provide useful information for marker-assisted selection of Fhb1 in wheat breeding.

  8. Cross-study analysis of genomic data defines the ciliate multigenic epiplasmin family: strategies for functional analysis in Paramecium tetraurelia

    Directory of Open Access Journals (Sweden)

    Ravet Viviane

    2009-06-01

    Full Text Available Abstract Background The sub-membranous skeleton of the ciliate Paramecium, the epiplasm, is composed of hundreds of epiplasmic scales centered on basal bodies, and presents a complex set of proteins, epiplasmins, which belong to a multigenic family. The repeated duplications observed in the P. tetraurelia genome present an interesting model of the organization and evolution of a multigenic family within a single cell. Results To study this multigenic family, we used phylogenetic, structural, and analytical transcriptional approaches. The phylogenetic method defines 5 groups of epiplasmins in the multigenic family. A refined analysis by Hydrophobic Cluster Analysis (HCA identifies structural characteristics of 51 epiplasmins, defining five separate groups, and three classes. Depending on the sequential arrangement of their structural domains, the epiplasmins are defined as symmetric, asymmetric or atypical. The EST data aid in this classification, in the identification of putative regulating sequences such as TATA or CAAT boxes. When specific RNAi experiments were conducted using sequences from either symmetric or asymmetric classes, phenotypes were drastic. Local effects show either disrupted or ill-shaped epiplasmic scales. In either case, this results in aborted cell division. Using structural features, we show that 4 epiplasmins are also present in another ciliate, Tetrahymena thermophila. Their affiliation with the distinctive structural groups of Paramecium epiplasmins demonstrates an interspecific multigenic family. Conclusion The epiplasmin multigenic family illustrates the history of genomic duplication in Paramecium. This study provides a framework which can guide functional analysis of epiplasmins, the major components of the membrane skeleton in ciliates. We show that this set of proteins handles an important developmental information in Paramecium since maintenance of epiplasm organization is crucial for cell morphogenesis.

  9. The effect of genealogy-based haplotypes on genomic prediction

    DEFF Research Database (Denmark)

    Edriss, Vahid; Fernando, Rohan L.; Su, Guosheng

    2013-01-01

    on haplotypes instead of regression on individual markers. The aim of this study was to investigate the accuracy of genomic prediction using haplotypes based on local genealogy information. Methods A total of 4429 Danish Holstein bulls were genotyped with the 50K SNP chip. Haplotypes were constructed using...... local genealogical trees. Effects of haplotype covariates were estimated with two types of prediction models: (1) assuming that effects had the same distribution for all haplotype covariates, i.e. the GBLUP method and (2) assuming that a large proportion (pi) of the haplotype covariates had zero effect......, i.e. a Bayesian mixture method. Results About 7.5 times more covariate effects were estimated when fitting haplotypes based on local genealogical trees compared to fitting individuals markers. Genealogy-based haplotype clustering slightly increased the accuracy of genomic prediction and, in some...

  10. Determination of haplotypes at structurally complex regions using emulsion haplotype fusion PCR.

    Science.gov (United States)

    Tyson, Jess; Armour, John A L

    2012-12-11

    Genotyping and massively-parallel sequencing projects result in a vast amount of diploid data that is only rarely resolved into its constituent haplotypes. It is nevertheless this phased information that is transmitted from one generation to the next and is most directly associated with biological function and the genetic causes of biological effects. Despite progress made in genome-wide sequencing and phasing algorithms and methods, problems assembling (and reconstructing linear haplotypes in) regions of repetitive DNA and structural variation remain. These dynamic and structurally complex regions are often poorly understood from a sequence point of view. Regions such as these that are highly similar in their sequence tend to be collapsed onto the genome assembly. This is turn means downstream determination of the true sequence haplotype in these regions poses a particular challenge. For structurally complex regions, a more focussed approach to assembling haplotypes may be required. In order to investigate reconstruction of spatial information at structurally complex regions, we have used an emulsion haplotype fusion PCR approach to reproducibly link sequences of up to 1kb in length to allow phasing of multiple variants from neighbouring loci, using allele-specific PCR and sequencing to detect the phase. By using emulsion systems linking flanking regions to amplicons within the CNV, this led to the reconstruction of a 59kb haplotype across the DEFA1A3 CNV in HapMap individuals. This study has demonstrated a novel use for emulsion haplotype fusion PCR in addressing the issue of reconstructing structural haplotypes at multiallelic copy variable regions, using the DEFA1A3 locus as an example.

  11. Determination of haplotypes at structurally complex regions using emulsion haplotype fusion PCR

    Directory of Open Access Journals (Sweden)

    Tyson Jess

    2012-12-01

    Full Text Available Abstract Background Genotyping and massively-parallel sequencing projects result in a vast amount of diploid data that is only rarely resolved into its constituent haplotypes. It is nevertheless this phased information that is transmitted from one generation to the next and is most directly associated with biological function and the genetic causes of biological effects. Despite progress made in genome-wide sequencing and phasing algorithms and methods, problems assembling (and reconstructing linear haplotypes in regions of repetitive DNA and structural variation remain. These dynamic and structurally complex regions are often poorly understood from a sequence point of view. Regions such as these that are highly similar in their sequence tend to be collapsed onto the genome assembly. This is turn means downstream determination of the true sequence haplotype in these regions poses a particular challenge. For structurally complex regions, a more focussed approach to assembling haplotypes may be required. Results In order to investigate reconstruction of spatial information at structurally complex regions, we have used an emulsion haplotype fusion PCR approach to reproducibly link sequences of up to 1kb in length to allow phasing of multiple variants from neighbouring loci, using allele-specific PCR and sequencing to detect the phase. By using emulsion systems linking flanking regions to amplicons within the CNV, this led to the reconstruction of a 59kb haplotype across the DEFA1A3 CNV in HapMap individuals. Conclusion This study has demonstrated a novel use for emulsion haplotype fusion PCR in addressing the issue of reconstructing structural haplotypes at multiallelic copy variable regions, using the DEFA1A3 locus as an example.

  12. Data analysis-based autonomic bandwidth adjustment in software defined multi-vendor optical transport networks.

    Science.gov (United States)

    Li, Yajie; Zhao, Yongli; Zhang, Jie; Yu, Xiaosong; Jing, Ruiquan

    2017-11-27

    Network operators generally provide dedicated lightpaths for customers to meet the demand for high-quality transmission. Considering the variation of traffic load, customers usually rent peak bandwidth that exceeds the practical average traffic requirement. In this case, bandwidth provisioning is unmetered and customers have to pay according to peak bandwidth. Supposing that network operators could keep track of traffic load and allocate bandwidth dynamically, bandwidth can be provided as a metered service and customers would pay for the bandwidth that they actually use. To achieve cost-effective bandwidth provisioning, this paper proposes an autonomic bandwidth adjustment scheme based on data analysis of traffic load. The scheme is implemented in a software defined networking (SDN) controller and is demonstrated in the field trial of multi-vendor optical transport networks. The field trial shows that the proposed scheme can track traffic load and realize autonomic bandwidth adjustment. In addition, a simulation experiment is conducted to evaluate the performance of the proposed scheme. We also investigate the impact of different parameters on autonomic bandwidth adjustment. Simulation results show that the step size and adjustment period have significant influences on bandwidth savings and packet loss. A small value of step size and adjustment period can bring more benefits by tracking traffic variation with high accuracy. For network operators, the scheme can serve as technical support of realizing bandwidth as metered service in the future.

  13. Defining and measuring suspicion of sepsis: an analysis of routine data.

    Science.gov (United States)

    Inada-Kim, Matthew; Page, Bethan; Maqsood, Imran; Vincent, Charles

    2017-06-09

    To define the target population of patients who have suspicion of sepsis (SOS) and to provide a basis for assessing the burden of SOS, and the evaluation of sepsis guidelines and improvement programmes. Retrospective analysis of routinely collected hospital administrative data. Secondary care, eight National Health Service (NHS) Acute Trusts. Hospital Episode Statistics data for 2013-2014 was used to identify all admissions with a primary diagnosis listed in the 'suspicion of sepsis' (SOS) coding set. The SOS coding set consists of all bacterial infective diagnoses. We identified 47 475 admissions with SOS, equivalent to a rate of 17 admissions per 1000 adults in a given year. The mortality for this group was 7.2% during their acute hospital admission. Urinary tract infection was the most common diagnosis and lobar pneumonia was associated with the most deaths. A short list of 10 diagnoses can account for 85% of the deaths. Patients with SOS can be identified in routine administrative data. It is these patients who should be screened for sepsis and are the target of programmes to improve the detection and treatment of sepsis. The effectiveness of such programmes can be evaluated by examining the outcomes of patients with SOS. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  14. Off-line analysis of positron annihilation spectra. II. Defining crystal frame origin

    International Nuclear Information System (INIS)

    Adam, Gh.; Adam, S.

    1997-01-01

    This paper is devoted to the consistent definition of the origin Γ of the crystal frame (CF) of an n-axis-projected histogram (where n-vector denotes a principal crystallographic axis) obtained by the technique of the two dimensional angular correlation of positron-electron annihilation radiation (2D-ACAR). This is shown to need agreement with each other of two alternative definitions of Γ as center of symmetry and center of gravity of areas entering the signature of crystal symmetry (SCS) of the spectrum defined in a previous paper. This requirement singles out the projection of the first Brillouin zone onto the histogram plane as the area containing the information which is the least distorted by the instrumental artifacts. The derivation of Γ involves two steps described in Section 2 and 3, respectively. Consistency with each other of the obtained solutions provides a first family of validation tests. The CF validation is to be decided from the analysis of the artifact distribution in the Cf histogram. The histogram reformulation in the crystal frame is legitimate provided the Euler angle θ relating the crystal and laboratory frames is negligible . Among the criteria for the validation of the analysis of primary importance is the requirement of close agreement between the two alternative definitions of the zero-momentum projection of the momentum distribution onto the histogram plane. The histogram redefinition in the crystal frame results in specific discretization errors. To check there magnitude the SCS values are computed again and the derivation CF parameters repeated the convergence of this iterative refinement of the CF parameters offers a supplementary insight into the crystal-detector alignment and crystal quality. The described procedure is applied to three 2D-ACAR histograms

  15. Haplotypes of CYP3A4 and their close linkage with CYP3A5 haplotypes in a Japanese population.

    Science.gov (United States)

    Fukushima-Uesaka, Hiromi; Saito, Yoshiro; Watanabe, Hidemi; Shiseki, Kisho; Saeki, Mayumi; Nakamura, Takahiro; Kurose, Kouichi; Sai, Kimie; Komamura, Kazuo; Ueno, Kazuyuki; Kamakura, Shiro; Kitakaze, Masafumi; Hanai, Sotaro; Nakajima, Toshiharu; Matsumoto, Kenji; Saito, Hirohisa; Goto, Yu-ichi; Kimura, Hideo; Katoh, Masaaki; Sugai, Kenji; Minami, Narihiro; Shirao, Kuniaki; Tamura, Tomohide; Yamamoto, Noboru; Minami, Hironobu; Ohtsu, Atsushi; Yoshida, Teruhiko; Saijo, Nagahiro; Kitamura, Yutaka; Kamatani, Naoyuki; Ozawa, Shogo; Sawada, Jun-ichi

    2004-01-01

    In order to identify single nucleotide polymorphisms (SNPs) and haplotype frequencies of CYP3A4 in a Japanese population, the distal enhancer and proximal promoter regions, all exons, and the surrounding introns were sequenced from genomic DNA of 416 Japanese subjects. We found 24 SNPs, including 17 novel ones: two in the distal enhancer, four in the proximal promoter, one in the 5'-untranslated region (UTR), seven in the introns, and three in the 3'-UTR. The most common SNP was c.1026+12G>A (IVS10+12G>A), with a 0.249 frequency. Four non-synonymous SNPs, c.554C>G (p.T185S, CYP3A4(*)16), c.830_831insA (p.E277fsX8, (*)6), c.878T>C (p.L293P, (*)18), and c.1088 C>T (p.T363M, (*)11) were found with frequencies of 0.014, 0.001, 0.028, and 0.002, respectively. No SNP was found in the known nuclear transcriptional factor-binding sites in the enhancer and promoter regions. Using these 24 SNPs, 16 haplotypes were unambiguously identified, and nine haplotypes were inferred by aid of an expectation-maximization-based program. In addition, using data from 186 subjects enabled a close linkage to be found between CYP3A4 and CYP3A5 SNPs, especially among the SNPs at c.1026+12 in CYP3A4 and c.219-237 (IVS3-237, a key SNP site for CYP3A5(*)3), c.865+77 (IVS9+77) and c.1523 in CYP3A5. This result suggested that CYP3A4 and CYP3A5 are within the same gene block. Haplotype analysis between CYP3A4 and CYP3A5 revealed several major haplotype combinations in the CYP3A4-CYP3A5 block. Our findings provide fundamental and useful information for genotyping CYP3A4 (and CYP3A5) in the Japanese, and probably Asian populations. Copyright 2003 Wiley-Liss, Inc.

  16. A haplotype specific to North European wheat (Triticum aestivum L.)

    Czech Academy of Sciences Publication Activity Database

    Tsombalova, J.; Karafiátová, Miroslava; Vrána, Jan; Kubaláková, Marie; Peusa, H.; Jakobson, I.; Jarve, M.; Valárik, Miroslav; Doležel, Jaroslav; Jarve, K.

    2017-01-01

    Roč. 64, č. 4 (2017), s. 653-664 ISSN 0925-9864 R&D Projects: GA MŠk(CZ) LO1204; GA ČR(CZ) GA14-07164S Institutional support: RVO:61389030 Keywords : bread wheat * genetic diversity * polyploid wheat * introgression lines * molecular analysis * tetraploid wheat * hexaploid wheat * powdery mildew * spelta l. * map * Common wheat * Triticum aestivum L * Spelt * Triticum spelta L * Chromosome 4A * Zero alleles * Haplotype * Linkage disequilibrium Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Plant sciences, botany Impact factor: 1.294, year: 2016

  17. A Haplotype Information Theory Method Reveals Genes of Evolutionary Interest in European vs. Asian Pigs.

    Science.gov (United States)

    Hudson, Nicholas J; Naval-Sánchez, Marina; Porto-Neto, Laercio; Pérez-Enciso, Miguel; Reverter, Antonio

    2018-06-05

    Asian and European wild boars were independently domesticated ca. 10,000 years ago. Since the 17th century, Chinese breeds have been imported to Europe to improve the genetics of European animals by introgression of favourable alleles, resulting in a complex mosaic of haplotypes. To interrogate the structure of these haplotypes further, we have run a new haplotype segregation analysis based on information theory, namely compression efficiency (CE). We applied the approach to sequence data from individuals from each phylogeographic region (n = 23 from Asia and Europe) including a number of major pig breeds. Our genome-wide CE is able to discriminate the breeds in a manner reflecting phylogeography. Furthermore, 24,956 non-overlapping sliding windows (each comprising 1,000 consecutive SNP) were quantified for extent of haplotype sharing within and between Asia and Europe. The genome-wide distribution of extent of haplotype sharing was quite different between groups. Unlike European pigs, Asian pigs haplotype sharing approximates a normal distribution. In line with this, we found the European breeds possessed a number of genomic windows of dramatically higher haplotype sharing than the Asian breeds. Our CE analysis of sliding windows capture some of the genomic regions reported to contain signatures of selection in domestic pigs. Prominent among these regions, we highlight the role of a gene encoding the mitochondrial enzyme LACTB which has been associated with obesity, and the gene encoding MYOG a fundamental transcriptional regulator of myogenesis. The origin of these regions likely reflects either a population bottleneck in European animals, or selective targets on commercial phenotypes reducing allelic diversity in particular genes and/or regulatory regions.

  18. A comprehensive literature review of haplotyping software and methods for use with unrelated individuals

    Directory of Open Access Journals (Sweden)

    Salem Rany M

    2005-03-01

    Full Text Available Abstract Interest in the assignment and frequency analysis of haplotypes in samples of unrelated individuals has increased immeasurably as a result of the emphasis placed on haplotype analyses by, for example, the International HapMap Project and related initiatives. Although there are many available computer programs for haplotype analysis applicable to samples of unrelated individuals, many of these programs have limitations and/or very specific uses. In this paper, the key features of available haplotype analysis software for use with unrelated individuals, as well as pooled DNA samples from unrelated individuals, are summarised. Programs for haplotype analysis were identified through keyword searches on PUBMED and various internet search engines, a review of citations from retrieved papers and personal communications, up to June 2004. Priority was given to functioning computer programs, rather than theoretical models and methods. The available software was considered in light of a number of factors: the algorithm(s used, algorithm accuracy, assumptions, the accommodation of genotyping error, implementation of hypothesis testing, handling of missing data, software characteristics and web-based implementations. Review papers comparing specific methods and programs are also summarised. Forty-six haplotyping programs were identified and reviewed. The programs were divided into two groups: those designed for individual genotype data (a total of 43 programs and those designed for use with pooled DNA samples (a total of three programs. The accuracy of programs using various criteria are assessed and the programs are categorised and discussed in light of: algorithm and method, accuracy, assumptions, genotyping error, hypothesis testing, missing data, software characteristics and web implementation. Many available programs have limitations (eg some cannot accommodate missing data and/or are designed with specific tasks in mind (eg estimating

  19. MalHaploFreq: A computer programme for estimating malaria haplotype frequencies from blood samples

    Directory of Open Access Journals (Sweden)

    Smith Thomas A

    2008-07-01

    Full Text Available Abstract Background Molecular markers, particularly those associated with drug resistance, are important surveillance tools that can inform policy choice. People infected with falciparum malaria often contain several genetically-distinct clones of the parasite; genotyping the patients' blood reveals whether or not the marker is present (i.e. its prevalence, but does not reveal its frequency. For example a person with four malaria clones may contain both mutant and wildtype forms of a marker but it is not possible to distinguish the relative frequencies of the mutant and wildtypes i.e. 1:3, 2:2 or 3:1. Methods An appropriate method for obtaining frequencies from prevalence data is by Maximum Likelihood analysis. A computer programme has been developed that allows the frequency of markers, and haplotypes defined by up to three codons, to be estimated from blood phenotype data. Results The programme has been fully documented [see Additional File 1] and provided with a user-friendly interface suitable for large scale analyses. It returns accurate frequencies and 95% confidence intervals from simulated dataset sets and has been extensively tested on field data sets. Additional File 1 User manual for MalHaploFreq. Click here for file Conclusion The programme is included [see Additional File 2] and/or may be freely downloaded from 1. It can then be used to extract molecular marker and haplotype frequencies from their prevalence in human blood samples. This should enhance the use of frequency data to inform antimalarial drug policy choice. Additional File 2 executable programme compiled for use on DOS or windows Click here for file

  20. F8 haplotype and inhibitor risk: results from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort

    Science.gov (United States)

    Schwarz, John; Astermark, Jan; Menius, Erika D.; Carrington, Mary; Donfield, Sharyne M.; Gomperts, Edward D.; Nelson, George W.; Oldenburg, Johannes; Pavlova, Anna; Shapiro, Amy D.; Winkler, Cheryl A.; Berntorp, Erik

    2012-01-01

    Background Ancestral background, specifically African descent, confers higher risk for development of inhibitory antibodies to factor VIII (FVIII) in hemophilia A. It has been suggested that differences in the distribution of factor VIII gene (F8) haplotypes, and mismatch between endogenous F8 haplotypes and those comprising products used for treatment could contribute to risk. Design and Methods Data from the HIGS Combined Cohort were used to determine the association between F8 haplotype 3 (H3) vs. haplotypes 1 and 2 (H1+H2) and inhibitor risk among individuals of genetically-determined African descent. Other variables known to affect inhibitor risk including type of F8 mutation and HLA were included in the analysis. A second research question regarding risk related to mismatch in endogenous F8 haplotype and recombinant FVIII products used for treatment was addressed. Results H3 was associated with higher inhibitor risk among those genetically-identified (N=49) as of African ancestry, but the association did not remain significant after adjustment for F8 mutation type and the HLA variables. Among subjects of all racial ancestries enrolled in HIGS who reported early use of recombinant products (N=223), mismatch in endogenous haplotype and the FVIII proteins constituting the products used did not confer greater risk for inhibitor development. Conclusion H3 was not an independent predictor of inhibitor risk. Further, our findings did not support a higher risk of inhibitors in the presence of a haplotype mismatch between the FVIII molecule infused and that of the individual. PMID:22958194

  1. Haplotypes in CCR5-CCR2, CCL3 and CCL5 are associated with natural resistance to HIV-1 infection in a Colombian cohort.

    Science.gov (United States)

    Vega, Jorge A; Villegas-Ospina, Simón; Aguilar-Jiménez, Wbeimar; Rugeles, María T; Bedoya, Gabriel; Zapata, Wildeman

    2017-06-01

    Variants in genes encoding for HIV-1 co-receptors and their natural ligands have been individually associated to natural resistance to HIV-1 infection. However, the simultaneous presence of these variants has been poorly studied. To evaluate the association of single and multilocus haplotypes in genes coding for the viral co-receptors CCR5 and CCR2, and their ligands CCL3 and CCL5, with resistance or susceptibility to HIV-1 infection. Nine variants in CCR5-CCR2, two SNPs in CCL3 and two in CCL5 were genotyped by PCR-RFLP in 35 seropositive (cases) and 49 HIV-1-exposed seronegative Colombian individuals (controls). Haplotypes were inferred using the Arlequin software, and their frequency in individual or combined loci was compared between cases and controls by the chi-square test. A p' value ;0.05 after Bonferroni correction was considered significant. Homozygosis of the human haplogroup (HH) E was absent in controls and frequent in cases, showing a tendency to susceptibility. The haplotypes C-C and T-T in CCL3 were associated with susceptibility (p'=0.016) and resistance (p';0.0001) to HIV-1 infection, respectively. Finally, in multilocus analysis, the haplotype combinations formed by HHC in CCR5-CCR2, T-T in CCL3 and G-C in CCL5 were associated with resistance (p'=0.006). Our results suggest that specific combinations of variants in genes from the same signaling pathway can define an HIV-1 resistant phenotype. Despite our small sample size, our statistically significant associations suggest strong effects; however, these results should be further validated in larger cohorts.

  2. [Construction of haplotype and haplotype block based on tag single nucleotide polymorphisms and their applications in association studies].

    Science.gov (United States)

    Gu, Ming-liang; Chu, Jia-you

    2007-12-01

    Human genome has structures of haplotype and haplotype block which provide valuable information on human evolutionary history and may lead to the development of more efficient strategies to identify genetic variants that increase susceptibility to complex diseases. Haplotype block can be divided into discrete blocks of limited haplotype diversity. In each block, a small fraction of ptag SNPsq can be used to distinguish a large fraction of the haplotypes. These tag SNPs can be potentially useful for construction of haplotype and haplotype block, and association studies in complex diseases. There are two general classes of methods to construct haplotype and haplotype blocks based on genotypes on large pedigrees and statistical algorithms respectively. The author evaluate several construction methods to assess the power of different association tests with a variety of disease models and block-partitioning criteria. The advantages, limitations and applications of each method and the application in the association studies are discussed equitably. With the completion of the HapMap and development of statistical algorithms for addressing haplotype reconstruction, ideas of construction of haplotype based on combination of mathematics, physics, and computer science etc will have profound impacts on population genetics, location and cloning for susceptible genes in complex diseases, and related domain with life science etc.

  3. Genetic differences in the two main groups of the Japanese population based on autosomal SNPs and haplotypes.

    Science.gov (United States)

    Yamaguchi-Kabata, Yumi; Tsunoda, Tatsuhiko; Kumasaka, Natsuhiko; Takahashi, Atsushi; Hosono, Naoya; Kubo, Michiaki; Nakamura, Yusuke; Kamatani, Naoyuki

    2012-05-01

    Although the Japanese population has a rather low genetic diversity, we recently confirmed the presence of two main clusters (the Hondo and Ryukyu clusters) through principal component analysis of genome-wide single-nucleotide polymorphism (SNP) genotypes. Understanding the genetic differences between the two main clusters requires further genome-wide analyses based on a dense SNP set and comparison of haplotype frequencies. In the present study, we determined haplotypes for the Hondo cluster of the Japanese population by detecting SNP homozygotes with 388,591 autosomal SNPs from 18,379 individuals and estimated the haplotype frequencies. Haplotypes for the Ryukyu cluster were inferred by a statistical approach using the genotype data from 504 individuals. We then compared the haplotype frequencies between the Hondo and Ryukyu clusters. In most genomic regions, the haplotype frequencies in the Hondo and Ryukyu clusters were very similar. However, in addition to the human leukocyte antigen region on chromosome 6, other genomic regions (chromosomes 3, 4, 5, 7, 10 and 12) showed dissimilarities in haplotype frequency. These regions were enriched for genes involved in the immune system, cell-cell adhesion and the intracellular signaling cascade. These differentiated genomic regions between the Hondo and Ryukyu clusters are of interest because they (1) should be examined carefully in association studies and (2) likely contain genes responsible for morphological or physiological differences between the two groups.

  4. Reliable reconstruction of HIV-1 whole genome haplotypes reveals clonal interference and genetic hitchhiking among immune escape variants

    Science.gov (United States)

    2014-01-01

    Background Following transmission, HIV-1 evolves into a diverse population, and next generation sequencing enables us to detect variants occurring at low frequencies. Studying viral evolution at the level of whole genomes was hitherto not possible because next generation sequencing delivers relatively short reads. Results We here provide a proof of principle that whole HIV-1 genomes can be reliably reconstructed from short reads, and use this to study the selection of immune escape mutations at the level of whole genome haplotypes. Using realistically simulated HIV-1 populations, we demonstrate that reconstruction of complete genome haplotypes is feasible with high fidelity. We do not reconstruct all genetically distinct genomes, but each reconstructed haplotype represents one or more of the quasispecies in the HIV-1 population. We then reconstruct 30 whole genome haplotypes from published short sequence reads sampled longitudinally from a single HIV-1 infected patient. We confirm the reliability of the reconstruction by validating our predicted haplotype genes with single genome amplification sequences, and by comparing haplotype frequencies with observed epitope escape frequencies. Conclusions Phylogenetic analysis shows that the HIV-1 population undergoes selection driven evolution, with successive replacement of the viral population by novel dominant strains. We demonstrate that immune escape mutants evolve in a dependent manner with various mutations hitchhiking along with others. As a consequence of this clonal interference, selection coefficients have to be estimated for complete haplotypes and not for individual immune escapes. PMID:24996694

  5. Mitochondrial control region haplotypes of the South American sea lion Otaria flavescens (Shaw, 1800).

    Science.gov (United States)

    Artico, L O; Bianchini, A; Grubel, K S; Monteiro, D S; Estima, S C; Oliveira, L R de; Bonatto, S L; Marins, L F

    2010-09-01

    The South American sea lion, Otaria flavescens, is widely distributed along the Pacific and Atlantic coasts of South America. However, along the Brazilian coast, there are only two nonbreeding sites for the species (Refúgio de Vida Silvestre da Ilha dos Lobos and Refúgio de Vida Silvestre do Molhe Leste da Barra do Rio Grande), both in Southern Brazil. In this region, the species is continuously under the effect of anthropic activities, mainly those related to environmental contamination with organic and inorganic chemicals and fishery interactions. This paper reports, for the first time, the genetic diversity of O. flavescens found along the Southern Brazilian coast. A 287-bp fragment of the mitochondrial DNA control region (D-loop) was analyzed. Seven novel haplotypes were found in 56 individuals (OFA1-OFA7), with OFA1 being the most frequent (47.54%). Nucleotide diversity was moderate (π = 0.62%) and haplotype diversity was relatively low (67%). Furthermore, the median joining network analysis indicated that Brazilian haplotypes formed a reciprocal monophyletic clade when compared to the haplotypes from the Peruvian population on the Pacific coast. These two populations do not share haplotypes and may have become isolated some time back. Further genetic studies covering the entire species distribution are necessary to better understand the biological implications of the results reported here for the management and conservation of South American sea lions.

  6. Mitochondrial control region haplotypes of the South American sea lion Otaria flavescens (Shaw, 1800

    Directory of Open Access Journals (Sweden)

    L.O. Artico

    2010-09-01

    Full Text Available The South American sea lion, Otaria flavescens, is widely distributed along the Pacific and Atlantic coasts of South America. However, along the Brazilian coast, there are only two nonbreeding sites for the species (Refúgio de Vida Silvestre da Ilha dos Lobos and Refúgio de Vida Silvestre do Molhe Leste da Barra do Rio Grande, both in Southern Brazil. In this region, the species is continuously under the effect of anthropic activities, mainly those related to environmental contamination with organic and inorganic chemicals and fishery interactions. This paper reports, for the first time, the genetic diversity of O. flavescens found along the Southern Brazilian coast. A 287-bp fragment of the mitochondrial DNA control region (D-loop was analyzed. Seven novel haplotypes were found in 56 individuals (OFA1-OFA7, with OFA1 being the most frequent (47.54%. Nucleotide diversity was moderate (π = 0.62% and haplotype diversity was relatively low (67%. Furthermore, the median joining network analysis indicated that Brazilian haplotypes formed a reciprocal monophyletic clade when compared to the haplotypes from the Peruvian population on the Pacific coast. These two populations do not share haplotypes and may have become isolated some time back. Further genetic studies covering the entire species distribution are necessary to better understand the biological implications of the results reported here for the management and conservation of South American sea lions.

  7. Defining the student burnout construct: a structural analysis from three burnout inventories.

    Science.gov (United States)

    Maroco, João; Campos, Juliana Alvares Duarte Bonini

    2012-12-01

    College student burnout has been assessed mainly with the Maslach burnout inventory (MBI). However, the construct's definition and measurement with MBI has drawn several criticisms and new inventories have been suggested for the evaluation of the syndrome. A redefinition of the construct of student burnout is proposed by means of a structural equation model, reflecting burnout as a second order factor defined by factors from the MBI-student survey (MBI-SS); the Copenhagen burnout inventory-student survey (CBI-SS) and the Oldenburg burnout inventory-student survey (OLBI-SS). Standardized regression weights from Burnout to Exhaustion and Cynicism from the MBI-SS scale, personal burnout and studies related burnout from the CBI, and exhaustion and disengagement from OLBI, show that these factors are strong manifestations of students' burnout. For college students, the burnout construct is best defined by two dimensions described as "physical and psychological exhaustion" and "cynicism and disengagement".

  8. Using genetic algorithms to calibrate the user-defined parameters of IIST model for SBLOCA analysis

    International Nuclear Information System (INIS)

    Tsai, Chiung-Wen; Shih, Chunkuan; Wang, Jong-Rong

    2014-01-01

    Highlights: • The genetic algorithm is proposed to search the user-defined parameters of important correlations. • The TRACE IIST model was employed as a case study to demonstrate the capability of GAs. • The multi-objective optimization strategy was incorporated to evaluate multi objective functions simultaneously. - Abstract: The thermal–hydraulic system codes, i.e., TRACE, have been designed to predict, investigate, and simulate nuclear reactor transients and accidents. Implementing relevant correlations, these codes are able to represent important phenomena such as two-phase flow, critical flow, and countercurrent flow. Furthermore, the thermal–hydraulic system codes permit users to modify the coefficients corresponding to the correlations, providing a certain degree of freedom to calibrate the numerical results, i.e., peak cladding temperature. These coefficients are known as user-defined parameters (UDPs). Practically, defining a series of UDPs is complex, highly relied on expert opinions and engineering experiences. This study proposes another approach – the genetic algorithms (GAs), providing rigorous procedures and mitigating human judgments and mistakes, to calibrate the UDPs of important correlations for a 2% small break loss of coolant accident (SBLOCA). The TRACE IIST model was employed as a case study to demonstrate the capability of GAs. The UDPs were evolved by GAs to reduce the deviations between TRACE results and IIST experimental data

  9. Haplotypes and Sequence Variation in the Ovine Adiponectin Gene (ADIPOQ

    Directory of Open Access Journals (Sweden)

    Qing-Ming An

    2015-11-01

    Full Text Available The adiponectin gene (ADIPOQ plays an important role in energy homeostasis. In this study five separate regions (regions 1 to 5 of ovine ADIPOQ were analysed using PCR-SSCP. Four different PCR-SSCP patterns (A1-D1, A2-D2 were detected in region-1 and region-2, respectively, with seven and six SNPs being revealed. In region-3, three different patterns (A3-C3 and three SNPs were observed. Two patterns (A4-B4, A5-B5 and two and one SNPs were observed in region-4 and region-5, respectively. In total, nineteen SNPs were detected, with five of them in the coding region and two (c.46T/C and c.515G/A putatively resulting in amino acid changes (p.Tyr16His and p.Lys172Arg. In region-1, -2 and -3 of 316 sheep from eight New Zealand breeds, variants A1, A2 and A3 were the most common, although variant frequencies differed in the eight breeds. Across region-1 and region-3, nine haplotypes were identified and haplotypes A1-A3, A1-C3, B1-A3 and B1-C3 were most common. These results indicate that the ADIPOQ gene is polymorphic and suggest that further analysis is required to see if the variation in the gene is associated with animal production traits.

  10. Distribution pattern of Plasmodium falciparum chloroquine transporter (pfcrt) gene haplotypes in Sri Lanka 1996-2006

    DEFF Research Database (Denmark)

    Zhang, Jenny J; Senaratne, Tharanga N; Daniels, Rachel

    2011-01-01

    Abstract. Widespread antimalarial resistance has been a barrier to malaria elimination efforts in Sri Lanka. Analysis of genetic markers in historic parasites may uncover trends in the spread of resistance. We examined the frequency of Plasmodium falciparum chloroquine transporter (pfcrt; codons 72......-76) haplotypes in Sri Lanka in 1996-1998 and 2004-2006 using a high-resolution melting assay. Among 59 samples from 1996 to 1998, we detected the SVMNT (86%), CVMNK (10%), and CVIET (2%) haplotypes, with a positive trend in SVMNT and a negative trend in CVMNK frequency (P = 0.004) over time. Among 24 samples...

  11. Genomic sequence of 'Candidatus Liberibacter solanacearum' haplotype C and its comparison with haplotype A and B genomes.

    Directory of Open Access Journals (Sweden)

    Jinhui Wang

    Full Text Available Haplotypes A and B of 'Candidatus Liberibacter solanacearum' (CLso are associated with diseases of solanaceous plants, especially Zebra chip disease of potato, and haplotypes C, D and E are associated with symptoms on apiaceous plants. To date, one complete genome of haplotype B and two high quality draft genomes of haplotype A have been obtained for these unculturable bacteria using metagenomics from the psyllid vector Bactericera cockerelli. Here, we present the first genomic sequences obtained for the carrot-associated CLso. These two genomic sequences of haplotype C, FIN114 (1.24 Mbp and FIN111 (1.20 Mbp, were obtained from carrot psyllids (Trioza apicalis harboring CLso. Genomic comparisons between the haplotypes A, B and C revealed that the genome organization differs between these haplotypes, due to large inversions and other recombinations. Comparison of protein-coding genes indicated that the core genome of CLso consists of 885 ortholog groups, with the pan-genome consisting of 1327 ortholog groups. Twenty-seven ortholog groups are unique to CLso haplotype C, whilst 11 ortholog groups shared by the haplotypes A and B, are not found in the haplotype C. Some of these ortholog groups that are not part of the core genome may encode functions related to interactions with the different host plant and psyllid species.

  12. An unusual haplotype structure on human chromosome 8p23 derived from the inversion polymorphism.

    Science.gov (United States)

    Deng, Libin; Zhang, Yuezheng; Kang, Jian; Liu, Tao; Zhao, Hongbin; Gao, Yang; Li, Chaohua; Pan, Hao; Tang, Xiaoli; Wang, Dunmei; Niu, Tianhua; Yang, Huanming; Zeng, Changqing

    2008-10-01

    Chromosomal inversion is an important type of genomic variations involved in both evolution and disease pathogenesis. Here, we describe the refined genetic structure of a 3.8-Mb inversion polymorphism at chromosome 8p23. Using HapMap data of 1,073 SNPs generated from 209 unrelated samples from CEPH-Utah residents with ancestry from northern and western Europe (CEU); Yoruba in Ibadan, Nigeria (YRI); and Asian (ASN) samples, which were comprised of Han Chinese from Beijing, China (CHB) and Japanese from Tokyo, Japan (JPT)-we successfully deduced the inversion orientations of all their 418 haplotypes. In particular, distinct haplotype subgroups were identified based on principal component analysis (PCA). Such genetic substructures were consistent with clustering patterns based on neighbor-joining tree reconstruction, which revealed a total of four haplotype clades across all samples. Metaphase fluorescence in situ hybridization (FISH) in a subset of 10 HapMap samples verified their inversion orientations predicted by PCA or phylogenetic tree reconstruction. Positioning of the outgroup haplotype within one of YRI clades suggested that Human NCBI Build 36-inverted order is most likely the ancestral orientation. Furthermore, the population differentiation test and the relative extended haplotype homozygosity (REHH) analysis in this region discovered multiple selection signals, also in a population-specific manner. A positive selection signal was detected at XKR6 in the ASN population. These results revealed the correlation of inversion polymorphisms to population-specific genetic structures, and various selection patterns as possible mechanisms for the maintenance of a large chromosomal rearrangement at 8p23 region during evolution. In addition, our study also showed that haplotype-based clustering methods, such as PCA, can be applied in scanning for cryptic inversion polymorphisms at a genome-wide scale.

  13. Análise dos haplótipos do gene da betaS-globina no Ceará Analysis of betaS-globin gene haplotypes in Ceará, Brazil

    Directory of Open Access Journals (Sweden)

    Gentil Claudino de Galiza Neto

    2005-10-01

    Full Text Available No presente trabalho abordam-se vários aspectos relacionados à natureza molecular da anemia falciforme (AF, desordem hematológica de caráter hereditário. A descoberta do polimorfismo do DNA no grupamento do gene betaS, originando diferentes haplótipos da doença, permitiu ampliar o conhecimento em torno da heterogeneidade clínica observada nos pacientes falcêmicos nas mais diversas regiões do mundo. Analisaram-se os diferentes haplótipos e seus parâmetros hematológicos, presentes em um grupo de 22 pacientes naturais e procedentes do estado do Ceará. A distribuição das freqüências dos haplótipos encontrados foi de 55,9% para Benin; 41,2% para República Centro-Africana (CAR; e de 2,9% para o haplótipo Senegal. Esses dados, em comparação com os demais estudos realizados no Brasil, mostram associação entre os seus valores para um alfa de 5% (p The present work deals with numerous aspects related to the molecular nature of sickle cell anemia. The discovery of the DNA polymorphism in the betas-globin gene cluster, gave origin to different haplotypes of the disease, making possible to enlarge the knowledge about the clinical heterogenity observed on the patients with sickle cell disease, in the various regions of the world. The different haplotypes and its hematological parameters were analysed in a group of 22 patients born in the State of Ceará, northeast of Brazil. The distribution found in the haplotypes frequency was of 55.9% for the Benin, of 41.2% for the CAR, and of 2.9% for Senegal haplotype. The data, compared to the others works done in Brazil, show relations among their values to alpha of 5% (p < 0,05. The results make possible a full understanding of the pathophisiology of the illness and of its clinical complexity in our State, as well as it allows a better knowledge of the sickle cell disease in our country.

  14. Different origin and dispersal of sulfadoxine-resistant Plasmodium falciparum haplotypes between Eastern Africa and Democratic Republic of Congo

    DEFF Research Database (Denmark)

    Baraka, Vito; Delgado-Ratto, Christopher; Nag, Sidsel

    2017-01-01

    Sulfadoxine/pyrimethamine (SP) is still used for malaria control in sub-Saharan Africa; however, widespread resistance is a major concern. This study aimed to determine the dispersal and origin of sulfadoxine resistance lineages in the Democratic Republic of the Congo compared with East African.......3 and 7.7 kb) flanking the Pfdhps gene were assayed. Evolutionary analysis revealed a shared origin of Pfdhps haplotypes in East Africa, with a distinct population clustering in DR Congo. Furthermore, in Tanzania there was an independent distinct origin of Pfdhps SGEGA resistant haplotype. In Uganda...... and Tanzania, gene flow patterns contribute to the dispersal and shared origin of parasites carrying double- and triple-mutant Pfdhps haplotypes associated with poor outcomes of intermittent preventive treatment during pregnancy using SP (IPTp-SP). However, the origins of the Pfdhps haplotypes in DR Congo...

  15. Defining the spatial scale in modern regional analysis new challenges from data at local level

    CERN Document Server

    Fernández Vázquez, Esteban

    2014-01-01

    This book discusses the concept of region, including techniques of ecological inference applied to estimating disaggregated data from observable aggregates. The final part presents applications in line with the functional areas definition in regional analysis.

  16. The Application of Work Domain Analysis to Defining Australia’s Air Combat Capability

    Science.gov (United States)

    2014-03-01

    Capability. References Brady, A., Naikar, N., & Treadwell, A. (2013). Organisational storytelling with work domain analysis: Case study of air power...UNCLASSIFIED 20 Brady, A., Naikar, N., & Treadwell, A. (2013). Organisational storytelling with work domain analysis: Case study of air power doctrine and...maturity model? A framework of general design principles for maturity model and its demonstration in business process management. Proceedings of the

  17. PARTITION: A program for defining the source term/consequence analysis interface in the NUREG--1150 probabilistic risk assessments

    International Nuclear Information System (INIS)

    Iman, R.L.; Helton, J.C.; Johnson, J.D.

    1990-05-01

    The individual plant analyses in the US Nuclear Regulatory Commission's reassessment of the risk from commercial nuclear power plants (NUREG-1150) consist of four parts: systems analysis, accident progression analysis, source term analysis, and consequence analysis. Careful definition of the interfaces between these parts is necessary for both information flow and computational efficiency. This document has been designed for users of the PARTITION computer program developed by the authors at Sandia National Laboratories for defining the interface between the source term analysis (performed with the XXSOR programs) and the consequence analysis (performed with the MACCS program). This report provides a tutorial that details how the interactive partitioning is performed, along with detailed information on the partitioning process. The PARTITION program was written in ANSI standard FORTRAN 77 to make the code as machine-independent (i.e., portable) as possible. 9 refs., 4 figs

  18. Performance Analysis of Congestion Control Mechanism in Software Defined Network (SDN

    Directory of Open Access Journals (Sweden)

    Rahman M. Z. A.

    2017-01-01

    Full Text Available In the near future, the traditional networks architecture will be difficult to be managed. Hence, Software Defined Network (SDN will be an alternative in the future of programmable networks to replace the conventional network architecture. The main idea of SDN architecture is to separate the forwarding plane and control plane of network system, where network operators can program packet forwarding behaviour to improve the network performance. Congestion control is important mechanism for network traffic to improve network capability and achieve high end Quality of Service (QoS. In this paper, extensive simulation is conducted to analyse the performance of SDN by implementing Link Layer Discovery Protocol (LLDP under congested network. The simulation was conducted on Mininet by creating four different fanout and the result was analysed based on differences of matrix performance. As a result, the packet loss and throughput reduction were observed when number of fanout in the topology was increased. By using LLDP protocol, huge reduction in packet loss rate has been achieved while maximizing percentage packet delivery ratio.

  19. Labeling and defining severe and enduring anorexia nervosa: A systematic review and critical analysis.

    Science.gov (United States)

    Broomfield, Catherine; Stedal, Kristin; Touyz, Stephen; Rhodes, Paul

    2017-06-01

    With anorexia nervosa (AN) having various presentations, attention has been directed towards particularly durable forms of the condition in both research and clinical contexts. A major hindrance in terms of advancing the field is the inconsistent labeling and defining of this subgroup. This has two implications; first, the inconsistent recruitment of participants when researching this sample, and second, the misdiagnosing of patients who may or may not have a durable course of the disease. The current research had the purpose of providing an overview of the current labels and criteria used for defining cases of severe and enduring AN, and critically analysing the implications of these findings. In accordance with PRISMA guidelines, a literature search was conducted using four electronic databases (PsycINFO, MEDLINE, Web of Science and Scopus) in order to identify 32 records that met the standards stipulated by the criteria. Data extraction included explicit labeling, the definition or criteria used to describe the subgroup, along with participant age and study design. It was found that the terms chronic and severe and enduring were the most commonly used adjectives when referring to this subgroup. In terms of criteria, illness duration and the number of previously failed treatment attempts were the most common defining features within the literature. It is the aim of the authors to inspire further research into what is the most appropriate label and defining features for the subgroup in order to facilitate a better approach and outcome for the individuals affected. Objetivo Con la Anorexia Nervosa (AN) teniendo varias presentaciones, tanto en la investigación como en los contextos clínicos, la atención se ha dirigido particularmente hacia las formas duraderas de esta condición. Un obstáculo importante en términos de avanzar en el campo es la inconsistencia en el etiquetado y definición de este subgrupo. Esto tiene dos implicaciones; Primero, el inconsistente

  20. The interaction between coagulation factor 2 receptor and interleukin 6 haplotypes increases the risk of myocardial infarction in men.

    Directory of Open Access Journals (Sweden)

    Bruna Gigante

    Full Text Available The aim of the study was to investigate if the interaction between the coagulation factor 2 receptor (F2R and the interleukin 6 (IL6 haplotypes modulates the risk of myocardial infarction (MI in the Stockholm Heart Epidemiology Program (SHEEP. Seven SNPs at the F2R locus and three SNPs at the IL6 locus were genotyped. Haplotypes and haplotype pairs (IL6*F2R were generated. A logistic regression analysis was performed to analyze the association of the haplotypes and haplotype pairs with the MI risk. Presence of an interaction between the two haplotypes in each haplotype pair was calculated using two different methods: the statistical, on a multiplicative scale, which includes the cross product of the two factors into the logistic regression model; the biological, on an additive scale, which evaluates the relative risk associated with the joint presence of both factors. The ratio between the observed and the predicted effect of the joint exposure, the synergy index (S, indicates the presence of a synergy (S>1 or of an antagonism (S<1. None of the haplotypes within the two loci was associated with the risk of MI. Out of 22 different haplotype pairs, the haplotype pair 17 GGG*ADGTCCT was associated with an increased risk of MI with an OR (95%CI of 1.58 (1.05-2.41 (p = 0.02 in the crude and an OR of 1.72 (1.11-2.67 (p = 0.01 in the adjusted analysis. We observed the presence of an interaction on a multiplicative scale with an OR (95%CI of 2.24 (1.27-3.95 (p = 0.005 and a slight interactive effect between the two haplotypes on an additive scale with an OR (95%CI of 1.56 (1.02-2.37 (p = 0.03 and S of 1.66 (0.89-31. In conclusion, our results support the hypothesis that the interaction between these two functionally related genes may influence the risk of MI and suggest new mechanisms involved in the genetic susceptibility to MI.

  1. The Role of Business Agreements in Defining Textbook Affordability and Digital Materials: A Document Analysis

    Science.gov (United States)

    Raible, John; deNoyelles, Aimee

    2015-01-01

    Adopting digital materials such as eTextbooks and e-coursepacks is a potential strategy to address textbook affordability in the United States. However, university business relationships with bookstore vendors implicitly structure which instructional resources are available and in what manner. In this study, a document analysis was conducted on…

  2. Twenty First Century Cyberbullying Defined: An Analysis of Intent, Repetition and Emotional Response

    Science.gov (United States)

    Walker, Carol Marie

    2012-01-01

    The purpose of this study was to analyze the extent and impact that cyberbullying has on the undergraduate college student and provide a current definition for the event. A priori power analysis guided this research to provide an 80 percent probability of detecting a real effect with medium effect size. Adequate research power was essential to…

  3. Application of Maxent Multivariate Analysis to Define Climate-Change Effects on Species Distributions and Changes

    Science.gov (United States)

    2014-09-01

    tracts of land for the species preservation and augmentation. The issue that results from their presence is that these lands may also be desirable for...turtle is a fa- miliar amphibian species that ranges throughout the Eastern United States. Its preservation is less problematic for the Army, so it...Forb Regeneration -0.4613 Pasture /Hay -0.6268 Cultivated Cropland Adding land cover information to the analysis results in better identifica

  4. A new 500 kb haplotype associated with high CD8+ T-lymphocyte numbers predicts a less severe expression of hereditary hemochromatosis

    Directory of Open Access Journals (Sweden)

    Mascarenhas Cláudia

    2008-11-01

    Full Text Available Abstract Background Hereditary Hemochromatosis(HH is a common genetic disorder of iron overload where the large majority of patients are homozygous for one ancestral mutation in the HFE gene. In spite of this remarkable genetic homogeneity, the condition is clinically heterogeneous, varying from a severe disease to an asymptomatic phenotype with only abnormal biochemical parameters. The recent recognition of the variable penetrance of the HH mutation in different large population studies demands the need to search for new modifiers of its phenotypic expression. The present study follows previous observations that MHC class-I linked genetic markers, associated with the setting of CD8+ T-lymphocyte numbers, could be clinically relevant modifiers of the phenotypic expression in HH, and aimed to find new markers that could be used as more reliable prognostic variables. Methods Haplotype analysis, including seven genetic markers within a 1 Mb region around the microsatellite D6S105 was performed in a group of 56 previously characterized C282Y homozygous Portuguese patients. Parameters analyzed in this study were total body iron stores, clinical manifestations related with HH and immunological parameters (total lymphocyte numbers, CD4+ and CD8+ T-lymphocyte numbers. An independent group of 10 C282Y homozygous patients from Vancouver, Canada, were also included in this study and analyzed for the same parameters. Results A highly conserved ancestral haplotype defined by the SNP markers PGBD1-A, ZNF193-A, ZNF165-T (designated as A-A-T was found associated with both abnormally low CD8+ T-lymphocyte numbers and the development of a severe clinical expression of HH. In a small proportion of patients, another conserved haplotype defined by the SNP markers PGBD1-G, ZNF193-G, ZNF165-G (designated as G-G-G was found associated with high CD8+ T-lymphocyte numbers and a milder clinical expression. Remarkably, the two conserved haplotypes defined in Portuguese

  5. A Data-Driven Analysis of the Rules Defining Bilateral Leg Movements during Sleep.

    Science.gov (United States)

    Ferri, Raffaele; Manconi, Mauro; Rundo, Francesco; Zucconi, Marco; Aricò, Debora; Bruni, Oliviero; Ferini-Strambi, Luigi; Fulda, Stephany

    2016-02-01

    The aim of this study was to describe and analyze the association between bilateral leg movements (LMs) during sleep in subjects with restless legs syndrome (RLS), in order to eventually support or challenge the current scoring rules defining bilateral LMs. Polysomnographic recordings of 100 untreated patients with RLS (57 women and 43 males, mean age 57 y) were included. In each recording, we selected as reference all LMs that occurred during sleep and that were separated from another ipsilateral LM by at least 10 sec of EMG inactivity. For each reference LM and an evaluation interval from 5 sec before the onset to 5 sec after the offset of the reference LM, we evaluated (1) the presence or absence of contralateral leg movement activity and (2) the distribution of the onset-to-onset and (3) the offset-to-onset differences between bilateral LMs. We selected a mean of 368 (± 222 standard deviation [SD]) reference LMs per subject. For 42% (± 22%) of the reference LMs no contralateral leg movement activity was observed within the evaluation interval. In 55% (± 22%) exactly one and in 3% (± 2%) more than one contralateral LM was observed. A further evaluation of events where exactly one contralateral LM was observed showed that in most (1) the two LMs were overlapping (93% ± 9% SD) and (2) were classified as bilateral according to the World Association of Sleep Medicine and the International Restless Legs Syndrome Study Group (WASM/ IRLSSG) (96% ± 6% SD) and (3) the American Academy of Sleep Medicine scoring rules (99% ± 2% SD). Although there was a systematic and statistically significant difference in standard LM indices during sleep based on the two different definitions of bilateral LMs, the size of the difference was not clinically meaningful (maximum individual, absolute difference in LM indices ± 2.5). In addition, we found that the duration of LMs within bilateral LM pairs was longer compared to monolateral LMs and that the duration of the single LMs in

  6. A conjoint analysis to consumer choice in Brazil: Defining device attributes for recognizing customized foods characteristics.

    Science.gov (United States)

    Calegari, L P; Barbosa, J; Marodin, G A; Fettermann, D C

    2018-07-01

    the availability of information about food products may be an essential factor in the consumer's value perception in their purchasing decision. As the food product becomes personalized, the customization of this information becomes complex due to the possible combinations of product components. The use of smart technology in devices is one way to provide customers with customized food information. In the following research five attributes were identified in the composition of these devices: (A) portability; (B) precision; (C) diet customization; (D) food quality analysis; and (E) price. This study aims to identify the appropriate combination of possible functionalities or attributes that must be present in a device in order to detect the food composition of customized foods and their relation to market characteristics. One experiment used fractional factorial project to present the attributes in the form of scenarios following the Choice-Based Conjoint Analysis (CBCA) method. The data collection was done using survey methodology, through online questionnaire, with some 303 Brazilian respondents. So, the Logistic Regression was applied to data analysis. The moderating variables-gender, age, gluten restriction, lactose restriction and other restrictions-were also added to verify potential interactions with the primary attributes. From the results obtained, it was possible to observe higher significance for the primary attributes of diet personalization and quality food analyzes function. Our study contributes to the literature by enhancing the understanding about what the attributes should be in a technological device that has the purpose of recognizing food characteristics and is capable of generating information about customized food products. Furthermore, this device can enabler the production of mass customized food with the nutritional labels for each possible combination. Copyright © 2018 Elsevier Ltd. All rights reserved.

  7. Mathematics and history: history and analysis epistemology: from exhaustion method to defined integral

    Directory of Open Access Journals (Sweden)

    Mario Mandrone

    2015-06-01

    Full Text Available The creation of the calculation (differential, in the terminology of Leibniz, bending in that of Newton is the event that, in the second half of the seventeenth century, marked, in a sense, the transition from classical to modern mathematics. The aim of this work is a historical analysis of the rigor and epistemological question and the "metaphysics" of calculus that takes account of the methods of the ancient (eg. Of Archimedes' method of exhaustion, as well as interpretations of Leibniz and Newton and their successors. The problem of searching for a sure foundation on which to base the calculus, glimpsed by D'Alembert in the theory of limits and taken up by Lagrange to the theory of infinite series, and that the derivative functions, found in Cachy the pioneer of a new way to seek rigor in analysis. The Cauchy setting will be tightened by Weierstrass in the second half of the 800 with the definition of limit, with the epsilon-delta method, which in turn is based on definitions concerning the real numbers. In this sense we speak of "arithmetisation" analysis.         Matematica e storia: storia ed epistemologia dell’analisi: dal metodo  di esaustione  all’integrale  definito La creazione del calcolo (differenziale, nella terminologia leibniziana flessionale in quella di Newton è l’evento che, nella seconda metà del seicento, ha segnato, in un certo senso, il passaggio dalla matematica classica a quella moderna. Obiettivo del presente lavoro è una analisi storica ed epistemologica della questione del rigore e della “metafisica” del calcolo infinitesimale che tenga conto dei metodi degli antichi (ad es.  del metodo di esaustione di Archimede, nonché delle interpretazioni di Leibniz e Newton e dei loro successori. Il problema della ricerca di un fondamento sicuro su cui basare il calcolo infinitesimale, intravisto da D’Alembert nella teoria dei limiti e ripreso da Lagrange con la teoria delle serie infinite e quella delle

  8. Quantitative Analysis of Memristance Defined Exponential Model for Multi-bits Titanium Dioxide Memristor Memory Cell

    Directory of Open Access Journals (Sweden)

    DAOUD, A. A. D.

    2016-05-01

    Full Text Available The ability to store multiple bits in a single memristor based memory cell is a key feature for high-capacity memory packages. Studying multi-bit memristor circuits requires high accuracy in modelling the memristance change. A memristor model based on a novel definition of memristance is proposed. A design of a single memristor memory cell using the proposed model for the platinum electrodes titanium dioxide memristor is illustrated. A specific voltage pulse is used with varying its parameters (amplitude or pulse width to store different number of states in a single memristor. New state variation parameters associated with the utilized model are provided and their effects on write and read processes of memristive multi-states are analysed. PSPICE simulations are also held, and they show a good agreement with the data obtained from the analysis.

  9. Interaction proteomics analysis of polycomb proteins defines distinct PRC1 complexes in mammalian cells

    DEFF Research Database (Denmark)

    Vandamme, Julien; Völkel, Pamela; Rosnoblet, Claire

    2011-01-01

    Polycomb group (PcG) proteins maintain transcriptional repression of hundreds of genes involved in development, signaling or cancer using chromatin-based epigenetic mechanisms. Biochemical studies in Drosophila have revealed that PcG proteins associate in at least two classes of protein complexes...... known as Polycomb repressive complexes 1 and 2 (PRC1 and PRC2). Drosophila core PRC1 is composed of four subunits, Polycomb (Pc), Sex combs extra (Sce), Polyhomeotic (Ph), and Posterior sex combs (Psc). Each of these proteins has multiple orthologs in vertebrates classified respectively as the CBX, RING...... in order to identify interacting partners of CBX family proteins under the same experimental conditions. Our analysis identified with high confidence about 20 proteins co-eluted with CBX2 and CBX7 tagged proteins, about 40 with CBX4, and around 60 with CBX6 and CBX8. We provide evidences that the CBX...

  10. Approaches to defining «financial potential» concept as of economic analysis object

    Directory of Open Access Journals (Sweden)

    O.M. Dzyubenkо

    2017-12-01

    Full Text Available The research analyzes the works of scientists who studied the issues of financial potential as an economic category. Due to analyzing the approaches of the scientists to the concept of "financial potential" the author identifies six approaches to the interpretation of its essence, they are: the totality of the enterprise financial resources, the sources of the enterprise economic activity financing, the enterprise economic activity development, the enterprise financial indicators, the system of enterprise financial management, the enterprise efficiency characteristics. It is established that the financial potential is the multifaceted category that characterizes the financial and economic activity of enterprises. The author's definition of the financial potential in the context of its place in the objects of economic analysis is proposed. It is established that the financial potential is the object of the enterprise economic activity management and is the subject to analytical assessments for establishing its state and directions of development.

  11. The role of business agreements in defining textbook affordability and digital materials: A document analysis

    Directory of Open Access Journals (Sweden)

    John Raible

    2015-12-01

    Full Text Available Adopting digital materials such as eTextbooks and e-coursepacks is a potential strategy to address textbook affordability in the United States. However, university business relationships with bookstore vendors implicitly structure which instructional resources are available and in what manner. In this study, a document analysis was conducted on the bookstore contracts for the universities included in the State University System of Florida. Namely, issues of textbook affordability, digital material terminology and seller exclusivity were investigated. It was found that textbook affordability was generally conceived in terms of print rental textbooks and buyback programs, and that eTextbooks were priced higher than print textbooks (25% to 30% markup. Implications and recommendations for change are shared. DOI: 10.18870/hlrc.v5i4.284

  12. Defining Earth Smarts: A Construct Analysis for Socioecological Literacy Based on Justly Maintaining Quality of Life

    Science.gov (United States)

    Nichols, Bryan H.

    This paper describes the creation and validation of a new educational construct. Socioecological literacy, or earth smarts, describes the qualities we need to justly maintain or improve our quality of life in a changing world. It was created using construct analysis techniques and systems tools, drawing on an extensive, transdisciplinary body of literature. Concepts related to environmental, ecological and scientific literacy, sustainability and citizenship were combined with educational frameworks, new research in science education, and modern cognitive psychology. After the initial formulation, the results were considered by a variety of experts and professionals from the fields of ecology, environmental science and education, using surveys, conference presentations and interviews. The resulting qualitative and quantitative feedback was used to refine and validate the framework. Four domains emerged from the analysis: concepts, competencies, sense of place, and values. The first two are common in formal education, although many of the more specific components that emerged are not adequately addressed. The second two domains are unlikely to be achieved solely in traditional educational settings, although they emerged as equally important. Sense of place includes affective components such as self-efficacy, while values includes moral development, respect, and justice as fairness. To make culturally and ecologically appropriate localization as accessible as possible, the earth smarts framework (www.earthsmarts.info ) is deliberately nonpartisan and was designed using free and open-source software. It can help educators, policy makers, and researchers interested in more resilient, just and adaptable communities to coordinate their efforts, particularly in the nexus between formal and informal education, which have different strengths and weaknesses.

  13. Failure analysis of satellite subsystems to define suitable de-orbit devices

    Science.gov (United States)

    Palla, Chiara; Peroni, Moreno; Kingston, Jennifer

    2016-11-01

    Space missions in Low Earth Orbit (LEO) are severely affected by the build-up of orbital debris. A key practice, to be compliant with IADC (Inter-Agency Space Debris Coordination Committee) mitigation guidelines, is the removal of space systems that interfere with the LEO region not later than 25 years after the End of Mission. It is important to note that the current guidelines are not generally legally binding, even if different Space Agencies are now looking at the compliance for their missions. If the guidelines will change in law, it will be mandatory to have a postmission disposal strategy for all satellites, including micro and smaller classes. A potential increased number of these satellites is confirmed by different projections, in particular in the commercial sector. Micro and smaller spacecraft are, in general, not provided with propulsion capabilities to achieve a controlled re-entry, so they need different de-orbit disposal methods. When considering the utility of different debris mitigation methods, it is useful to understand which spacecraft subsystems are most likely to fail and how this may affect the operation of a de-orbit system. This also helps the consideration of which components are the most relevant or should be redundant depending on the satellite mass class. This work is based on a sample of LEO and MEO satellites launched between January 2000 and December 2014 with mass lower than 1000 kg. Failure analysis of satellite subsystems is performed by means of the Kaplan-Meier survival analysis; the parametric fits are conducted with Weibull distributions. The study is carried out by using the satellite database SpaceTrak™ which provides anomalies, failures, and trends information for spacecraft subsystems and launch vehicles. The database identifies five states for each satellite subsystem: three degraded states, one fully operational state, and one failed state (complete failure). The results obtained can guide the identification of the

  14. Define Project

    DEFF Research Database (Denmark)

    Munk-Madsen, Andreas

    2005-01-01

    "Project" is a key concept in IS management. The word is frequently used in textbooks and standards. Yet we seldom find a precise definition of the concept. This paper discusses how to define the concept of a project. The proposed definition covers both heavily formalized projects and informally...... organized, agile projects. Based on the proposed definition popular existing definitions are discussed....

  15. "Dermatitis" defined.

    Science.gov (United States)

    Smith, Suzanne M; Nedorost, Susan T

    2010-01-01

    The term "dermatitis" can be defined narrowly or broadly, clinically or histologically. A common and costly condition, dermatitis is underresourced compared to other chronic skin conditions. The lack of a collectively understood definition of dermatitis and its subcategories could be the primary barrier. To investigate how dermatologists define the term "dermatitis" and determine if a consensus on the definition of this term and other related terms exists. A seven-question survey of dermatologists nationwide was conducted. Of respondents (n  =  122), half consider dermatitis to be any inflammation of the skin. Nearly half (47.5%) use the term interchangeably with "eczema." Virtually all (> 96%) endorse the subcategory "atopic" under the terms "dermatitis" and "eczema," but the subcategories "contact," "drug hypersensitivity," and "occupational" are more highly endorsed under the term "dermatitis" than under the term "eczema." Over half (55.7%) personally consider "dermatitis" to have a broad meaning, and even more (62.3%) believe that dermatologists as a whole define the term broadly. There is a lack of consensus among experts in defining dermatitis, eczema, and their related subcategories.

  16. Microarray Gene Expression Analysis of Murine Tumor Heterogeneity Defined by Dynamic Contrast-Enhanced MRI

    Directory of Open Access Journals (Sweden)

    Nick G. Costouros

    2002-07-01

    Full Text Available Current methods of studying angiogenesis are limited in their ability to serially evaluate in vivo function throughout a target tissue. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI and pharmacokinetic modeling provide a useful method for evaluating tissue vasculature based on contrast accumulation and washout. While it is often assumed that areas of high contrast enhancement and washout comprise areas of increased angiogenesis and tumor activity, the actual molecular pathways that are active in such areas are poorly understood. Using DCE-MRI in a murine subcutaneous tumor model, we were able to perform pharmacokinetic functional analysis of a tumor, coregistration of MRI images with histological cross-sections, immunohistochemistry, laser capture microdissection, and genetic profiling of tumor heterogeneity based on pharmacokinetic parameters. Using imaging as a template for biologic investigation, we have not found evidence of increased expression of proangiogenic modulators at the transcriptional level in either distinct pharmacokinetic region. Furthermore, these regions show no difference on histology and CD31 immunohistochemistry. However, the expression of ribosomal proteins was greatly increased in high enhancement and washout regions, implying increased protein translation and consequent increased cellular activity. Together, these findings point to the potential importance of posttranscriptional regulation in angiogenesis and the need for the development of angiogenesis-specific contrast agents to evaluate in vivo angiogenesis at a molecular level.

  17. Secretome analysis defines the major role of SecDF in Staphylococcus aureus virulence.

    Directory of Open Access Journals (Sweden)

    Chantal Quiblier

    Full Text Available The Sec pathway plays a prominent role in protein export and membrane insertion, including the secretion of major bacterial virulence determinants. The accessory Sec constituent SecDF has been proposed to contribute to protein export. Deletion of Staphylococcus aureus secDF has previously been shown to reduce resistance, to alter cell separation, and to change the expression of certain virulence factors. To analyse the impact of the secDF deletion in S. aureus on protein secretion, a quantitative secretome analysis was performed. Numerous Sec signal containing proteins involved in virulence were found to be decreased in the supernatant of the secDF mutant. However, two Sec-dependent hydrolases were increased in comparison to the wild type, suggesting additional indirect, regulatory effects to occur upon deletion of secDF. Adhesion, invasion, and cytotoxicity of the secDF mutant were reduced in human umbilical vein endothelial cells. Virulence was significantly reduced using a Galleria mellonella insect model. Altogether, SecDF is a promising therapeutic target for controlling S. aureus infections.

  18. Bioelectrical impedance analysis to define an excess of body fat: evaluation in patients with psoriasis.

    Science.gov (United States)

    Galluzzo, M; Talamonti, M; Perino, F; Servoli, S; Giordano, D; Chimenti, S; De Simone, C; Peris, K

    2017-06-01

    There is strong evidence that obesity is closely associated with psoriasis. However, data on body composition are lacking in psoriasis. The purpose of this study were to investigate the body composition in psoriasis patients using bioelectrical impedance analysis and to correlate the bioelectrical impedance data with disease severity and laboratory parameters. Anthropometric measurements and bioelectrical impedance analyses were performed on patients with psoriasis, naïve to any systemic treatment, who attended the outpatient clinics of two University centers. Data of 164 adult patients were analyzed. Compared to men, women had several significantly higher bioelectrical impedance parameters including reactance, fat mass% and adipose tissue%. The values of adipose tissue were positively correlated only with patients age (p = .021) and age at disease onset (p = .0006), but not with disease severity. In addition, we observed that the use of BMI cutoffs allowed to categorize 36.7% of women and 19.2% of men as obese, while fat mass% showed that 53.3% of women and 48.1% of men were obese. In our study, psoriasis is been associated with a high fat mass%. We suggest that screening for body fat distribution in psoriatic patients might be useful to identify early obesity-related disease.

  19. DEFINING THE RELEVANT OUTCOME MEASURES IN MEDICAL DEVICE ASSESSMENTS: AN ANALYSIS OF THE DEFINITION PROCESS IN HEALTH TECHNOLOGY ASSESSMENT.

    Science.gov (United States)

    Jacobs, Esther; Antoine, Sunya-Lee; Prediger, Barbara; Neugebauer, Edmund; Eikermann, Michaela

    2017-01-01

    Defining relevant outcome measures for clinical trials on medical devices (MD) is complex, as there is a large variety of potentially relevant outcomes. The chosen outcomes vary widely across clinical trials making the assessment in evidence syntheses very challenging. The objective is to provide an overview on the current common procedures of health technology assessment (HTA) institutions in defining outcome measures in MD trials. In 2012-14, the Web pages of 126 institutions involved in HTA were searched for methodological manuals written in English or German that describe methods for the predefinition process of outcome measures. Additionally, the institutions were contacted by email. Relevant information was extracted. All process steps were performed independently by two reviewers. Twenty-four manuals and ten responses from the email request were included in the analysis. Overall, 88.5 percent of the institutions describe the type of outcomes that should be considered in detail and 84.6 percent agree that the main focus should be on patient relevant outcomes. Specifically related to MD, information could be obtained in 26 percent of the included manuals and email responses. Eleven percent of the institutions report a particular consideration of MD related outcomes. This detailed analysis on common procedures of HTA institutions in the context of defining relevant outcome measures for the assessment of MD shows that standardized procedures for MD from the perspective of HTA institutions are not widespread. This leads to the question if a homogenous approach should be implemented in the field of HTA on MD.

  20. HapCol : Accurate and memory-efficient haplotype assembly from long reads

    NARCIS (Netherlands)

    Pirola, Yuri; Zaccaria, Simone; Dondi, Riccardo; Klau, Gunnar W.; Pisanti, Nadia; Bonizzoni, Paola

    2016-01-01

    Motivation: Haplotype assembly is the computational problem of reconstructing haplotypes in diploid organisms and is of fundamental importance for characterizing the effects of single-nucleotide polymorphisms on the expression of phenotypic traits. Haplotype assembly highly benefits from the advent

  1. HapCol: Accurate and Memory-efficient Haplotype Assembly from Long Reads

    NARCIS (Netherlands)

    Y. Pirola (Yuri); S. Zaccaria (Simone); R. Dondi (Riccardo); G.W. Klau (Gunnar); N. Pisanti (Nadia); P. Bonizzoni (Paola)

    2015-01-01

    htmlabstractMotivation: Haplotype assembly is the computational problem of reconstructing haplotypes in diploid organisms and is of fundamental importance for characterizing the effects of single-nucleotide polymorphisms on the expression of phenotypic traits. Haplotype assembly highly benefits from

  2. Teleology and Defining Sex.

    Science.gov (United States)

    Gamble, Nathan K; Pruski, Michal

    2018-07-01

    Disorders of sexual differentiation lead to what is often referred to as an intersex state. This state has medical, as well as some legal, recognition. Nevertheless, the question remains whether intersex persons occupy a state in between maleness and femaleness or whether they are truly men or women. To answer this question, another important conundrum needs to be first solved: what defines sex? The answer seems rather simple to most people, yet when morphology does not coincide with haplotypes, and genetics might not correlate with physiology the issue becomes more complex. This paper tackles both issues by establishing where the essence of sex is located and by superimposing that framework onto the issue of the intersex. This is achieved through giving due consideration to the biology of sexual development, as well as through the use of a teleological framework of the meaning of sex. Using a range of examples, the paper establishes that sex cannot be pinpointed to one biological variable but is rather determined by how the totality of one's biology is oriented towards biological reproduction. A brief consideration is also given to the way this situation could be comprehended from a Christian understanding of sex and suffering.

  3. Long term electricity expansion analysis to define energy policies for Mexico

    International Nuclear Information System (INIS)

    Martin del Campo, C.; Guadarrama, R.; Sanchez, O.; Francois, J. L.; Estrada, G.; Izarra, J.; Perez, A.

    2010-10-01

    A new multi-criteria decision making process based on regret behavior is described. The name we gave it is position vector of minimum regret. A reference which combines the best values of all the criteria is created and positioned in the center of the coordinates of the n-dimensional space; n being the number of criteria. Every alternative is represented by a vector and the magnitude of the position vector is the minimum distance to the reference. The smaller the magnitude of the position vector, the better the corresponding alternative, given that we are looking for the minimum regret. Different weights can be assigned to the criteria. The position vector of minimum regret was applied to the long term electricity expansion planning for Mexico. The study evaluates four parameters: the total generating cost obtained from the objective function after the WASP-IV optimization, the economic risk associated with fuel prices increases, the diversity of fuels participating in the mix of electricity generation, and the external costs associated with health and environmental impacts. The WASP-IV code was used for finding the optimal expansion plan for the Mexican power generating system over the 2008 to 2030 period, under certain restrictions. We decided to study a base case and four additional expansion cases, which are similar to the base case, but each does not consider a certain candidate technology which uses a particular fuel. The reason of studying these five contrasting cases is to quantify the impact, on the evaluation parameters, when a particular fuel is omitted in the expansion plan, and this is very useful for the definition of energy polices concerning diversification by means of nuclear and other CO 2 free options in the mix. The base case is plan A which considers six candidates for expanding the generation system. Plan B does not consider coal, plan C does not consider oil, plan D excludes nuclear energy, and plan E natural gas. After the decision analysis

  4. Haplotype mapping of a diploid non-meiotic organism using existing and induced aneuploidies.

    Directory of Open Access Journals (Sweden)

    Melanie Legrand

    2008-01-01

    Full Text Available Haplotype maps (HapMaps reveal underlying sequence variation and facilitate the study of recombination and genetic diversity. In general, HapMaps are produced by analysis of Single-Nucleotide Polymorphism (SNP segregation in large numbers of meiotic progeny. Candida albicans, the most common human fungal pathogen, is an obligate diploid that does not appear to undergo meiosis. Thus, standard methods for haplotype mapping cannot be used. We exploited naturally occurring aneuploid strains to determine the haplotypes of the eight chromosome pairs in the C. albicans laboratory strain SC5314 and in a clinical isolate. Comparison of the maps revealed that the clinical strain had undergone a significant amount of genome rearrangement, consisting primarily of crossover or gene conversion recombination events. SNP map haplotyping revealed that insertion and activation of the UAU1 cassette in essential and non-essential genes can result in whole chromosome aneuploidy. UAU1 is often used to construct homozygous deletions of targeted genes in C. albicans; the exact mechanism (trisomy followed by chromosome loss versus gene conversion has not been determined. UAU1 insertion into the essential ORC1 gene resulted in a large proportion of trisomic strains, while gene conversion events predominated when UAU1 was inserted into the non-essential LRO1 gene. Therefore, induced aneuploidies can be used to generate HapMaps, which are essential for analyzing genome alterations and mitotic recombination events in this clonal organism.

  5. The Prognostic Value of Haplotypes in the Vascular Endothelial Growth Factor A Gene in Colorectal Cancer

    International Nuclear Information System (INIS)

    Hansen, Torben F.; Spindler, Karen-Lise G.; Andersen, Rikke F.; Lindebjerg, Jan; Kølvraa, Steen; Brandslund, Ivan; Jakobsen, Anders

    2010-01-01

    New prognostic markers in patients with colorectal cancer (CRC) are a prerequisite for individualized treatment. Prognostic importance of single nucleotide polymorphisms (SNPs) in the vascular endothelial growth factor A (VEGF-A) gene has been proposed. The objective of the present study was to investigate the prognostic importance of haplotypes in the VEGF-A gene in patients with CRC. The study included 486 patients surgically resected for stage II and III CRC, divided into two independent cohorts. Three SNPs in the VEGF-A gene were analyzed by polymerase chain reaction. Haplotypes were estimated using the PHASE program. The prognostic influence was evaluated using Kaplan-Meir plots and log rank tests. Cox regression method was used to analyze the independent prognostic importance of different markers. All three SNPs were significantly related to survival. A haplotype combination, responsible for this effect, was present in approximately 30% of the patients and demonstrated a significant relationship with poor survival, and it remained an independent prognostic marker after multivariate analysis, hazard ratio 2.46 (95% confidence interval 1.49–4.06), p < 0.001. Validation was provided by consistent findings in a second and independent cohort. Haplotype combinations call for further investigation

  6. Divergence at the casein haplotypes in dairy and meat goat breeds.

    Science.gov (United States)

    Küpper, Julia; Chessa, Stefania; Rignanese, Daniela; Caroli, Anna; Erhardt, Georg

    2010-02-01

    Casein genes have been proved to have an influence on milk properties, and are in addition appropriate for phylogeny studies. A large number of casein polymorphisms exist in goats, making their analysis quite complex. The four casein loci were analyzed by molecular techniques for genetic polymorphism detection in the two dairy goat breeds Bunte Deutsche Edelziege (BDE; n=96), Weisse Deutsche Edelziege (WDE; n=91), and the meat goat breed Buren (n=75). Of the 35 analyzed alleles, 18 were found in BDE, and 17 in Buren goats and WDE. In addition, a new allele was identified at the CSN1S1 locus in the BDE, showing a frequency of 0.05. This variant, named CSN1S1*A', is characterized by a t-->c transversion in intron 9. Linkage disequilibrium was found at the casein haplotype in all three breeds. A total of 30 haplotypes showed frequencies higher than 0.01. In the Buren breed only one haplotype showed a frequency higher than 0.1. The ancestral haplotype B-A-A-B (in the order: CSN1S1-CSN2-CSN1S2-CSN3) occurred in all three breeds, showing a very high frequency (>0.8) in the Buren.

  7. A class representative model for Pure Parsimony Haplotyping under uncertain data.

    Directory of Open Access Journals (Sweden)

    Daniele Catanzaro

    Full Text Available The Pure Parsimony Haplotyping (PPH problem is a NP-hard combinatorial optimization problem that consists of finding the minimum number of haplotypes necessary to explain a given set of genotypes. PPH has attracted more and more attention in recent years due to its importance in analysis of many fine-scale genetic data. Its application fields range from mapping complex disease genes to inferring population histories, passing through designing drugs, functional genomics and pharmacogenetics. In this article we investigate, for the first time, a recent version of PPH called the Pure Parsimony Haplotype problem under Uncertain Data (PPH-UD. This version mainly arises when the input genotypes are not accurate, i.e., when some single nucleotide polymorphisms are missing or affected by errors. We propose an exact approach to solution of PPH-UD based on an extended version of Catanzaro et al.[1] class representative model for PPH, currently the state-of-the-art integer programming model for PPH. The model is efficient, accurate, compact, polynomial-sized, easy to implement, solvable with any solver for mixed integer programming, and usable in all those cases for which the parsimony criterion is well suited for haplotype estimation.

  8. Novel full-length major histocompatibility complex class I allele discovery and haplotype definition in pig-tailed macaques.

    Science.gov (United States)

    Semler, Matthew R; Wiseman, Roger W; Karl, Julie A; Graham, Michael E; Gieger, Samantha M; O'Connor, David H

    2017-11-13

    Pig-tailed macaques (Macaca nemestrina, Mane) are important models for human immunodeficiency virus (HIV) studies. Their infectability with minimally modified HIV makes them a uniquely valuable animal model to mimic human infection with HIV and progression to acquired immunodeficiency syndrome (AIDS). However, variation in the pig-tailed macaque major histocompatibility complex (MHC) and the impact of individual transcripts on the pathogenesis of HIV and other infectious diseases is understudied compared to that of rhesus and cynomolgus macaques. In this study, we used Pacific Biosciences single-molecule real-time circular consensus sequencing to describe full-length MHC class I (MHC-I) transcripts for 194 pig-tailed macaques from three breeding centers. We then used the full-length sequences to infer Mane-A and Mane-B haplotypes containing groups of MHC-I transcripts that co-segregate due to physical linkage. In total, we characterized full-length open reading frames (ORFs) for 313 Mane-A, Mane-B, and Mane-I sequences that defined 86 Mane-A and 106 Mane-B MHC-I haplotypes. Pacific Biosciences technology allows us to resolve these Mane-A and Mane-B haplotypes to the level of synonymous allelic variants. The newly defined haplotypes and transcript sequences containing full-length ORFs provide an important resource for infectious disease researchers as certain MHC haplotypes have been shown to provide exceptional control of simian immunodeficiency virus (SIV) replication and prevention of AIDS-like disease in nonhuman primates. The increased allelic resolution provided by Pacific Biosciences sequencing also benefits transplant research by allowing researchers to more specifically match haplotypes between donors and recipients to the level of nonsynonymous allelic variation, thus reducing the risk of graft-versus-host disease.

  9. Identification of the ancestral haplotype for apolipoprotein B suggests an African origin of Homo sapiens sapiens and traces their subsequent migration to Europe and the Pacific

    Energy Technology Data Exchange (ETDEWEB)

    Rapacz, J.; Hasler-Rapacz, J.O. (Univ. of Wisconsin, Madison (United States)); Chen, L.; Wu, Mingjiuan; Schumaker, V.N. (Univ. of California, Los Angeles (United States)); Butler-Brunner, E.; Butler, R. (Swiss Red Cross Blood Transfusion Service, Bern (Switzerland))

    1991-02-15

    The probable ancestral haplotype for human apolipoprotein B (apoB) has been identified through immunological analysis of chimpanzee and gorilla serum and sequence analysis of their DNA. Moreover, the frequency of this ancestral apoB haplotype among different human populations provides strong support for the African origin of Homo sapiens sapiens and their subsequent migration from Africa to Europe and to the Pacific. The approach used here for the identification of the ancestral human apoB haplotype is likely to be applicable to many other genes.

  10. Identification of the ancestral haplotype for apolipoprotein B suggests an African origin of Homo sapiens sapiens and traces their subsequent migration to Europe and the Pacific

    International Nuclear Information System (INIS)

    Rapacz, J.; Hasler-Rapacz, J.O.; Chen, L.; Wu, Mingjiuan; Schumaker, V.N.; Butler-Brunner, E.; Butler, R.

    1991-01-01

    The probable ancestral haplotype for human apolipoprotein B (apoB) has been identified through immunological analysis of chimpanzee and gorilla serum and sequence analysis of their DNA. Moreover, the frequency of this ancestral apoB haplotype among different human populations provides strong support for the African origin of Homo sapiens sapiens and their subsequent migration from Africa to Europe and to the Pacific. The approach used here for the identification of the ancestral human apoB haplotype is likely to be applicable to many other genes

  11. A spatial haplotype copying model with applications to genotype imputation.

    Science.gov (United States)

    Yang, Wen-Yun; Hormozdiari, Farhad; Eskin, Eleazar; Pasaniuc, Bogdan

    2015-05-01

    Ever since its introduction, the haplotype copy model has proven to be one of the most successful approaches for modeling genetic variation in human populations, with applications ranging from ancestry inference to genotype phasing and imputation. Motivated by coalescent theory, this approach assumes that any chromosome (haplotype) can be modeled as a mosaic of segments copied from a set of chromosomes sampled from the same population. At the core of the model is the assumption that any chromosome from the sample is equally likely to contribute a priori to the copying process. Motivated by recent works that model genetic variation in a geographic continuum, we propose a new spatial-aware haplotype copy model that jointly models geography and the haplotype copying process. We extend hidden Markov models of haplotype diversity such that at any given location, haplotypes that are closest in the genetic-geographic continuum map are a priori more likely to contribute to the copying process than distant ones. Through simulations starting from the 1000 Genomes data, we show that our model achieves superior accuracy in genotype imputation over the standard spatial-unaware haplotype copy model. In addition, we show the utility of our model in selecting a small personalized reference panel for imputation that leads to both improved accuracy as well as to a lower computational runtime than the standard approach. Finally, we show our proposed model can be used to localize individuals on the genetic-geographical map on the basis of their genotype data.

  12. Defining chaos.

    Science.gov (United States)

    Hunt, Brian R; Ott, Edward

    2015-09-01

    In this paper, we propose, discuss, and illustrate a computationally feasible definition of chaos which can be applied very generally to situations that are commonly encountered, including attractors, repellers, and non-periodically forced systems. This definition is based on an entropy-like quantity, which we call "expansion entropy," and we define chaos as occurring when this quantity is positive. We relate and compare expansion entropy to the well-known concept of topological entropy to which it is equivalent under appropriate conditions. We also present example illustrations, discuss computational implementations, and point out issues arising from attempts at giving definitions of chaos that are not entropy-based.

  13. Oestrogen receptor α gene haplotype and postmenopausal breast cancer risk: a case control study

    International Nuclear Information System (INIS)

    Wedrén, Sara; Stiger, Fredrik; Persson, Ingemar; Baron, John; Weiderpass, Elisabete; Lovmar, Lovisa; Humphreys, Keith; Magnusson, Cecilia; Melhus, Håkan; Syvänen, Ann-Christine; Kindmark, Andreas; Landegren, Ulf; Fermér, Maria Lagerström

    2004-01-01

    Oestrogen receptor α, which mediates the effect of oestrogen in target tissues, is genetically polymorphic. Because breast cancer development is dependent on oestrogenic influence, we have investigated whether polymorphisms in the oestrogen receptor α gene (ESR1) are associated with breast cancer risk. We genotyped breast cancer cases and age-matched population controls for one microsatellite marker and four single-nucleotide polymorphisms (SNPs) in ESR1. The numbers of genotyped cases and controls for each marker were as follows: TA n , 1514 cases and 1514 controls; c.454-397C → T, 1557 cases and 1512 controls; c.454-351A → G, 1556 cases and 1512 controls; c.729C → T, 1562 cases and 1513 controls; c.975C → G, 1562 cases and 1513 controls. Using logistic regression models, we calculated odds ratios (ORs) and 95% confidence intervals (CIs). Haplotype effects were estimated in an exploratory analysis, using expectation-maximisation algorithms for case-control study data. There were no compelling associations between single polymorphic loci and breast cancer risk. In haplotype analyses, a common haplotype of the c.454-351A → G or c.454-397C → T and c.975C → G SNPs appeared to be associated with an increased risk for ductal breast cancer: one copy of the c.454-351A → G and c.975C → G haplotype entailed an OR of 1.19 (95% CI 1.06–1.33) and two copies with an OR of 1.42 (95% CI 1.15–1.77), compared with no copies, under a model of multiplicative penetrance. The association with the c.454-397C → T and c.975C → G haplotypes was similar. Our data indicated that these haplotypes were more influential in women with a high body mass index. Adjustment for multiple comparisons rendered the associations statistically non-significant. We found suggestions of an association between common haplotypes in ESR1 and the risk for ductal breast cancer that is stronger in heavy women

  14. Minimal sharing of Y-chromosome STR haplotypes among five endogamous population groups from western and southwestern India.

    Science.gov (United States)

    Das, Birajalaxmi; Chauhan, P S; Seshadri, M

    2004-10-01

    We attempt to address the issue of genetic variation and the pattern of male gene flow among and between five Indian population groups of two different geographic and linguistic affiliations using Y-chromosome markers. We studied 221 males at three Y-chromosome biallelic loci and 184 males for the five Y-chromosome STRs. We observed 111 Y-chromosome STR haplotypes. An analysis of molecular variance (AMOVA) based on Y-chromosome STRs showed that the variation observed between the population groups belonging to two major regions (western and southwestern India) was 0.17%, which was significantly lower than the level of genetic variance among the five populations (0.59%) considered as a single group. Combined haplotype analysis of the five STRs and the biallelic locus 92R7 revealed minimal sharing of haplotypes among these five ethnic groups, irrespective of the similar origin of the linguistic and geographic affiliations; this minimal sharing indicates restricted male gene flow. As a consequence, most of the haplotypes were population specific. Network analysis showed that the haplotypes, which were shared between the populations, seem to have originated from different mutational pathways at different loci. Biallelic markers showed that all five ethnic groups have a similar ancestral origin despite their geographic and linguistic diversity.

  15. Fitchi: haplotype genealogy graphs based on the Fitch algorithm.

    Science.gov (United States)

    Matschiner, Michael

    2016-04-15

    : In population genetics and phylogeography, haplotype genealogy graphs are important tools for the visualization of population structure based on sequence data. In this type of graph, node sizes are often drawn in proportion to haplotype frequencies and edge lengths represent the minimum number of mutations separating adjacent nodes. I here present Fitchi, a new program that produces publication-ready haplotype genealogy graphs based on the Fitch algorithm. http://www.evoinformatics.eu/fitchi.htm : michaelmatschiner@mac.com Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  16. Introgression of a Rare Haplotype from Southeastern Africa to Breed California Blackeyes with Larger Seeds

    Directory of Open Access Journals (Sweden)

    Mitchell R Lucas

    2015-03-01

    Full Text Available Seed size distinguishes most crops from their wild relatives and is an important quality trait for the grain legume cowpea. In order to breed cowpea varieties with larger seeds we introgressed a rare haplotype associated with large seeds at the Css-1 locus from an African buff seed type cultivar, IT82E-18 (18.5g/100 seeds, into a blackeye seed type cultivar, CB27 (22g/100 seed. Four RILs derived from these two parents were chosen for marker-assisted breeding based on SNP genotyping with a goal of stacking large seed haplotypes into a CB27 background. Foreground and background selection were performed during two cycles of backcrossing based on genome-wide SNP markers. The average seed size of introgression lines homozygous for haplotypes associated with large seeds was 28.7g/100 seed and 24.8g/100 seed for cycles 1 and 2, respectively. One cycle 1 introgression line with desirable seed quality was selfed for two generations to make families with very large seeds (28-35g/100 seeds. Field-based performance trials helped identify breeding lines that not only have large seeds but are also desirable in terms of yield, maturity, and plant architecture when compared to industry standards. A principal component analysis was used to explore the relationships between the parents relative to a core set of landraces and improved varieties based on high-density SNP data. The geographic distribution of haplotypes at the Css-1 locus suggest the haplotype associated with large seeds is unique to accessions collected from Southeastern Africa. Therefore this QTL has a strong potential to develop larger seeded varieties for other growing regions which is demonstrated in this work using a California pedigree.

  17. The IGF1 small dog haplotype is derived from Middle Eastern grey wolves

    Directory of Open Access Journals (Sweden)

    Ostrander Elaine A

    2010-02-01

    Full Text Available Abstract Background A selective sweep containing the insulin-like growth factor 1 (IGF1 gene is associated with size variation in domestic dogs. Intron 2 of IGF1 contains a SINE element and single nucleotide polymorphism (SNP found in all small dog breeds that is almost entirely absent from large breeds. In this study, we surveyed a large sample of grey wolf populations to better understand the ancestral pattern of variation at IGF1 with a particular focus on the distribution of the small dog haplotype and its relationship to the origin of the dog. Results We present DNA sequence data that confirms the absence of the derived small SNP allele in the intron 2 region of IGF1 in a large sample of grey wolves and further establishes the absence of a small dog associated SINE element in all wild canids and most large dog breeds. Grey wolf haplotypes from the Middle East have higher nucleotide diversity suggesting an origin there. Additionally, PCA and phylogenetic analyses suggests a closer kinship of the small domestic dog IGF1 haplotype with those from Middle Eastern grey wolves. Conclusions The absence of both the SINE element and SNP allele in grey wolves suggests that the mutation for small body size post-dates the domestication of dogs. However, because all small dogs possess these diagnostic mutations, the mutations likely arose early in the history of domestic dogs. Our results show that the small dog haplotype is closely related to those in Middle Eastern wolves and is consistent with an ancient origin of the small dog haplotype there. Thus, in concordance with past archeological studies, our molecular analysis is consistent with the early evolution of small size in dogs from the Middle East. See associated opinion by Driscoll and Macdonald: http://jbiol.com/content/9/2/10

  18. Defining Cyberbullying.

    Science.gov (United States)

    Englander, Elizabeth; Donnerstein, Edward; Kowalski, Robin; Lin, Carolyn A; Parti, Katalin

    2017-11-01

    Is cyberbullying essentially the same as bullying, or is it a qualitatively different activity? The lack of a consensual, nuanced definition has limited the field's ability to examine these issues. Evidence suggests that being a perpetrator of one is related to being a perpetrator of the other; furthermore, strong relationships can also be noted between being a victim of either type of attack. It also seems that both types of social cruelty have a psychological impact, although the effects of being cyberbullied may be worse than those of being bullied in a traditional sense (evidence here is by no means definitive). A complicating factor is that the 3 characteristics that define bullying (intent, repetition, and power imbalance) do not always translate well into digital behaviors. Qualities specific to digital environments often render cyberbullying and bullying different in circumstances, motivations, and outcomes. To make significant progress in addressing cyberbullying, certain key research questions need to be addressed. These are as follows: How can we define, distinguish between, and understand the nature of cyberbullying and other forms of digital conflict and cruelty, including online harassment and sexual harassment? Once we have a functional taxonomy of the different types of digital cruelty, what are the short- and long-term effects of exposure to or participation in these social behaviors? What are the idiosyncratic characteristics of digital communication that users can be taught? Finally, how can we apply this information to develop and evaluate effective prevention programs? Copyright © 2017 by the American Academy of Pediatrics.

  19. HERC1 polymorphisms: population-specific variations in haplotype composition.

    Science.gov (United States)

    Yuasa, Isao; Umetsu, Kazuo; Nishimukai, Hiroaki; Fukumori, Yasuo; Harihara, Shinji; Saitou, Naruya; Jin, Feng; Chattopadhyay, Prasanta K; Henke, Lotte; Henke, Jürgen

    2009-08-01

    Human HERC1 is one of six HERC proteins and may play an important role in intracellular membrane trafficking. The human HERC1 gene is suggested to have been affected by local positive selection. To assess the global frequency distributions of coding and non-coding single nucleotide polymorphisms (SNPs) in the HERC1 gene, we developed a new simultaneous genotyping method for four SNPs, and applied this method to investigate 1213 individuals from 12 global populations. The results confirmed remarked differences in the allele and haplotype frequencies between East Asian and non-East Asian populations. One of the three common haplotypes observed was found to be characteristic of East Asians, who showed a relatively uniform distribution of haplotypes. Information on haplotypes would be useful for testing the function of polymorphisms in the HERC1 gene. This is the first study to investigate the distribution of HERC1 polymorphisms in various populations. (c) 2009 John Wiley & Sons, Ltd.

  20. Honey bee-inspired algorithms for SNP haplotype reconstruction problem

    Science.gov (United States)

    PourkamaliAnaraki, Maryam; Sadeghi, Mehdi

    2016-03-01

    Reconstructing haplotypes from SNP fragments is an important problem in computational biology. There have been a lot of interests in this field because haplotypes have been shown to contain promising data for disease association research. It is proved that haplotype reconstruction in Minimum Error Correction model is an NP-hard problem. Therefore, several methods such as clustering techniques, evolutionary algorithms, neural networks and swarm intelligence approaches have been proposed in order to solve this problem in appropriate time. In this paper, we have focused on various evolutionary clustering techniques and try to find an efficient technique for solving haplotype reconstruction problem. It can be referred from our experiments that the clustering methods relying on the behaviour of honey bee colony in nature, specifically bees algorithm and artificial bee colony methods, are expected to result in more efficient solutions. An application program of the methods is available at the following link. http://www.bioinf.cs.ipm.ir/software/haprs/

  1. Haplotype inference in general pedigrees with two sites

    Directory of Open Access Journals (Sweden)

    Doan Duong D

    2011-04-01

    Full Text Available Abstract Background Genetic disease studies investigate relationships between changes in chromosomes and genetic diseases. Single haplotypes provide useful information for these studies but extracting single haplotypes directly by biochemical methods is expensive. A computational method to infer haplotypes from genotype data is therefore important. We investigate the problem of computing the minimum number of recombination events for general pedigrees with two sites for all members. Results We show that this NP-hard problem can be parametrically reduced to the Bipartization by Edge Removal problem and therefore can be solved by an O(2k · n2 exact algorithm, where n is the number of members and k is the number of recombination events. Conclusions Our work can therefore be useful for genetic disease studies to track down how changes in haplotypes such as recombinations relate to genetic disease.

  2. Identification of Tribolium castaneum (Herbst) haplotypes, the pest of ...

    African Journals Online (AJOL)

    SARAH

    2016-07-31

    Jul 31, 2016 ... haplotypes of T. castaneum and their distribution in Senegal. Methodology ... very strong marketing of cereals and vegetables in that area. The mutations ..... for each channel by sampling the various parameters every 1000 ...

  3. Birth of a healthy infant following preimplantation PKHD1 haplotyping for autosomal recessive polycystic kidney disease using multiple displacement amplification

    Science.gov (United States)

    Janson, Marleen M.; Roesler, Mark R.; Avner, Ellis D.; Strawn, Estil Y.; Bick, David P.

    2010-01-01

    Purpose To develop a reliable preimplantation genetic diagnosis protocol for couples who both carry a mutant PKHD1 gene wishing to conceive children unaffected with autosomal recessive polycystic kidney disease (ARPKD). Methods Development of a unique protocol for preimplantation genetic testing using whole genome amplification of single blastomeres by multiple displacement amplification (MDA), and haplotype analysis with novel short tandem repeat (STR) markers from the PKHD1 gene and flanking sequences, and a case report of successful utilization of the protocol followed by successful IVF resulting in the birth of an infant unaffected with ARPKD. Results We have developed 20 polymorphic STR markers suitable for linkage analysis of ARPKD. These linked STR markers have enabled unambiguous identification of the PKHD1 haplotypes of embryos produced by at-risk couples. Conclusions We have developed a reliable protocol for preimplantation genetic diagnosis of ARPKD using single-cell MDA products for PKHD1 haplotyping. PMID:20490649

  4. Sequence variation of bovine mitochondrial ND-5 between haplotypes of composite and Hereford Breeds of beef cattle

    Directory of Open Access Journals (Sweden)

    SUTARNO

    2002-07-01

    Full Text Available The aims of the study were to: Investigate polymorphisms in the ND-5 region of bovine mitochondrial DNA in the composite and purebred Hereford herds from the Wokalup selection experiment, sequencing and compare the sequences between haplotypes and published sequence from Genebank. A total of 194 Hereford and 235 composite breed cattle from Wokalup Research Station were used in this study. The mitochondrial DNA was extracted using Wizard genomic DNA purification system from Promega. ND-5 fragment of mitochondrial DNA was amplified using PCR and continued with RFLP. Each haplotypes were sequenced. PCR products of each haplotype were cloned into pCR II, transformed, colonies selection, plasmid DNA extraction continued with cycle sequencing. Polymorphisms were found in both breeds of cattle in ND-5 region of mitochondrial DNA by PCR-RFLP analysis. Sequencing analysis confirmed the RFLPs data.

  5. MHC Class II haplotypes of Colombian Amerindian tribes

    Science.gov (United States)

    Yunis, Juan J.; Yunis, Edmond J.; Yunis, Emilio

    2013-01-01

    We analyzed 1041 individuals belonging to 17 Amerindian tribes of Colombia, Chimila, Bari and Tunebo (Chibcha linguistic family), Embera, Waunana (Choco linguistic family), Puinave and Nukak (Maku-Puinave linguistic families), Cubeo, Guanano, Tucano, Desano and Piratapuyo (Tukano linguistic family), Guahibo and Guayabero (Guayabero Linguistic Family), Curripaco and Piapoco (Arawak linguistic family) and Yucpa (Karib linguistic family). for MHC class II haplotypes (HLA-DRB1, DQA1, DQB1). Approximately 90% of the MHC class II haplotypes found among these tribes are haplotypes frequently encountered in other Amerindian tribes. Nonetheless, striking differences were observed among Chibcha and non-Chibcha speaking tribes. The DRB1*04:04, DRB1*04:11, DRB1*09:01 carrying haplotypes were frequently found among non-Chibcha speaking tribes, while the DRB1*04:07 haplotype showed significant frequencies among Chibcha speaking tribes, and only marginal frequencies among non-Chibcha speaking tribes. Our results suggest that the differences in MHC class II haplotype frequency found among Chibcha and non-Chibcha speaking tribes could be due to genetic differentiation in Mesoamerica of the ancestral Amerindian population into Chibcha and non-Chibcha speaking populations before they entered into South America. PMID:23885196

  6. Defining greed

    NARCIS (Netherlands)

    Seuntjens, Terri G.; Zeelenberg, Marcel; Breugelmans, Seger M.; van de Ven, Niels

    2015-01-01

    Although greed is both hailed as the motor of economic growth and blamed as the cause of economic crises, very little is known about its psychological underpinnings. Five studies explored lay conceptualizations of greed among US and Dutch participants using a prototype analysis. Study 1 identified

  7. Strategies for haplotype-based association mapping in complex pedigreed populations

    DEFF Research Database (Denmark)

    Boleckova, J; Christensen, Ole Fredslund; Sørensen, Peter

    2012-01-01

    In association mapping, haplotype-based methods are generally regarded to provide higher power and increased precision than methods based on single markers. For haplotype-based association mapping most studies use a fixed haplotype effect in the model. However, an increase in haplotype length inc...

  8. Do polymorphisms and haplotypes of mismatch repair genes modulate risk of sporadic colorectal cancer?

    Czech Academy of Sciences Publication Activity Database

    Tulupová, Elena; Kumar, R.; Hánová, Monika; Slyšková, Jana; Pardini, Barbara; Poláková, Veronika; Naccarati, Alessio; Vodičková, Ludmila; Novotný, J.; Halamková, J.; Hemminki, K.; Vodička, Pavel

    2008-01-01

    Roč. 648, 1-2 (2008), s. 40-45 ISSN 0027-5107 R&D Projects: GA ČR GA310/07/1430 Institutional research plan: CEZ:AV0Z50390512; CEZ:AV0Z50390703 Keywords : DNA mismatch repair * Genetic polymorphism * Haplotype analysis Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.198, year: 2008

  9. Novel Nucleotide Variations, Haplotypes Structure and Associations with Growth Related Traits of Goat AT Motif-Binding Factor ( Gene

    Directory of Open Access Journals (Sweden)

    Xiaoyan Zhang

    2015-10-01

    Full Text Available The AT motif-binding factor (ATBF1 not only interacts with protein inhibitor of activated signal transducer and activator of transcription 3 (STAT3 (PIAS3 to suppress STAT3 signaling regulating embryo early development and cell differentiation, but is required for early activation of the pituitary specific transcription factor 1 (Pit1 gene (also known as POU1F1 critically affecting mammalian growth and development. The goal of this study was to detect novel nucleotide variations and haplotypes structure of the ATBF1 gene, as well as to test their associations with growth-related traits in goats. Herein, a total of seven novel single nucleotide polymorphisms (SNPs (SNP 1-7 within this gene were found in two well-known Chinese native goat breeds. Haplotypes structure analysis demonstrated that there were four haplotypes in Hainan black goat while seventeen haplotypes in Xinong Saanen dairy goat, and both breeds only shared one haplotype (hap1. Association testing revealed that the SNP2, SNP5, SNP6, and SNP7 loci were also found to significantly associate with growth-related traits in goats, respectively. Moreover, one diplotype in Xinong Saanen dairy goats significantly linked to growth related traits. These preliminary findings not only would extend the spectrum of genetic variations of the goat ATBF1 gene, but also would contribute to implementing marker-assisted selection in genetics and breeding in goats.

  10. Delirium diagnosis defined by cluster analysis of symptoms versus diagnosis by DSM and ICD criteria: diagnostic accuracy study.

    Science.gov (United States)

    Sepulveda, Esteban; Franco, José G; Trzepacz, Paula T; Gaviria, Ana M; Meagher, David J; Palma, José; Viñuelas, Eva; Grau, Imma; Vilella, Elisabet; de Pablo, Joan

    2016-05-26

    Information on validity and reliability of delirium criteria is necessary for clinicians, researchers, and further developments of DSM or ICD. We compare four DSM and ICD delirium diagnostic criteria versions, which were developed by consensus of experts, with a phenomenology-based natural diagnosis delineated using cluster analysis of delirium features in a sample with a high prevalence of dementia. We also measured inter-rater reliability of each system when applied by two evaluators from distinct disciplines. Cross-sectional analysis of 200 consecutive patients admitted to a skilled nursing facility, independently assessed within 24-48 h after admission with the Delirium Rating Scale-Revised-98 (DRS-R98) and for DSM-III-R, DSM-IV, DSM-5, and ICD-10 criteria for delirium. Cluster analysis (CA) delineated natural delirium and nondelirium reference groups using DRS-R98 items and then diagnostic systems' performance were evaluated against the CA-defined groups using logistic regression and crosstabs for discriminant analysis (sensitivity, specificity, percentage of subjects correctly classified by each diagnostic system and their individual criteria, and performance for each system when excluding each individual criterion are reported). Kappa Index (K) was used to report inter-rater reliability for delirium diagnostic systems and their individual criteria. 117 (58.5 %) patients had preexisting dementia according to the Informant Questionnaire on Cognitive Decline in the Elderly. CA delineated 49 delirium subjects and 151 nondelirium. Against these CA groups, delirium diagnosis accuracy was highest using DSM-III-R (87.5 %) followed closely by DSM-IV (86.0 %), ICD-10 (85.5 %) and DSM-5 (84.5 %). ICD-10 had the highest specificity (96.0 %) but lowest sensitivity (53.1 %). DSM-III-R had the best sensitivity (81.6 %) and the best sensitivity-specificity balance. DSM-5 had the highest inter-rater reliability (K =0.73) while DSM-III-R criteria were the least

  11. Association of ATG16L1 gene haplotype with inflammatory bowel disease in Indians.

    Directory of Open Access Journals (Sweden)

    Srinivasan Pugazhendhi

    Full Text Available Inflammatory bowel disease (IBD is characterized by multigenic inheritance. Defects in autophagy related genes are considered to show genetic heterogeneity between populations. We evaluated the association of several single nucleotide polymorphisms (SNPs in the autophagy related 16 like 1 (ATG16L1 gene with IBD in Indians. The ATG16L1 gene was genotyped for ten different SNPs using DNA extracted from peripheral blood of 234 patients with Crohn's disease (CD, 249 patients with ulcerative colitis (UC and 393 healthy controls The SNPs rs2241880, rs4663396, rs3792106, rs10210302, rs3792109, rs2241877, rs6737398, rs11682898, rs4663402 and rs4663421 were genotyped using the Sequenom MassArray platform. PLINK was used for the association analysis and pairwise linkage disequilibrium (LD values. Haplotype analysis was done using Haploview. All SNPs were in Hardy Weinberg equilibrium in cases and controls. The G allele at rs6737398 exhibited a protective association with both CD and UC. The T allele at rs4663402 and C allele at rs4663421 were positively associated with CD and UC. The T allele at rs2241877 exhibited protective association with UC only. The AA genotype at rs4663402 and the GG genotype at rs4663421 were protectively associated with both CD and UC. Haplotype analysis revealed that all the SNPs in tight LD (D' = 0.76-1.0 and organized in a single haplotype block. Haplotype D was positively associated with IBD (P = 5.8 x 10-6 for CD and 0.002 for UC. SNPs in ATG16L1 were associated with IBD in Indian patients. The relevance to management of individual patients requires further study.

  12. A DRD1 haplotype is associated with risk for autism spectrum disorders in male-only affected sib-pair families.

    Science.gov (United States)

    Hettinger, Joe A; Liu, Xudong; Schwartz, Charles E; Michaelis, Ron C; Holden, Jeanette J A

    2008-07-05

    Individuals with autism spectrum disorders (ASDs) have impairments in executive function and social cognition, with males generally being more severely affected in these areas than females. Because the dopamine D1 receptor (encoded by DRD1) is integral to the neural circuitry mediating these processes, we examined the DRD1 gene for its role in susceptibility to ASDs by performing single marker and haplotype case-control comparisons, family-based association tests, and genotype-phenotype assessments (quantitative transmission disequilibrium tests: QTDT) using three DRD1 polymorphisms, rs265981C/T, rs4532A/G, and rs686T/C. Our previous findings suggested that the dopaminergic system may be more integrally involved in families with affected males only than in other families. We therefore restricted our study to families with two or more affected males (N = 112). There was over-transmission of rs265981-C and rs4532-A in these families (P = 0.040, P = 0.038), with haplotype TDT analysis showing over-transmission of the C-A-T haplotype (P = 0.022) from mothers to affected sons (P = 0.013). In addition, haplotype case-control comparisons revealed an increase of this putative risk haplotype in affected individuals relative to a comparison group (P = 0.004). QTDT analyses showed associations of the rs265981-C, rs4532-A, rs686-T alleles, and the C-A-T haplotype with more severe problems in social interaction, greater difficulties with nonverbal communication and increased stereotypies compared to individuals with other haplotypes. Preferential haplotype transmission of markers at the DRD1 locus and an increased frequency of a specific haplotype support the DRD1 gene as a risk gene for core symptoms of ASD in families having only affected males. Copyright 2008 Wiley-Liss, Inc.

  13. Defining greed.

    Science.gov (United States)

    Seuntjens, Terri G; Zeelenberg, Marcel; Breugelmans, Seger M; van de Ven, Niels

    2015-08-01

    Although greed is both hailed as the motor of economic growth and blamed as the cause of economic crises, very little is known about its psychological underpinnings. Five studies explored lay conceptualizations of greed among U.S. and Dutch participants using a prototype analysis. Study 1 identified features related to greed. Study 2 determined the importance of these features; the most important features were classified as central (e.g., self-interested, never satisfied), whereas less important features were classified as peripheral (e.g., ambition, addiction). Subsequently, we found that, compared to peripheral features, participants recalled central features better (Study 3), faster (Study 4), and these central features were more present in real-life episodes of greed (Study 5). These findings provide a better understanding of the elements that make up the experience of greed and provide insights into how greed can be manipulated and measured in future research. © 2014 The British Psychological Society.

  14. Dimensional Anxiety Mediates Linkage of GABRA2 Haplotypes With Alcoholism

    Science.gov (United States)

    Enoch, Mary-Anne; Schwartz, Lori; Albaugh, Bernard; Virkkunen, Matti; Goldman, David

    2015-01-01

    The GABAAα2 receptor gene (GABRA2) modulates anxiety and stress response. Three recent association studies implicate GABRA2 in alcoholism, however in these papers both common, opposite-configuration haplotypes in the region distal to intron3 predict risk. We have now replicated the GABRA2 association with alcoholism in 331 Plains Indian men and women and 461 Finnish Caucasian men. Using a dimensional measure of anxiety, harm avoidance (HA), we also found that the association with alcoholism is mediated, or moderated, by anxiety. Nine SNPs were genotyped revealing two haplotype blocks. Within the previously implicated block 2 region, we identified the two common, opposite-configuration risk haplotypes, A and B. Their frequencies differed markedly in Finns and Plains Indians. In both populations, most block 2 SNPs were significantly associated with alcoholism. The associations were due to increased frequencies of both homozygotes in alcoholics, indicating the possibility of alcoholic subtypes with opposite genotypes. Congruently, there was no significant haplotype association. Using HA as an indicator variable for anxiety, we found haplotype linkage to alcoholism with high and low dimensional anxiety, and to HA itself, in both populations. High HA alcoholics had the highest frequency of the more abundant haplotype (A in Finns, B in Plains Indians); low HA alcoholics had the highest frequency of the less abundant haplotype (B in Finns, A in Plains Indians) (Finns: P α0.007, OR α2.1, Plains Indians: P α0.040, OR α1.9). Non-alcoholics had intermediate frequencies. Our results suggest that within the distal GABRA2 region is a functional locus or loci that may differ between populations but that alters risk for alcoholism via the mediating action of anxiety. PMID:16874763

  15. New Cases of Thelazia callipaeda Haplotype 1 in Dogs Suggest a Wider Distribution in Romania.

    Science.gov (United States)

    Ioniţă, Mariana; Mitrea, Ioan Liviu; Ionică, Angela Monica; Morariu, Sorin; Mihalca, Andrei Daniel

    2016-03-01

    Thelazia callipaeda is an emerging vector-borne zoonotic helminth parasitizing the conjunctival sac of a broad spectrum of definitive hosts, such as dogs, cats, rabbits, wild carnivores, and humans. Its presence is associated with mild to severe ocular disease. Here, we report two new clinical cases in dogs originating from western and southern Romania, with no travel history. On clinical examination, the nematodes were retrieved from the conjunctival sac and identified using morphological keys and molecular tools. Twenty-two adult nematodes (8 males, 14 females) were collected and were identified as T. callipaeda by morphology. The molecular analysis revealed a 100% identity with haplotype h1 of T. callipaeda. This study describes the occurrence of new autochthonous cases of thelaziosis in Romania, reinforcing the spreading trend of this zoonotic eyeworm and highlighting the need for increased awareness among medical and veterinary practitioners. Moreover, we provide additional molecular evidence for the exclusive distribution of haplotype 1 of T. callipaeda in Europe.

  16. Haplotype of platelet receptor P2RY12 gene is associated with residual clopidogrel on-treatment platelet reactivity.

    Science.gov (United States)

    Nie, Xiao-Yan; Li, Jun-Lei; Zhang, Yong; Xu, Yang; Yang, Xue-Li; Fu, Yu; Liang, Guang-Kai; Lu, Yun; Liu, Jian; Shi, Lu-Wen

    To investigate a possible association between common variations of the P2RY12 and the residual clopidogrel on-treatment platelet reactivity after adjusting for the influence of CYP2C19 tested by thromboelastography (TEG). One hundred and eighty patients with acute coronary syndrome (ACS) treated with clopidogrel and aspirin were included and platelet function was assessed by TEG. Five selected P2RY12 single nucleotide polymorphisms (SNPs; rs6798347, rs6787801, rs6801273, rs6785930, and rs2046934), which cover the common variations in the P2RY12 gene and its regulatory regions, and three CYP2C19 SNPs ( * 2, * 3, * 17) were genotyped and possible haplotypes were analyzed. The high on-treatment platelet reactivity (HTPR) prevalence defined by a platelet inhibition rate <30% by TEG in adenosine diphosphate (ADP)-channel was 69 (38.33%). Six common haplotypes were inferred from four of the selected P2RY12 SNPs (denoted H 0 to H 5 ) according to the linkage disequilibrium R square (except for rs2046934). Haplotype H 1 showed a significantly lower incidence of HTPR than the reference haplotype (H 0 ) in the total study population while haplotypes H 1 and H 2 showed significantly lower incidences of HTPR than H 0 in the nonsmoker subgroup after adjusting for CYP2C19 effects and demographic characteristics. rs2046934 (T744C) did not show any significant association with HTPR. The combination of common P2RY12 variations including regulatory regions rather than rs2046934 (T744C) that related to pharmacodynamics of clopidogrel in patients with ACS was independently associated with residual on-clopidogrel platelet reactivity. This is apart from the established association of the CYP2C19. This association seemed more important in the subgroup defined by smoking.

  17. Genomic identification of founding haplotypes reveals the history of the selfing species Capsella rubella.

    Directory of Open Access Journals (Sweden)

    Yaniv Brandvain

    Full Text Available The shift from outcrossing to self-fertilization is among the most common evolutionary transitions in flowering plants. Until recently, however, a genome-wide view of this transition has been obscured by both a dearth of appropriate data and the lack of appropriate population genomic methods to interpret such data. Here, we present a novel population genomic analysis detailing the origin of the selfing species, Capsella rubella, which recently split from its outcrossing sister, Capsella grandiflora. Due to the recency of the split, much of the variation within C. rubella is also found within C. grandiflora. We can therefore identify genomic regions where two C. rubella individuals have inherited the same or different segments of ancestral diversity (i.e. founding haplotypes present in C. rubella's founder(s. Based on this analysis, we show that C. rubella was founded by multiple individuals drawn from a diverse ancestral population closely related to extant C. grandiflora, that drift and selection have rapidly homogenized most of this ancestral variation since C. rubella's founding, and that little novel variation has accumulated within this time. Despite the extensive loss of ancestral variation, the approximately 25% of the genome for which two C. rubella individuals have inherited different founding haplotypes makes up roughly 90% of the genetic variation between them. To extend these findings, we develop a coalescent model that utilizes the inferred frequency of founding haplotypes and variation within founding haplotypes to estimate that C. rubella was founded by a potentially large number of individuals between 50 and 100 kya, and has subsequently experienced a twenty-fold reduction in its effective population size. As population genomic data from an increasing number of outcrossing/selfing pairs are generated, analyses like the one developed here will facilitate a fine-scaled view of the evolutionary and demographic impact of the

  18. Cystic fibrosis transmembrane regulator haplotypes in households of patients with cystic fibrosis.

    Science.gov (United States)

    Furgeri, Daniela Tenório; Marson, Fernando Augusto Lima; Correia, Cyntia Arivabeni Araújo; Ribeiro, José Dirceu; Bertuzzo, Carmen Sílvia

    2018-01-30

    Nearly 2000 mutations in the cystic fibrosis transmembrane regulator (CFTR) gene have been reported. The F508del mutation occurs in approximately 50-65% of patients with cystic fibrosis (CF). However, molecular diagnosis is not always possible. Therefore, silent polymorphisms can be used to label the mutant allele in households of patients with CF. To verify the haplotypes of four polymorphisms at the CFTR locus in households of patients with CF for pre-fertilization, pre-implantation, and prenatal indirect mutation diagnosis to provide better genetic counseling for families and patients with CF and to associate the genotypes/haplotypes with the F508del mutation screening. GATT polymorphism analysis was performed using direct polymerase chain reaction amplification, and the MP6-D9, TUB09 and TUB18 polymorphism analyses were performed using restriction fragment length polymorphism. Nine haplotypes were found in 37 CFTR alleles, and of those, 24 were linked with the F508del mutation and 13 with other CFTR mutations. The 6 (GATT), C (MP6-D9), G (TUB09), and C (TUB18) haplotypes showed the highest prevalence (48%) of the mutant CFTR allele and were linked to the F508del mutation (64%). In 43% of households analyzed, at least one informative polymorphism can be used for the indirect diagnostic test. CFTR polymorphisms are genetic markers that are useful for identifying the mutant CFTR alleles in households of patients with CF when it is not possible to establish the complete CFTR genotype. Moreover, the polymorphisms can be used for indirect CFTR mutation identification in cases of pre-fertilization, pre-implantation and prenatal analysis. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Effects of the number of markers per haplotype and clustering of haplotypes on the accuracy of QTL mapping and prediction of genomic breeding values

    NARCIS (Netherlands)

    Calus, M.P.L.; Meuwissen, T.H.E.; Windig, J.J.; Knol, E.F.; Schrooten, C.; Vereijken, A.L.J.; Veerkamp, R.F.

    2009-01-01

    The aim of this paper was to compare the effect of haplotype definition on the precision of QTL-mapping and on the accuracy of predicted genomic breeding values. In a multiple QTL model using identity-by-descent (IBD) probabilities between haplotypes, various haplotype definitions were tested i.e.

  20. Compound Heterozygosity for Null Mutations and a Common Hypomorphic Risk Haplotype in TBX6 Causes Congenital Scoliosis.

    Science.gov (United States)

    Takeda, Kazuki; Kou, Ikuyo; Kawakami, Noriaki; Iida, Aritoshi; Nakajima, Masahiro; Ogura, Yoji; Imagawa, Eri; Miyake, Noriko; Matsumoto, Naomichi; Yasuhiko, Yukuto; Sudo, Hideki; Kotani, Toshiaki; Nakamura, Masaya; Matsumoto, Morio; Watanabe, Kota; Ikegawa, Shiro

    2017-03-01

    Congenital scoliosis (CS) occurs as a result of vertebral malformations and has an incidence of 0.5-1/1,000 births. Recently, TBX6 on chromosome 16p11.2 was reported as a disease gene for CS; about 10% of Chinese CS patients were compound heterozygotes for rare null mutations and a common haplotype defined by three SNPs in TBX6. All patients had hemivertebrae. We recruited 94 Japanese CS patients, investigated the TBX6 locus for both mutations and the risk haplotype, examined transcriptional activities of mutant TBX6 in vitro, and evaluated clinical and radiographic features. We identified TBX6 null mutations in nine patients, including a missense mutation that had a loss of function in vitro. All had the risk haplotype in the opposite allele. One of the mutations showed dominant negative effect. Although all Chinese patients had one or more hemivertebrae, two Japanese patients did not have hemivertebra. The compound heterozygosity of null mutations and the common risk haplotype in TBX6 also causes CS in Japanese patients with similar incidence. Hemivertebra was not a specific type of spinal malformation in TBX6-associated CS (TACS). A heterozygous TBX6 loss-of-function mutation has been reported in a family with autosomal-dominant spondylocostal dysostosis, but it may represent a spectrum of the same disease with TACS. © 2017 WILEY PERIODICALS, INC.

  1. Mineralocorticoid receptor haplotype, oral contraceptives and emotional information processing.

    Science.gov (United States)

    Hamstra, D A; de Kloet, E R; van Hemert, A M; de Rijk, R H; Van der Does, A J W

    2015-02-12

    Oral contraceptives (OCs) affect mood in some women and may have more subtle effects on emotional information processing in many more users. Female carriers of mineralocorticoid receptor (MR) haplotype 2 have been shown to be more optimistic and less vulnerable to depression. To investigate the effects of oral contraceptives on emotional information processing and a possible moderating effect of MR haplotype. Cross-sectional study in 85 healthy premenopausal women of West-European descent. We found significant main effects of oral contraceptives on facial expression recognition, emotional memory and decision-making. Furthermore, carriers of MR haplotype 1 or 3 were sensitive to the impact of OCs on the recognition of sad and fearful faces and on emotional memory, whereas MR haplotype 2 carriers were not. Different compounds of OCs were included. No hormonal measures were taken. Most naturally cycling participants were assessed in the luteal phase of their menstrual cycle. Carriers of MR haplotype 2 may be less sensitive to depressogenic side-effects of OCs. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  2. How do older adult drivers self-regulate? Characteristics of self-regulation classes defined by latent class analysis.

    Science.gov (United States)

    Bergen, Gwen; West, Bethany A; Luo, Feijun; Bird, Donna C; Freund, Katherine; Fortinsky, Richard H; Staplin, Loren

    2017-06-01

    Motor-vehicle crashes were the second leading cause of injury death for adults aged 65-84years in 2014. Some older drivers choose to self-regulate their driving to maintain mobility while reducing driving risk, yet the process remains poorly understood. Data from 729 older adults (aged ≥60years) who joined an older adult ride service program between April 1, 2010 and November 8, 2013 were analyzed to define and describe classes of driving self-regulation. Latent class analysis was employed to characterize older adult driving self-regulation classes using driving frequency and avoidance of seven driving situations. Logistic regression was used to explore associations between characteristics affecting mobility and self-regulation class. Three classes were identified (low, medium, and high self-regulation). High self-regulating participants reported the highest proportion of always avoiding seven risky driving situations and the lowest driving frequency followed by medium and low self-regulators. Those who were female, aged 80years or older, visually impaired, assistive device users, and those with special health needs were more likely to be high self-regulating compared with low self-regulating. Avoidance of certain driving situations and weekly driving frequency are valid indicators for describing driving self-regulation classes in older adults. Understanding the unique characteristics and mobility limitations of each class can guide optimal transportation strategies for older adults. Published by Elsevier Ltd.

  3. Body weight and incidence of breast cancer defined by estrogen and progesterone receptor status--a meta-analysis.

    Science.gov (United States)

    Suzuki, Reiko; Orsini, Nicola; Saji, Shigehira; Key, Timothy J; Wolk, Alicja

    2009-02-01

    Epidemiological evidence indicates that the association between body weight and breast cancer risk may differ across menopausal status as well as the estrogen receptor (ER) and progesterone receptor (PR) tumor status. To date, no meta-analysis has been conducted to assess the association between body weight and ER/PR defined breast cancer risk, taking into account menopausal status and study design. We searched MEDLINE for relevant studies published from January 1, 1970 through December 31, 2007. Summarized risk estimates with 95% confidence intervals (CIs) were calculated using a random-effects model. The summarized results of 9 cohorts and 22 case-control studies comparing the highest versus the reference categories of relative body weight showed that the risk for ER+PR+ tumors was 20% lower (95% CI=-30% to -8%) among premenopausal (2,643 cases) and 82% higher (95% CI=55-114%) among postmenopausal (5,469 cases) women. The dose-response meta-analysis of ER+PR+ tumors showed that each 5-unit increase in body mass index (BMI, kg/m2) was associated with a 33% increased risk among postmenopausal women (95% CI=20-48%) and 10% decreased risk among premenopausal women (95% CI=-18% to -1%). No associations were observed for ER-PR- or ER+PR- tumors. For discordant tumors ER+PR- (pre) and ER-PR+ (pre/post) the number of cases were too small (weight and breast cancer risk is critically dependent on the tumor's ER/PR status and the woman's menopausal status. Body weight control is the effective strategy for preventing ER+PR+ tumors after menopause. Copyright (c) 2008 Wiley-Liss, Inc.

  4. Analysis of C. elegans NR2E nuclear receptors defines three conserved clades and ligand-independent functions

    Directory of Open Access Journals (Sweden)

    Weber Katherine P

    2012-06-01

    Full Text Available Abstract Background The nuclear receptors (NRs are an important class of transcription factors that are conserved across animal phyla. Canonical NRs consist of a DNA-binding domain (DBD and ligand-binding domain (LBD. While most animals have 20–40 NRs, nematodes of the genus Caenorhabditis have experienced a spectacular proliferation and divergence of NR genes. The LBDs of evolutionarily-conserved Caenorhabditis NRs have diverged sharply from their Drosophila and vertebrate orthologs, while the DBDs have been strongly conserved. The NR2E family of NRs play critical roles in development, especially in the nervous system. In this study, we explore the phylogenetics and function of the NR2E family of Caenorhabditis elegans, using an in vivo assay to test LBD function. Results Phylogenetic analysis reveals that the NR2E family of NRs consists of three broadly-conserved clades of orthologous NRs. In C. elegans, these clades are defined by nhr-67, fax-1 and nhr-239. The vertebrate orthologs of nhr-67 and fax-1 are Tlx and PNR, respectively. While the nhr-239 clade includes orthologs in insects (Hr83, an echinoderm, and a hemichordate, the gene appears to have been lost from vertebrate lineages. The C. elegans and C. briggsae nhr-239 genes have an apparently-truncated and highly-diverged LBD region. An additional C. elegans NR2E gene, nhr-111, appears to be a recently-evolved paralog of fax-1; it is present in C. elegans, but not C. briggsae or other animals with completely-sequenced genomes. Analysis of the relatively unstudied nhr-111 and nhr-239 genes demonstrates that they are both expressed—nhr-111 very broadly and nhr-239 in a small subset of neurons. Analysis of the FAX-1 LBD in an in vivo assay revealed that it is not required for at least some developmental functions. Conclusions Our analysis supports three conserved clades of NR2E receptors, only two of which are represented in vertebrates, indicating three ancestral NR2E genes in the

  5. BMP4 and FGF3 haplotypes increase the risk of tendinopathy in volleyball athletes.

    Science.gov (United States)

    Salles, José Inácio; Amaral, Marcus Vinícius; Aguiar, Diego Pinheiro; Lira, Daisy Anne; Quinelato, Valquiria; Bonato, Letícia Ladeira; Duarte, Maria Eugenia Leite; Vieira, Alexandre Rezende; Casado, Priscila Ladeira

    2015-03-01

    To investigate whether genetic variants can be correlated with tendinopathy in elite male volleyball athletes. Case-control study. Fifteen single nucleotide polymorphisms within BMP4, FGF3, FGF10, FGFR1 genes were investigated in 138 elite volleyball athletes, aged between 18 and 35 years, who undergo 4-5h of training per day: 52 with tendinopathy and 86 with no history of pain suggestive of tendinopathy in patellar, Achilles, shoulder, and hip abductors tendons. The clinical diagnostic criterion was progressive pain during training, confirmed by magnetic resonance image. Genomic DNA was obtained from saliva samples. Genetic markers were genotyped using TaqMan real-time PCR. Chi-square test compared genotypes and haplotype differences between groups. Multivariate logistic regression analyzed the significance of covariates and incidence of tendinopathy. Statistical analysis revealed participant age (p=0.005) and years of practice (p=0.004) were risk factors for tendinopathy. A significant association between BMP4 rs2761884 (p=0.03) and tendinopathy was observed. Athletes with a polymorphic genotype have 2.4 times more susceptibility to tendinopathy (OR=2.39; 95%CI=1.10-5.19). Also, association between disease and haplotype TTGGA in BMP4 (p=0.01) was observed. The FGF3 TGGTA haplotype showed a tendency of association with tendinopathy (p=0.05), and so did FGF10 rs900379. FGFR1 showed no association with disease. These findings indicate that haplotypes in BMP4 and FGF3 genes may contribute to the tendon disease process in elite volleyball athletes. Copyright © 2014 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

  6. Shrinkage Estimators for Robust and Efficient Inference in Haplotype-Based Case-Control Studies

    KAUST Repository

    Chen, Yi-Hau

    2009-03-01

    Case-control association studies often aim to investigate the role of genes and gene-environment interactions in terms of the underlying haplotypes (i.e., the combinations of alleles at multiple genetic loci along chromosomal regions). The goal of this article is to develop robust but efficient approaches to the estimation of disease odds-ratio parameters associated with haplotypes and haplotype-environment interactions. We consider "shrinkage" estimation techniques that can adaptively relax the model assumptions of Hardy-Weinberg-Equilibrium and gene-environment independence required by recently proposed efficient "retrospective" methods. Our proposal involves first development of a novel retrospective approach to the analysis of case-control data, one that is robust to the nature of the gene-environment distribution in the underlying population. Next, it involves shrinkage of the robust retrospective estimator toward a more precise, but model-dependent, retrospective estimator using novel empirical Bayes and penalized regression techniques. Methods for variance estimation are proposed based on asymptotic theories. Simulations and two data examples illustrate both the robustness and efficiency of the proposed methods.

  7. Shrinkage Estimators for Robust and Efficient Inference in Haplotype-Based Case-Control Studies

    KAUST Repository

    Chen, Yi-Hau; Chatterjee, Nilanjan; Carroll, Raymond J.

    2009-01-01

    Case-control association studies often aim to investigate the role of genes and gene-environment interactions in terms of the underlying haplotypes (i.e., the combinations of alleles at multiple genetic loci along chromosomal regions). The goal of this article is to develop robust but efficient approaches to the estimation of disease odds-ratio parameters associated with haplotypes and haplotype-environment interactions. We consider "shrinkage" estimation techniques that can adaptively relax the model assumptions of Hardy-Weinberg-Equilibrium and gene-environment independence required by recently proposed efficient "retrospective" methods. Our proposal involves first development of a novel retrospective approach to the analysis of case-control data, one that is robust to the nature of the gene-environment distribution in the underlying population. Next, it involves shrinkage of the robust retrospective estimator toward a more precise, but model-dependent, retrospective estimator using novel empirical Bayes and penalized regression techniques. Methods for variance estimation are proposed based on asymptotic theories. Simulations and two data examples illustrate both the robustness and efficiency of the proposed methods.

  8. More powerful haplotype sharing by accounting for the mode of inheritance.

    Science.gov (United States)

    Ziegler, Andreas; Ewhida, Adel; Brendel, Michael; Kleensang, André

    2009-04-01

    The concept of haplotype sharing (HS) has received considerable attention recently, and several haplotype association methods have been proposed. Here, we extend the work of Beckmann and colleagues [2005 Hum. Hered. 59:67-78] who derived an HS statistic (BHS) as special case of Mantel's space-time clustering approach. The Mantel-type HS statistic correlates genetic similarity with phenotypic similarity across pairs of individuals. While phenotypic similarity is measured as the mean-corrected cross product of phenotypes, we propose to incorporate information of the underlying genetic model in the measurement of the genetic similarity. Specifically, for the recessive and dominant modes of inheritance we suggest the use of the minimum and maximum of shared length of haplotypes around a marker locus for pairs of individuals. If the underlying genetic model is unknown, we propose a model-free HS Mantel statistic using the max-test approach. We compare our novel HS statistics to BHS using simulated case-control data and illustrate its use by re-analyzing data from a candidate region of chromosome 18q from the Rheumatoid Arthritis (RA) Consortium. We demonstrate that our approach is point-wise valid and superior to BHS. In the re-analysis of the RA data, we identified three regions with point-wise P-values<0.005 containing six known genes (PMIP1, MC4R, PIGN, KIAA1468, TNFRSF11A and ZCCHC2) which might be worth follow-up.

  9. Effect of genetic type and casein haplotype on antioxidant activity of yogurts during storage.

    Science.gov (United States)

    Perna, A; Intaglietta, I; Simonetti, A; Gambacorta, E

    2013-06-01

    The aim of this work was to investigate the antioxidant activity of yogurt made from the milk of 2 breeds-Italian Brown and Italian Holstein-characterized by different casein haplotypes (αS1-, β-, and κ-caseins) during storage up to 15 d. The casein haplotype was determined by isoelectric focusing; antioxidant activity of yogurt was measured using 2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid). The statistical analysis showed a significant effect of the studied factors. Antioxidant activity increased during storage of both yogurt types, but yogurt produced with Italian Brown milk showed higher antioxidant activity than those produced with Italian Holstein milk. A high scavenging activity was present in yogurts with the allelic combination of BB-A(2)A(2)-BB. The results of this study suggest that the genetic type and the haplotype make a significant contribution in the production of yogurts with high nutraceutical value. Copyright © 2013 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  10. Grouping preprocess for haplotype inference from SNP and CNV data

    International Nuclear Information System (INIS)

    Shindo, Hiroyuki; Chigira, Hiroshi; Nagaoka, Tomoyo; Inoue, Masato; Kamatani, Naoyuki

    2009-01-01

    The method of statistical haplotype inference is an indispensable technique in the field of medical science. The authors previously reported Hardy-Weinberg equilibrium-based haplotype inference that could manage single nucleotide polymorphism (SNP) data. We recently extended the method to cover copy number variation (CNV) data. Haplotype inference from mixed data is important because SNPs and CNVs are occasionally in linkage disequilibrium. The idea underlying the proposed method is simple, but the algorithm for it needs to be quite elaborate to reduce the calculation cost. Consequently, we have focused on the details on the algorithm in this study. Although the main advantage of the method is accuracy, in that it does not use any approximation, its main disadvantage is still the calculation cost, which is sometimes intractable for large data sets with missing values.

  11. Grouping preprocess for haplotype inference from SNP and CNV data

    Energy Technology Data Exchange (ETDEWEB)

    Shindo, Hiroyuki; Chigira, Hiroshi; Nagaoka, Tomoyo; Inoue, Masato [Department of Electrical Engineering and Bioscience, School of Advanced Science and Engineering, Waseda University, 3-4-1, Okubo, Shinjuku-ku, Tokyo 169-8555 (Japan); Kamatani, Naoyuki, E-mail: masato.inoue@eb.waseda.ac.j [Institute of Rheumatology, Tokyo Women' s Medical University, 10-22, Kawada-cho, Shinjuku-ku, Tokyo 162-0054 (Japan)

    2009-12-01

    The method of statistical haplotype inference is an indispensable technique in the field of medical science. The authors previously reported Hardy-Weinberg equilibrium-based haplotype inference that could manage single nucleotide polymorphism (SNP) data. We recently extended the method to cover copy number variation (CNV) data. Haplotype inference from mixed data is important because SNPs and CNVs are occasionally in linkage disequilibrium. The idea underlying the proposed method is simple, but the algorithm for it needs to be quite elaborate to reduce the calculation cost. Consequently, we have focused on the details on the algorithm in this study. Although the main advantage of the method is accuracy, in that it does not use any approximation, its main disadvantage is still the calculation cost, which is sometimes intractable for large data sets with missing values.

  12. HLA-G Haplotypes Are Differentially Associated with Asthmatic Features

    Directory of Open Access Journals (Sweden)

    Camille Ribeyre

    2018-02-01

    Full Text Available Human leukocyte antigen (HLA-G, a HLA class Ib molecule, interacts with receptors on lymphocytes such as T cells, B cells, and natural killer cells to influence immune responses. Unlike classical HLA molecules, HLA-G expression is not found on all somatic cells, but restricted to tissue sites, including human bronchial epithelium cells (HBEC. Individual variation in HLA-G expression is linked to its genetic polymorphism and has been associated with many pathological situations such as asthma, which is characterized by epithelium abnormalities and inflammatory cell activation. Studies reported both higher and equivalent soluble HLA-G (sHLA-G expression in different cohorts of asthmatic patients. In particular, we recently described impaired local expression of HLA-G and abnormal profiles for alternatively spliced isoforms in HBEC from asthmatic patients. sHLA-G dosage is challenging because of its many levels of polymorphism (dimerization, association with β2-microglobulin, and alternative splicing, thus many clinical studies focused on HLA-G single-nucleotide polymorphisms as predictive biomarkers, but few analyzed HLA-G haplotypes. Here, we aimed to characterize HLA-G haplotypes and describe their association with asthmatic clinical features and sHLA-G peripheral expression and to describe variations in transcription factor (TF binding sites and alternative splicing sites. HLA-G haplotypes were differentially distributed in 330 healthy and 580 asthmatic individuals. Furthermore, HLA-G haplotypes were associated with asthmatic clinical features showed. However, we did not confirm an association between sHLA-G and genetic, biological, or clinical parameters. HLA-G haplotypes were phylogenetically split into distinct groups, with each group displaying particular variations in TF binding or RNA splicing sites that could reflect differential HLA-G qualitative or quantitative expression, with tissue-dependent specificities. Our results, based on a

  13. Mineralocorticoid receptor haplotype, estradiol, progesterone and emotional information processing.

    Science.gov (United States)

    Hamstra, Danielle A; de Kloet, E Ronald; Quataert, Ina; Jansen, Myrthe; Van der Does, Willem

    2017-02-01

    Carriers of MR-haplotype 1 and 3 (GA/CG; rs5522 and rs2070951) are more sensitive to the influence of oral contraceptives (OC) and menstrual cycle phase on emotional information processing than MR-haplotype 2 (CA) carriers. We investigated whether this effect is associated with estradiol (E2) and/or progesterone (P4) levels. Healthy MR-genotyped premenopausal women were tested twice in a counterbalanced design. Naturally cycling (NC) women were tested in the early-follicular and mid-luteal phase and OC-users during OC-intake and in the pill-free week. At both sessions E2 and P4 were assessed in saliva. Tests included implicit and explicit positive and negative affect, attentional blink accuracy, emotional memory, emotion recognition, and risky decision-making (gambling). MR-haplotype 2 homozygotes had higher implicit happiness scores than MR-haplotype 2 heterozygotes (p=0.031) and MR-haplotype 1/3 carriers (pemotion recognition test than MR-haplotype 1/3 (p=0.001). Practice effects were observed for most measures. The pattern of correlations between information processing and P4 or E2 differed between sessions, as well as the moderating effects of the MR genotype. In the first session the MR-genotype moderated the influence of P4 on implicit anxiety (sr=-0.30; p=0.005): higher P4 was associated with reduction in implicit anxiety, but only in MR-haplotype 2 homozygotes (sr=-0.61; p=0.012). In the second session the MR-genotype moderated the influence of E2 on the recognition of facial expressions of happiness (sr=-0.21; p=0.035): only in MR-haplotype 1/3 higher E2 was correlated with happiness recognition (sr=0.29; p=0.005). In the second session higher E2 and P4 were negatively correlated with accuracy in lag2 trials of the attentional blink task (pemotional information processing. This moderating effect may depend on the novelty of the situation. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Genome patterns of selection and introgression of haplotypes in natural populations of the house mouse (Mus musculus.

    Directory of Open Access Journals (Sweden)

    Fabian Staubach

    Full Text Available General parameters of selection, such as the frequency and strength of positive selection in natural populations or the role of introgression, are still insufficiently understood. The house mouse (Mus musculus is a particularly well-suited model system to approach such questions, since it has a defined history of splits into subspecies and populations and since extensive genome information is available. We have used high-density single-nucleotide polymorphism (SNP typing arrays to assess genomic patterns of positive selection and introgression of alleles in two natural populations of each of the subspecies M. m. domesticus and M. m. musculus. Applying different statistical procedures, we find a large number of regions subject to apparent selective sweeps, indicating frequent positive selection on rare alleles or novel mutations. Genes in the regions include well-studied imprinted loci (e.g. Plagl1/Zac1, homologues of human genes involved in adaptations (e.g. alpha-amylase genes or in genetic diseases (e.g. Huntingtin and Parkin. Haplotype matching between the two subspecies reveals a large number of haplotypes that show patterns of introgression from specific populations of the respective other subspecies, with at least 10% of the genome being affected by partial or full introgression. Using neutral simulations for comparison, we find that the size and the fraction of introgressed haplotypes are not compatible with a pure migration or incomplete lineage sorting model. Hence, it appears that introgressed haplotypes can rise in frequency due to positive selection and thus can contribute to the adaptive genomic landscape of natural populations. Our data support the notion that natural genomes are subject to complex adaptive processes, including the introgression of haplotypes from other differentiated populations or species at a larger scale than previously assumed for animals. This implies that some of the admixture found in inbred strains of mice

  15. Risk of Pediatric Celiac Disease According to HLA Haplotype and Country

    Science.gov (United States)

    Liu, Edwin; Lee, Hye-Seung; Aronsson, Carin A.; Hagopian, William A.; Koletzko, Sibylle; Rewers, Marian J.; Eisenbarth, George S.; Bingley, Polly J.; Bonifacio, Ezio; Simell, Ville; Agardh, Daniel

    2014-01-01

    BACKGROUND The presence of HLA haplotype DR3–DQ2 or DR4–DQ8 is associated with an increased risk of celiac disease. In addition, nearly all children with celiac disease have serum antibodies against tissue transglutaminase (tTG). METHODS We studied 6403 children with HLA haplotype DR3–DQ2 or DR4–DQ8 prospectively from birth in the United States, Finland, Germany, and Sweden. The primary end point was the development of celiac disease autoimmunity, which was defined as the presence of tTG antibodies on two consecutive tests at least 3 months apart. The secondary end point was the development of celiac disease, which was defined for the purpose of this study as either a diagnosis on biopsy or persistently high levels of tTG antibodies. RESULTS The median follow-up was 60 months (interquartile range, 46 to 77). Celiac disease autoimmunity developed in 786 children (12%). Of the 350 children who underwent biopsy, 291 had confirmed celiac disease; an additional 21 children who did not undergo biopsy had persistently high levels of tTG antibodies. The risks of celiac disease autoimmunity and celiac disease by the age of 5 years were 11% and 3%, respectively, among children with a single DR3–DQ2 haplotype, and 26% and 11%, respectively, among those with two copies (DR3–DQ2 homozygosity). In the adjusted model, the hazard ratios for celiac disease autoimmunity were 2.09 (95% confidence interval [CI], 1.70 to 2.56) among heterozygotes and 5.70 (95% CI, 4.66 to 6.97) among homozygotes, as compared with children who had the lowest-risk genotypes (DR4–DQ8 heterozygotes or homozygotes). Residence in Sweden was also independently associated with an increased risk of celiac disease autoimmunity (hazard ratio, 1.90; 95% CI, 1.61 to 2.25). CONCLUSIONS Children with the HLA haplotype DR3–DQ2, especially homozygotes, were found to be at high risk for celiac disease autoimmunity and celiac disease early in childhood. The higher risk in Sweden than in other countries

  16. Genetic polymorphisms in MDR1 and CYP3A4 genes in Asians and the influence of MDR1 haplotypes on cyclosporin disposition in heart transplant recipients.

    Science.gov (United States)

    Chowbay, Balram; Cumaraswamy, Sivathasan; Cheung, Yin Bun; Zhou, Qingyu; Lee, Edmund J D

    2003-02-01

    Intestinal cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) both play a vital role in the metabolism of oral cyclosporine (CsA). We investigated the genetic polymorphisms in CYP3A4(promoter region and exons 5, 7 and 9) and MDR1 (exons 12, 21 and 26) genes and the impact of these polymorphisms on the pharmacokinetics of oral CsA in stable heart transplant patients (n = 14). CYP3A4 polymorphisms were rare in the Asian population and transplant patients. Haplotype analysis revealed 12 haplotypes in the Chinese, eight in the Malays and 10 in the Indians. T-T-T was the most common haplotype in all ethnic groups. The frequency of the homozygous mutant genotype at all three loci (TT-TT-TT) was highest in the Indians (31%) compared to 19% and 15% in the Chinese and Malays, respectively. In heart transplant patients, CsA exposure (AUC(0-4 h), AUC(0-12 h) and C(max)) was high in patients with the T-T-T haplotypes compared to those with C-G-C haplotypes. These findings suggest that haplotypes rather than genotypes influence CsA disposition in transplant patients.

  17. Bayesian genomic selection: the effect of haplotype lenghts and priors

    DEFF Research Database (Denmark)

    Villumsen, Trine Michelle; Janss, Luc

    2009-01-01

    Breeding values for animals with marker data are estimated using a genomic selection approach where data is analyzed using Bayesian multi-marker association models. Fourteen model scenarios with varying haplotype lengths, hyper parameter and prior distributions were compared to find the scenario ...

  18. Direct chromosome-length haplotyping by single-cell sequencing

    NARCIS (Netherlands)

    Porubský, David; Sanders, Ashley D; van Wietmarschen, Niek; Falconer, Ester; Hills, Mark; Spierings, Diana C J; Bevova, Marianna R; Guryev, Victor; Lansdorp, Peter Michael

    Haplotypes are fundamental to fully characterize the diploid genome of an individual, yet methods to directly chart the unique genetic makeup of each parental chromosome are lacking. Here we introduce single-cell DNA template strand sequencing (Strand-seq) as a novel approach to phasing diploid

  19. Dense and accurate whole-chromosome haplotyping of individual genomes

    NARCIS (Netherlands)

    Porubsky, David; Garg, Shilpa; Sanders, Ashley D.; Korbel, Jan O.; Guryev, Victor; Lansdorp, Peter M.; Marschall, Tobias

    2017-01-01

    The diploid nature of the human genome is neglected in many analyses done today, where a genome is perceived as a set of unphased variants with respect to a reference genome. This lack of haplotype-level analyses can be explained by a lack of methods that can produce dense and accurate

  20. Geographical distribution of a specific mitochondrial haplotype of Zymoseptoria tritici

    Directory of Open Access Journals (Sweden)

    Sameh BOUKEF

    2014-01-01

    Full Text Available Severity of disease caused by the fungus Zymoseptoria tritici throughout world cereal growing regions has elicited much debate on the potential evolutionary mechanism conferring high adaptability of the pathogen to diverse climate conditions and different wheat hosts (Triticum durum and T. aestivum. Specific mitochondrial DNA sequence was used to investigate geographic distribution of the type 4 haplotype (mtRFLP4 within 1363 isolates of Z. tritici originating from 21 countries. The mtRFLP4 haplotype was detected from both durum and bread wheat hosts with greater frequency on durum wheat. The distribution of mtRFLP4 was limited to populations sampled from the Mediterranean and the Red Sea region. Greater frequencies of mtRFLP4 were found in Tunisia (87% and Algeria (60%. The haplotype was absent within European, Australian, North and South American populations except Argentina. While alternative hypotheses such as climatic adaptation could not be ruled out, it is postulated that mtRFLP4 originated in North Africa (e.g. Tunisia or Algeria as an adaptation to durum wheat as the prevailing cereal crop. The specialized haplotype has subsequently spread as indicated by lower frequency of occurrence in the surrounding Mediterranean countries and on bread wheat hosts.

  1. Association of specific haplotype of TNFα with Helicobacter pylori ...

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Genetics; Volume 87; Issue 3. Association of specific haplotype of TNF with Helicobacter pylori-mediated duodenal ulcer in eastern Indian population. Meenakshi Chakravorty Dipanjana Datta De Abhijit Choudhury Amal Santra Susanta Roychoudhury. Research Note Volume 87 Issue 3 ...

  2. Genetics of chloroquine-resistant malaria: a haplotypic view

    Directory of Open Access Journals (Sweden)

    Gauri Awasthi

    2013-12-01

    Full Text Available The development and rapid spread of chloroquine resistance (CQR in Plasmodium falciparum have triggered the identification of several genetic target(s in the P. falciparum genome. In particular, mutations in the Pfcrt gene, specifically, K76T and mutations in three other amino acids in the region adjoining K76 (residues 72, 74, 75 and 76, are considered to be highly related to CQR. These various mutations form several different haplotypes and Pfcrt gene polymorphisms and the global distribution of the different CQR- Pfcrt haplotypes in endemic and non-endemic regions of P. falciparum malaria have been the subject of extensive study. Despite the fact that the Pfcrt gene is considered to be the primary CQR gene in P. falciparum , several studies have suggested that this may not be the case. Furthermore, there is a poor correlation between the evolutionary implications of the Pfcrt haplotypes and the inferred migration of CQR P. falciparum based on CQR epidemiological surveillance data. The present paper aims to clarify the existing knowledge on the genetic basis of the different CQR- Pfcrt haplotypes that are prevalent in worldwide populations based on the published literature and to analyse the data to generate hypotheses on the genetics and evolution of CQR malaria.

  3. Exact algorithms for haplotype assembly from whole-genome sequence data.

    Science.gov (United States)

    Chen, Zhi-Zhong; Deng, Fei; Wang, Lusheng

    2013-08-15

    Haplotypes play a crucial role in genetic analysis and have many applications such as gene disease diagnoses, association studies, ancestry inference and so forth. The development of DNA sequencing technologies makes it possible to obtain haplotypes from a set of aligned reads originated from both copies of a chromosome of a single individual. This approach is often known as haplotype assembly. Exact algorithms that can give optimal solutions to the haplotype assembly problem are highly demanded. Unfortunately, previous algorithms for this problem either fail to output optimal solutions or take too long time even executed on a PC cluster. We develop an approach to finding optimal solutions for the haplotype assembly problem under the minimum-error-correction (MEC) model. Most of the previous approaches assume that the columns in the input matrix correspond to (putative) heterozygous sites. This all-heterozygous assumption is correct for most columns, but it may be incorrect for a small number of columns. In this article, we consider the MEC model with or without the all-heterozygous assumption. In our approach, we first use new methods to decompose the input read matrix into small independent blocks and then model the problem for each block as an integer linear programming problem, which is then solved by an integer linear programming solver. We have tested our program on a single PC [a Linux (x64) desktop PC with i7-3960X CPU], using the filtered HuRef and the NA 12878 datasets (after applying some variant calling methods). With the all-heterozygous assumption, our approach can optimally solve the whole HuRef data set within a total time of 31 h (26 h for the most difficult block of the 15th chromosome and only 5 h for the other blocks). To our knowledge, this is the first time that MEC optimal solutions are completely obtained for the filtered HuRef dataset. Moreover, in the general case (without the all-heterozygous assumption), for the HuRef dataset our

  4. Beta-globin gene cluster haplotypes of Amerindian populations from the Brazilian Amazon region.

    Science.gov (United States)

    Guerreiro, J F; Figueiredo, M S; Zago, M A

    1994-01-01

    We have determined the beta-globin cluster haplotypes for 80 Indians from four Brazilian Amazon tribes: Kayapó, Wayampí, Wayana-Apalaí, and Arára. The results are analyzed together with 20 Yanomámi previously studied. From 2 to 4 different haplotypes were identified for each tribe, and 7 of the possible 32 haplotypes were found in a sample of 172 chromosomes for which the beta haplotypes were directly determined or derived from family studies. The haplotype distribution does not differ significantly among the five populations. The two most common haplotypes in all tribes were haplotypes 2 and 6, with average frequencies of 0.843 and 0.122, respectively. The genetic affinities between Brazilian Indians and other human populations were evaluated by estimates of genetic distance based on haplotype data. The lowest values were observed in relation to Asians, especially Chinese, Polynesians, and Micronesians.

  5. Molecular characterization of a long range haplotype affecting protein yield and mastitis susceptibility in Norwegian Red cattle

    Directory of Open Access Journals (Sweden)

    Hayes Ben J

    2011-08-01

    Full Text Available Abstract Background Previous fine mapping studies in Norwegian Red cattle (NRC in the region 86-90.4 Mb on Bos taurus chromosome 6 (BTA6 has revealed a quantitative trait locus (QTL for protein yield (PY around 88 Mb and a QTL for clinical mastitis (CM around 90 Mb. The close proximity of these QTLs may partly explain the unfavorable genetic correlation between these two traits in NRC. A long range haplotype covering this region was introduced into the NRC population through the importation of a Holstein-Friesian bull (1606 Frasse from Sweden in the 1970s. It has been suggested that this haplotype has a favorable effect on milk protein content but an unfavorable effect on mastitis susceptibility. Selective breeding for milk production traits is likely to have increased the frequency of this haplotype in the NRC population. Results Association mapping for PY and CM in NRC was performed using genotypes from 556 SNPs throughout the region 86-97 Mb on BTA6 and daughter-yield-deviations (DYDs from 2601 bulls made available from the Norwegian dairy herd recording system. Highest test scores for PY were found for single-nucleotide polymorphisms (SNPs within and surrounding the genes CSN2 and CSN1S2, coding for the β-casein and αS2-casein proteins. High coverage re-sequencing by high throughput sequencing technology enabled molecular characterization of a long range haplotype from 1606 Frasse encompassing these two genes. Haplotype analysis of a large number of descendants from this bull indicated that the haplotype was not markedly disrupted by recombination in this region. The haplotype was associated with both increased milk protein content and increased susceptibility to mastitis, which might explain parts of the observed genetic correlation between PY and CM in NRC. Plausible causal polymorphisms affecting PY were detected in the promoter region and in the 5'-flanking UTR of CSN1S2. These polymorphisms could affect transcription or translation of

  6. Defining Game Mechanics

    DEFF Research Database (Denmark)

    Sicart (Vila), Miguel Angel

    2008-01-01

    This article defins game mechanics in relation to rules and challenges. Game mechanics are methods invoked by agents for interacting with the game world. I apply this definition to a comparative analysis of the games Rez, Every Extend Extra and Shadow of the Colossus that will show the relevance...... of a formal definition of game mechanics. Udgivelsesdato: Dec 2008...

  7. The DAOA/G30 locus and affective disorders: haplotype based association study in a polydiagnostic approach

    Directory of Open Access Journals (Sweden)

    Knapp Michael

    2010-07-01

    Full Text Available Abstract Background The DAOA/G30 (D-amino acid oxidase activator gene complex at chromosomal region 13q32-33 is one of the most intriguing susceptibility loci for the major psychiatric disorders, although there is no consensus about the specific risk alleles or haplotypes across studies. Methods In a case-control sample of German descent (affective psychosis: n = 248; controls: n = 188 we examined seven single nucleotide polymorphisms (SNPs around DAOA/G30 (rs3916966, rs1935058, rs2391191, rs1935062, rs947267, rs3918342, and rs9558575 for genetic association in a polydiagnostic approach (ICD 10; Leonhard's classification. Results No single marker showed evidence of overall association with affective disorder neither in ICD10 nor Leonhard's classification. Haplotype analysis revealed no association with recurrent unipolar depression or bipolar disorder according to ICD10, within Leonhard's classification manic-depression was associated with a 3-locus haplotype (rs2391191, rs1935062, and rs3916966; P = 0.022 and monopolar depression with a 5-locus combination at the DAOA/G30 core region (P = 0.036. Conclusion Our data revealed potential evidence for partially overlapping risk haplotypes at the DAOA/G30 locus in Leonhard's affective psychoses, but do not support a common genetic contribution of the DAOA/G30 gene complex to the pathogenesis of affective disorders.

  8. Genome-wide association studies of mri-defined brain infarcts: Meta-analysis from the charge consortium

    NARCIS (Netherlands)

    S. Debette (Stéphanie); J.C. Bis (Joshua); M. Fornage (Myriam); H.A. Schmid (Herbert); M.A. Ikram (Arfan); S. Sigurdsson (Stefan); G. Heiss (Gerardo); M.V. Struchalin (Maksim); A.V. Smith (Albert Vernon); A. van der Lugt (Aad); C. DeCarli (Charles); T. Lumley (Thomas); D.S. Knopman (David); C. Enzinger (Christian); G. Eiriksdottir (Gudny); P.J. Koudstaal (Peter Jan); A.L. DeStefano (Anita); B.M. Psaty (Bruce); C. Dufouil (Carole); D.J. Catellier (Diane); F. Fazekas (Franz); T. Aspelund (Thor); Y.S. Aulchenko (Yurii); A. Beiser (Alexa); J.I. Rotter (Jerome); C. Tzourio (Christophe); D.K. Shibata (Dean); M. Tscherner (Maria); T.B. Harris (Tamara); F. Rivadeneira Ramirez (Fernando); L.D. Atwood (Larry); K. Rice (Kenneth); R.F. Gottesman (Rebecca); M.A. van Buchem (Mark); A.G. Uitterlinden (André); M. Kelly-Hayes (Margaret); M. Cushman (Mary Ann); Y. Zhu (Yicheng); E.A. Boerwinkle (Eric); V. Gudnason (Vilmundur); A. Hofman (Albert); J.R. Romero (Jose Rafael); M.M.B. Breteler (Monique); R. Schmidt (Reinhold); L.J. Launer (Lenore); W.T. Longstreth Jr

    2010-01-01

    textabstractBackground and Purpose-Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed

  9. PTCH1 gene haplotype association with basal cell carcinoma after transplantation.

    Science.gov (United States)

    Begnini, A; Tessari, G; Turco, A; Malerba, G; Naldi, L; Gotti, E; Boschiero, L; Forni, A; Rugiu, C; Piaserico, S; Fortina, A B; Brunello, A; Cascone, C; Girolomoni, G; Gomez Lira, M

    2010-08-01

    Basal cell carcinoma (BCC) is 10 times more frequent in organ transplant recipients (OTRs) than in the general population. Factors in OTRs conferring increased susceptibility to BCC include ultraviolet radiation exposure, immunosuppression, viral infections such as human papillomavirus, phototype and genetic predisposition. The PTCH1 gene is a negative regulator of the hedgehog pathway, that provides mitogenic signals to basal cells in skin. PTCH1 gene mutations cause naevoid BCC syndrome, and contribute to the development of sporadic BCC and other types of cancers. Associations have been reported between PTCH1 polymorphisms and BCC susceptibility in nontransplanted individuals. To search for novel common polymorphisms in the proximal 5' regulatory region upstream of PTCH1 gene exon 1B, and to investigate the possible association of PTCH1 polymorphisms and haplotypes with BCC risk after organ transplantation. Three PTCH1 single nucleotide polymorphisms (rs2297086, rs2066836 and rs357564) were analysed by restriction fragment length polymorphism analysis in 161 northern Italian OTRs (56 BCC cases and 105 controls). Two regions of the PTCH1 gene promoter were screened by heteroduplex analysis in 30 cases and 30 controls. Single locus analysis showed no significant association. Haplotype T(1686)-T(3944) appeared to confer a significantly higher risk for BCC development (odds ratio 2.98, 95% confidence interval 2.55-3.48; P = 0.001). Two novel rare polymorphisms were identified at positions 176 and 179 of the 5'UTR. Two novel alleles of the -4 (CGG)(n) microsatellite were identified. No association of this microsatellite with BCC was observed. Haplotypes containing T(1686)-T(3944) alleles were shown to be associated with an increased BCC risk in our study population. These data appear to be of great interest for further investigations in a larger group of transplant individuals. Our results do not support the hypothesis that common polymorphisms in the proximal 5

  10. Definably compact groups definable in real closed fields.II

    OpenAIRE

    Barriga, Eliana

    2017-01-01

    We continue the analysis of definably compact groups definable in a real closed field $\\mathcal{R}$. In [3], we proved that for every definably compact definably connected semialgebraic group $G$ over $\\mathcal{R}$ there are a connected $R$-algebraic group $H$, a definable injective map $\\phi$ from a generic definable neighborhood of the identity of $G$ into the group $H\\left(R\\right)$ of $R$-points of $H$ such that $\\phi$ acts as a group homomorphism inside its domain. The above result and o...

  11. Antifolate drug resistance: Novel mutations and haplotype ...

    Indian Academy of Sciences (India)

    N P Sarmah

    2017-09-27

    Sep 27, 2017 ... distribution in dhps and dhfr from Northeast India ... The findings of this study strongly discourage the use SP as a partner drug in ACT. ... led to critical hindrances in controlling of Plasmodium fal- ciparum (Pf) malaria in this part of India. ..... alignment editor and analysis programme for Windows95/98/. NT.

  12. In-depth analysis of protein inference algorithms using multiple search engines and well-defined metrics.

    Science.gov (United States)

    Audain, Enrique; Uszkoreit, Julian; Sachsenberg, Timo; Pfeuffer, Julianus; Liang, Xiao; Hermjakob, Henning; Sanchez, Aniel; Eisenacher, Martin; Reinert, Knut; Tabb, David L; Kohlbacher, Oliver; Perez-Riverol, Yasset

    2017-01-06

    In mass spectrometry-based shotgun proteomics, protein identifications are usually the desired result. However, most of the analytical methods are based on the identification of reliable peptides and not the direct identification of intact proteins. Thus, assembling peptides identified from tandem mass spectra into a list of proteins, referred to as protein inference, is a critical step in proteomics research. Currently, different protein inference algorithms and tools are available for the proteomics community. Here, we evaluated five software tools for protein inference (PIA, ProteinProphet, Fido, ProteinLP, MSBayesPro) using three popular database search engines: Mascot, X!Tandem, and MS-GF+. All the algorithms were evaluated using a highly customizable KNIME workflow using four different public datasets with varying complexities (different sample preparation, species and analytical instruments). We defined a set of quality control metrics to evaluate the performance of each combination of search engines, protein inference algorithm, and parameters on each dataset. We show that the results for complex samples vary not only regarding the actual numbers of reported protein groups but also concerning the actual composition of groups. Furthermore, the robustness of reported proteins when using databases of differing complexities is strongly dependant on the applied inference algorithm. Finally, merging the identifications of multiple search engines does not necessarily increase the number of reported proteins, but does increase the number of peptides per protein and thus can generally be recommended. Protein inference is one of the major challenges in MS-based proteomics nowadays. Currently, there are a vast number of protein inference algorithms and implementations available for the proteomics community. Protein assembly impacts in the final results of the research, the quantitation values and the final claims in the research manuscript. Even though protein

  13. Defining climate modeling user needs: which data are actually required to support impact analysis and adaptation policy development?

    Science.gov (United States)

    Swart, R. J.; Pagé, C.

    2010-12-01

    Until recently, the policy applications of Earth System Models in general and climate models in particular were focusing mainly on the potential future changes in the global and regional climate and attribution of observed changes to anthropogenic activities. Is climate change real? And if so, why do we have to worry about it? Following the broad acceptance of the reality of the risks by the majority of governments, particularly after the publication of IPCC’s 4th Assessment Report and the increasing number of observations of changes in ecological and socio-economic systems that are consistent with the observed climatic changes, governments, companies and other societal groups have started to evaluate their own vulnerability in more detail and to develop adaptation and mitigation strategies. After an early focus on the most vulnerable developing countries, recently, an increasing number of industrialized countries have embarked on the design of adaptation and mitigation plans, or on studies to evaluate the level of climate resilience of their development plans and projects. Which climate data are actually required to effectively support these activities? This paper reports on the efforts of the IS-ENES project, the infrastructure project of the European Network for Earth System Modeling, to address this question. How do we define user needs and can the existing gap between the climate modeling and impact research communities be bridged in support of the ENES long-term strategy? In contrast from the climate modeling community, which has a relatively long history of collaboration facilitated by a relatively uniform subject matter, commonly agreed definitions of key terminology and some level of harmonization of methods, the climate change impacts research community is very diverse and fragmented, using a wide variety of data sources, methods and tools. An additional complicating factor is that researchers working on adaptation usually closely collaborate with non

  14. Inheritance of the 8.1 ancestral haplotype in recurrent pregnancy loss

    DEFF Research Database (Denmark)

    Kolte, Astrid M; Nielsen, Henriette S; Steffensen, Rudi

    2015-01-01

    pleiotropy. It has also been proposed that the survival of long, conserved haplotypes may be due to gestational drive, i.e. selective miscarriage of fetuses who have not inherited the haplotype from a heterozygous mother. Recurrent pregnancy loss (RPL) is defined as three or more consecutive pregnancy losses....... The objective was to test the gestational drive theory for the 8.1AH in women with RPL and their live born children. METHODOLOGY: We investigated the inheritance of the 8.1AH from 82 heterozygous RPL women to 110 live born children. All participants were genotyped for HLA-A, -B and -DRB1 in DNA from EDTA......-treated blood or buccal swaps. Inheritance was compared with a Mendelian inheritance of 50% using a two-sided exact binomial test. RESULTS: We found that 55% of the live born children had inherited the 8.1AH, which was not significantly higher than the expected 50% (P = 0.29). Interestingly, we found a non...

  15. HLA alleles and haplotypes distribution in Dai population in Yunnan province, Southwest China.

    Science.gov (United States)

    Shi, L; Yao, Y F; Shi, L; Matsushita, M; Yu, L; Lin, Q K; Tao, Y F; Oka, T; Chu, J Y; Tokunaga, K

    2010-02-01

    Human leukocyte antigen (HLA) analysis would be a useful tool to trace the origin of modern humans. In this study, we provided the first four digital HLA-A, -B, -C and -DRB1 allele and haplotype data in the Dai ethnic population, which is a unique and representative Kam-Tai-speaking ethnic minority living in the Yunnan province of Southwestern China. Our results showed that the Dai population has unique HLA characteristic that are most closely related to the Southeastern Asia group and similar to the Kam-Tai speaking populations in China and Thailand.

  16. Use of Time-Frequency Analysis and Neural Networks for Mode Identification in a Wireless Software-Defined Radio Approach

    Directory of Open Access Journals (Sweden)

    Matteo Gandetto

    2004-09-01

    Full Text Available The use of time-frequency distributions is proposed as a nonlinear signal processing technique that is combined with a pattern recognition approach to identify superimposed transmission modes in a reconfigurable wireless terminal based on software-defined radio techniques. In particular, a software-defined radio receiver is described aiming at the identification of two coexistent communication modes: frequency hopping code division multiple access and direct sequence code division multiple access. As a case study, two standards, based on the previous modes and operating in the same band (industrial, scientific, and medical, are considered: IEEE WLAN 802.11b (direct sequence and Bluetooth (frequency hopping. Neural classifiers are used to obtain identification results. A comparison between two different neural classifiers is made in terms of relative error frequency.

  17. Finite element analysis in defining the optimal shape and safety factor of retentive clasp arms of removable partial denture

    Directory of Open Access Journals (Sweden)

    Šćepanović Miodrag

    2013-01-01

    Full Text Available Bacground/Aim. Retentive force of removable partial denture (RPD directly depends on elastic force of stretched retentive clasp arms (RCAs. During deflection RCA must have even stress distribution. Safety factor is the concept which can be applied in estimating durability and functionality of RCAs. This study was based on analyzing properties of clasps designed by conventional clasp wax profiles and defining the optimal shapes of RCAs for stress distribution and safety factor aspects. Methods. Computer-aided-design (CAD models of RCAs with simulated properties of materials used for fabrication of RPD cobalt-chromium-molybdenum (CoCrMo alloy, commercially pure titanium (CPTi and polyacetale were analyzed. Results. The research showed that geometrics of Rapidflex profiles from the BIOS concept are defined for designing and modeling RCAs from CoCrMo alloys. I-Bar and Bonihard clasps made from CPTi might have the same design as Co- CrMo clasp only by safety factor aspect, but it is obvious that CPTi are much more flexible, so their shape must be more massive. Polyacetale clasps should not be fabricated by BIOS concept for CoCrMo alloy. A proof for that is the low value of safety factor. Conclusion. The BIOS concept should be used only for RCAs made of CoCrMo alloy and different wax profiles should be used for fabricating clasps of other investigated materials. The contribution of this study may be the improvement of present systems for defining the clasps shapes made from CoCrMo alloys. The more significant application is possibility of creating new concepts in defining shapes of RCA made from CPTi and polyacetale.

  18. Modeling and performance analysis for composite network–compute service provisioning in software-defined cloud environments

    Directory of Open Access Journals (Sweden)

    Qiang Duan

    2015-08-01

    Full Text Available The crucial role of networking in Cloud computing calls for a holistic vision of both networking and computing systems that leads to composite network–compute service provisioning. Software-Defined Network (SDN is a fundamental advancement in networking that enables network programmability. SDN and software-defined compute/storage systems form a Software-Defined Cloud Environment (SDCE that may greatly facilitate composite network–compute service provisioning to Cloud users. Therefore, networking and computing systems need to be modeled and analyzed as composite service provisioning systems in order to obtain thorough understanding about service performance in SDCEs. In this paper, a novel approach for modeling composite network–compute service capabilities and a technique for evaluating composite network–compute service performance are developed. The analytic method proposed in this paper is general and agnostic to service implementation technologies; thus is applicable to a wide variety of network–compute services in SDCEs. The results obtained in this paper provide useful guidelines for federated control and management of networking and computing resources to achieve Cloud service performance guarantees.

  19. Identifying haplotypes for flowering and QTLs for fruit quality in the RosBREED Michigan and Oregon strawberry (Fragaria ×ananassa) breeding sets using pedigree-based analysis [abstract

    Science.gov (United States)

    Strawberry (Fragaria ×ananassa) is consumed for its flavor and health benefits. Over the last two decades, several quantitative trait loci (QTL) analysis studies for consumer traits were conducted using low-density genetic maps. The previous studies utilized low-throughput genotyping methodologies. ...

  20. Exploring and Harnessing Haplotype Diversity to Improve Yield Stability in Crops

    Directory of Open Access Journals (Sweden)

    Lunwen Qian

    2017-09-01

    Full Text Available In order to meet future food, feed, fiber, and bioenergy demands, global yields of all major crops need to be increased significantly. At the same time, the increasing frequency of extreme weather events such as heat and drought necessitates improvements in the environmental resilience of modern crop cultivars. Achieving sustainably increase yields implies rapid improvement of quantitative traits with a very complex genetic architecture and strong environmental interaction. Latest advances in genome analysis technologies today provide molecular information at an ultrahigh resolution, revolutionizing crop genomic research, and paving the way for advanced quantitative genetic approaches. These include highly detailed assessment of population structure and genotypic diversity, facilitating the identification of selective sweeps and signatures of directional selection, dissection of genetic variants that underlie important agronomic traits, and genomic selection (GS strategies that not only consider major-effect genes. Single-nucleotide polymorphism (SNP markers today represent the genotyping system of choice for crop genetic studies because they occur abundantly in plant genomes and are easy to detect. SNPs are typically biallelic, however, hence their information content compared to multiallelic markers is low, limiting the resolution at which SNP–trait relationships can be delineated. An efficient way to overcome this limitation is to construct haplotypes based on linkage disequilibrium, one of the most important features influencing genetic analyses of crop genomes. Here, we give an overview of the latest advances in genomics-based haplotype analyses in crops, highlighting their importance in the context of polyploidy and genome evolution, linkage drag, and co-selection. We provide examples of how haplotype analyses can complement well-established quantitative genetics frameworks, such as quantitative trait analysis and GS, ultimately

  1. Exploring and Harnessing Haplotype Diversity to Improve Yield Stability in Crops.

    Science.gov (United States)

    Qian, Lunwen; Hickey, Lee T; Stahl, Andreas; Werner, Christian R; Hayes, Ben; Snowdon, Rod J; Voss-Fels, Kai P

    2017-01-01

    In order to meet future food, feed, fiber, and bioenergy demands, global yields of all major crops need to be increased significantly. At the same time, the increasing frequency of extreme weather events such as heat and drought necessitates improvements in the environmental resilience of modern crop cultivars. Achieving sustainably increase yields implies rapid improvement of quantitative traits with a very complex genetic architecture and strong environmental interaction. Latest advances in genome analysis technologies today provide molecular information at an ultrahigh resolution, revolutionizing crop genomic research, and paving the way for advanced quantitative genetic approaches. These include highly detailed assessment of population structure and genotypic diversity, facilitating the identification of selective sweeps and signatures of directional selection, dissection of genetic variants that underlie important agronomic traits, and genomic selection (GS) strategies that not only consider major-effect genes. Single-nucleotide polymorphism (SNP) markers today represent the genotyping system of choice for crop genetic studies because they occur abundantly in plant genomes and are easy to detect. SNPs are typically biallelic, however, hence their information content compared to multiallelic markers is low, limiting the resolution at which SNP-trait relationships can be delineated. An efficient way to overcome this limitation is to construct haplotypes based on linkage disequilibrium, one of the most important features influencing genetic analyses of crop genomes. Here, we give an overview of the latest advances in genomics-based haplotype analyses in crops, highlighting their importance in the context of polyploidy and genome evolution, linkage drag, and co-selection. We provide examples of how haplotype analyses can complement well-established quantitative genetics frameworks, such as quantitative trait analysis and GS, ultimately providing an effective tool

  2. Haplotype and genetic relationship of 27 Y-STR loci in Han population of Chaoshan area of China

    Directory of Open Access Journals (Sweden)

    Qing-hua TIAN

    2017-04-01

    Full Text Available Objective  To investigate the genetic polymorphisms of 27 Y-chromosomal short tandem repeats (Y-STR loci included in Yfiler® Plus kit in Han population of Chaoshan area, and explore the population genetic relationships and evaluate its application value on forensic medicine. Methods  By detecting 795 unrelated Chaoshan Han males with Yfiler® Plus kit, haplotype frequencies and population genetics parameters of the 27 Y-STR loci were statistically analyzed and compared with available data of other populations from different races and regions for analyzing the genetic distance and clustering relation of Chaoshan Han population. Results  Seven hundred and eighty-seven different haplotypes were observed in 795 unrelated male individuals, of which 779 haplotypes were unique, and 8 haplotypes occurred twice. The haplotype diversity (HD was 0.999975 with discriminative capacity (DC of 98.99%. The gene diversity (GD at the 27 Y-STR loci ranged from 0.3637(DYS391 to 0.9559(DYS385a/b. Comparing with Asian reference populations, the genetic distance (Rst between Chaoshan Han and Guangdong Han was the smallest (0.0036, while it was relatively larger between Chaoshan Han and Gansu Tibetan population (0.0935. The multi-dimensional scaling (MDS plot based on Rst values was similar to the results of clustering analysis. Conclusion  Multiplex detection of the 27 Y-STR loci reveals a highly polymorphic genetic distribution in Chaoshan Han population, which demonstrates the important significance of Yfiler® Plus kit for establishing a Y-STR database, studying population genetics, and for good practice in forensic medicine. DOI: 10.11855/j.issn.0577-7402.2017.03.08

  3. Two extended haplotype blocks are associated with adaptation to high altitude habitats in East African honey bees.

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    Andreas Wallberg

    2017-05-01

    Full Text Available Understanding the genetic basis of adaption is a central task in biology. Populations of the honey bee Apis mellifera that inhabit the mountain forests of East Africa differ in behavior and morphology from those inhabiting the surrounding lowland savannahs, which likely reflects adaptation to these habitats. We performed whole genome sequencing on 39 samples of highland and lowland bees from two pairs of populations to determine their evolutionary affinities and identify the genetic basis of these putative adaptations. We find that in general, levels of genetic differentiation between highland and lowland populations are very low, consistent with them being a single panmictic population. However, we identify two loci on chromosomes 7 and 9, each several hundred kilobases in length, which exhibit near fixation for different haplotypes between highland and lowland populations. The highland haplotypes at these loci are extremely rare in samples from the rest of the world. Patterns of segregation of genetic variants suggest that recombination between haplotypes at each locus is suppressed, indicating that they comprise independent structural variants. The haplotype on chromosome 7 harbors nearly all octopamine receptor genes in the honey bee genome. These have a role in learning and foraging behavior in honey bees and are strong candidates for adaptation to highland habitats. Molecular analysis of a putative breakpoint indicates that it may disrupt the coding sequence of one of these genes. Divergence between the highland and lowland haplotypes at both loci is extremely high suggesting that they are ancient balanced polymorphisms that greatly predate divergence between the extant honey bee subspecies.

  4. Two extended haplotype blocks are associated with adaptation to high altitude habitats in East African honey bees

    Science.gov (United States)

    Schöning, Caspar

    2017-01-01

    Understanding the genetic basis of adaption is a central task in biology. Populations of the honey bee Apis mellifera that inhabit the mountain forests of East Africa differ in behavior and morphology from those inhabiting the surrounding lowland savannahs, which likely reflects adaptation to these habitats. We performed whole genome sequencing on 39 samples of highland and lowland bees from two pairs of populations to determine their evolutionary affinities and identify the genetic basis of these putative adaptations. We find that in general, levels of genetic differentiation between highland and lowland populations are very low, consistent with them being a single panmictic population. However, we identify two loci on chromosomes 7 and 9, each several hundred kilobases in length, which exhibit near fixation for different haplotypes between highland and lowland populations. The highland haplotypes at these loci are extremely rare in samples from the rest of the world. Patterns of segregation of genetic variants suggest that recombination between haplotypes at each locus is suppressed, indicating that they comprise independent structural variants. The haplotype on chromosome 7 harbors nearly all octopamine receptor genes in the honey bee genome. These have a role in learning and foraging behavior in honey bees and are strong candidates for adaptation to highland habitats. Molecular analysis of a putative breakpoint indicates that it may disrupt the coding sequence of one of these genes. Divergence between the highland and lowland haplotypes at both loci is extremely high suggesting that they are ancient balanced polymorphisms that greatly predate divergence between the extant honey bee subspecies. PMID:28542163

  5. Analysis of Luminex-based algorithms to define unacceptable HLA antibodies in CDC-crossmatch negative kidney transplant recipients.

    Science.gov (United States)

    Zecher, Daniel; Bach, Christian; Preiss, Adrian; Staudner, Christoph; Utpatel, Kirsten; Evert, Matthias; Jung, Bettina; Bergler, Tobias; Böger, Carsten A; Spriewald, Bernd M; Banas, Bernhard

    2018-02-20

    HLA-specific antibodies detected by solid phase assays are increasingly used to define unacceptable HLA antigen mismatches (UAM) prior to renal transplantation. The accuracy of this approach is unclear. Day of transplant sera from 211 CDC-crossmatch-negative patients were retrospectively analyzed for donor-specific anti-HLA antibodies (DSA) using Luminex technology. HLA were defined as UAM if DSA had mean fluorescence intensity above (I) 3000 (patients retransplanted and those with DSA against HLA class I and II) or 5000 (all other patients), (II) 5000 for HLA A, B and DR and 10,000 for HLA DQ or (III) 10,000 (all HLA). We then studied the accuracy of these algorithms to identify patients with antibody-mediated rejection (AMR) and graft loss. UAM were also determined in 256 transplant candidates and virtual panel-reactive antibody (vPRA) levels calculated. At transplantation, 67/211 patients had DSA. Of these, 31 (algorithm I), 24 (II) and 17 (III) had UAM. 9 (I and II) and 8 (III) of 11 early AMR episodes and 7 (I), 6 (II) and 5 (III) of 9 graft losses occurred in UAM-positive patients during 4.9 years of follow-up. Algorithms (I) and (II) identified patients with persistently lower GFR even in the absence of overt AMR. 23-33% of waiting list patients had UAM with median vPRA of 69.2-79.1%. Algorithms (I) and (II) had comparable efficacy but were superior to (III) in identifying at-risk patients at an acceptable false positive rate. However, Luminex-defined UAM significantly restrict the donor pool of affected patients, which might prolong waiting time.

  6. Bayesian population structure analysis reveals presence of phylogeographically specific sublineages within previously ill-defined T group of Mycobacterium tuberculosis.

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    Yann Reynaud

    Full Text Available Mycobacterium tuberculosis genetic structure, and evolutionary history have been studied for years by several genotyping approaches, but delineation of a few sublineages remains controversial and needs better characterization. This is particularly the case of T group within lineage 4 (L4 which was first described using spoligotyping to pool together a number of strains with ill-defined signatures. Although T strains were not traditionally considered as a real phylogenetic group, they did contain a few phylogenetically meaningful sublineages as shown using SNPs. We therefore decided to investigate if this observation could be corroborated using other robust genetic markers. We consequently made a first assessment of genetic structure using 24-loci MIRU-VNTRs data extracted from the SITVIT2 database (n = 607 clinical isolates collected in Russia, Albania, Turkey, Iraq, Brazil and China. Combining Minimum Spanning Trees and Bayesian population structure analyses (using STRUCTURE and TESS softwares, we distinctly identified eight tentative phylogenetic groups (T1-T8 with a remarkable correlation with geographical origin. We further compared the present structure observed with other L4 sublineages (n = 416 clinical isolates belonging to LAM, Haarlem, X, S sublineages, and showed that 5 out of 8 T groups seemed phylogeographically well-defined as opposed to the remaining 3 groups that partially mixed with other L4 isolates. These results provide with novel evidence about phylogeographically specificity of a proportion of ill-defined T group of M. tuberculosis. The genetic structure observed will now be further validated on an enlarged worldwide dataset using Whole Genome Sequencing (WGS.

  7. Defining the RNA Internal Loops Preferred by Benzimidazole Derivatives via Two-Dimensional Combinatorial Screening and Computational Analysis

    Science.gov (United States)

    Velagapudi, Sai Pradeep; Seedhouse, Steven J.; French, Jonathan

    2011-01-01

    RNA is an important therapeutic target, however, RNA targets are generally underexploited due to a lack of understanding of the small molecules that bind RNA and the RNA motifs that bind small molecules. Herein, we describe the identification of the RNA internal loops derived from a 4096-member 3×3 nucleotide loop library that are the most specific and highest affinity binders to a series of four designer, drug-like benzimidazoles. These studies establish a potentially general protocol to define the highest affinity and most specific RNA motif targets for heterocyclic small molecules. Such information could be used to target functionally important RNAs in genomic sequence. PMID:21604752

  8. A Dynamic Programming Algorithm for the k-Haplotyping Problem

    Institute of Scientific and Technical Information of China (English)

    Zhen-ping Li; Ling-yun Wu; Yu-ying Zhao; Xiang-sun Zhang

    2006-01-01

    The Minimum Fragments Removal (MFR) problem is one of the haplotyping problems: given a set of fragments, remove the minimum number of fragments so that the resulting fragments can be partitioned into k classes of non-conflicting subsets. In this paper, we formulate the k-MFR problem as an integer linear programming problem, and develop a dynamic programming approach to solve the k-MFR problem for both the gapless and gap cases.

  9. Combinatorial aspects of genome rearrangements and haplotype networks

    OpenAIRE

    Labarre , Anthony

    2008-01-01

    The dissertation covers two problems motivated by computational biology: genome rearrangements, and haplotype networks. Genome rearrangement problems are a particular case of edit distance problems, where one seeks to transform two given objects into one another using as few operations as possible, with the additional constraint that the set of allowed operations is fixed beforehand; we are also interested in computing the corresponding distances between those objects, i.e. merely computing t...

  10. The effect of using genealogy-based haplotypes for genomic prediction.

    Science.gov (United States)

    Edriss, Vahid; Fernando, Rohan L; Su, Guosheng; Lund, Mogens S; Guldbrandtsen, Bernt

    2013-03-06

    Genomic prediction uses two sources of information: linkage disequilibrium between markers and quantitative trait loci, and additive genetic relationships between individuals. One way to increase the accuracy of genomic prediction is to capture more linkage disequilibrium by regression on haplotypes instead of regression on individual markers. The aim of this study was to investigate the accuracy of genomic prediction using haplotypes based on local genealogy information. A total of 4429 Danish Holstein bulls were genotyped with the 50K SNP chip. Haplotypes were constructed using local genealogical trees. Effects of haplotype covariates were estimated with two types of prediction models: (1) assuming that effects had the same distribution for all haplotype covariates, i.e. the GBLUP method and (2) assuming that a large proportion (π) of the haplotype covariates had zero effect, i.e. a Bayesian mixture method. About 7.5 times more covariate effects were estimated when fitting haplotypes based on local genealogical trees compared to fitting individuals markers. Genealogy-based haplotype clustering slightly increased the accuracy of genomic prediction and, in some cases, decreased the bias of prediction. With the Bayesian method, accuracy of prediction was less sensitive to parameter π when fitting haplotypes compared to fitting markers. Use of haplotypes based on genealogy can slightly increase the accuracy of genomic prediction. Improved methods to cluster the haplotypes constructed from local genealogy could lead to additional gains in accuracy.

  11. Haplotype reconstruction error as a classical misclassification problem: introducing sensitivity and specificity as error measures.

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    Claudia Lamina

    Full Text Available BACKGROUND: Statistically reconstructing haplotypes from single nucleotide polymorphism (SNP genotypes, can lead to falsely classified haplotypes. This can be an issue when interpreting haplotype association results or when selecting subjects with certain haplotypes for subsequent functional studies. It was our aim to quantify haplotype reconstruction error and to provide tools for it. METHODS AND RESULTS: By numerous simulation scenarios, we systematically investigated several error measures, including discrepancy, error rate, and R(2, and introduced the sensitivity and specificity to this context. We exemplified several measures in the KORA study, a large population-based study from Southern Germany. We find that the specificity is slightly reduced only for common haplotypes, while the sensitivity was decreased for some, but not all rare haplotypes. The overall error rate was generally increasing with increasing number of loci, increasing minor allele frequency of SNPs, decreasing correlation between the alleles and increasing ambiguity. CONCLUSIONS: We conclude that, with the analytical approach presented here, haplotype-specific error measures can be computed to gain insight into the haplotype uncertainty. This method provides the information, if a specific risk haplotype can be expected to be reconstructed with rather no or high misclassification and thus on the magnitude of expected bias in association estimates. We also illustrate that sensitivity and specificity separate two dimensions of the haplotype reconstruction error, which completely describe the misclassification matrix and thus provide the prerequisite for methods accounting for misclassification.

  12. Defining the Medical Intensive Care Unit in the Words of Patients and Their Family Members: A Freelisting Analysis.

    Science.gov (United States)

    Auriemma, Catherine L; Lyon, Sarah M; Strelec, Lauren E; Kent, Saida; Barg, Frances K; Halpern, Scott D

    2015-07-01

    No validated conceptual framework exists for understanding the outcomes of patient- and family-centered care in critical care. To explore the meaning of intensive care unit among patients and their families by using freelisting. The phrase intensive care unit was used to prompt freelisting among intensive care unit patients and patients' family members. Freelisting is an anthropological technique in which individuals define a domain by listing all words that come to mind in response to a topic. Salience scores, derived from the frequency with which a word was mentioned, the order in which it was mentioned, and the length of each list, were calculated and analyzed. Among the 45 participants, many words were salient to both patients and patients' family members. Words salient solely for patients included consciousness, getting better, noisy, and personal care. Words salient solely for family members included sadness, busy, professional, and hope. The words suffering, busy, and team were salient solely for family members of patients who lived, whereas sadness, professionals, and hope were salient solely for family members of patients who died. The words caring and death were salient for both groups. Intensive care unit patients and their families define intensive care unit by using words to describe sickness, caring, medical staff, emotional states, and physical qualities of the unit. The results validate the importance of these topics among patients and their families in the intensive care unit and illustrate the usefulness of freelisting in critical care research. ©2015 American Association of Critical-Care Nurses.

  13. Inflammation, insulin resistance, and diabetes--Mendelian randomization using CRP haplotypes points upstream.

    Directory of Open Access Journals (Sweden)

    Eric J Brunner

    2008-08-01

    Full Text Available Raised C-reactive protein (CRP is a risk factor for type 2 diabetes. According to the Mendelian randomization method, the association is likely to be causal if genetic variants that affect CRP level are associated with markers of diabetes development and diabetes. Our objective was to examine the nature of the association between CRP phenotype and diabetes development using CRP haplotypes as instrumental variables.We genotyped three tagging SNPs (CRP + 2302G > A; CRP + 1444T > C; CRP + 4899T > G in the CRP gene and measured serum CRP in 5,274 men and women at mean ages 49 and 61 y (Whitehall II Study. Homeostasis model assessment-insulin resistance (HOMA-IR and hemoglobin A1c (HbA1c were measured at age 61 y. Diabetes was ascertained by glucose tolerance test and self-report. Common major haplotypes were strongly associated with serum CRP levels, but unrelated to obesity, blood pressure, and socioeconomic position, which may confound the association between CRP and diabetes risk. Serum CRP was associated with these potential confounding factors. After adjustment for age and sex, baseline serum CRP was associated with incident diabetes (hazard ratio = 1.39 [95% confidence interval 1.29-1.51], HOMA-IR, and HbA1c, but the associations were considerably attenuated on adjustment for potential confounding factors. In contrast, CRP haplotypes were not associated with HOMA-IR or HbA1c (p = 0.52-0.92. The associations of CRP with HOMA-IR and HbA1c were all null when examined using instrumental variables analysis, with genetic variants as the instrument for serum CRP. Instrumental variables estimates differed from the directly observed associations (p = 0.007-0.11. Pooled analysis of CRP haplotypes and diabetes in Whitehall II and Northwick Park Heart Study II produced null findings (p = 0.25-0.88. Analyses based on the Wellcome Trust Case Control Consortium (1,923 diabetes cases, 2,932 controls using three SNPs in tight linkage disequilibrium with our

  14. Overview of worldwide diversity of Diaphorina citri Kuwayama mitochondrial cytochrome oxidase 1 haplotypes: two Old World lineages and a New World invasion

    Science.gov (United States)

    Boykin, L.M.; De Barro, P.; Hall, D.G.; Hunter, W.B.; McKenzie, C.L.; Powell, C.A.; Shatters, R.G.

    2012-01-01

    Relationships among worldwide collections of Diaphorina citri (Asian citrus psyllid) were analyzed using mitochondrial cytochrome oxidase I (mtCOI) haplotypes from novel primers. Sequences were produced from PCR amplicons of an 821bp portion of the mtCOI gene using D. citri specific primers, derived from an existing EST library. An alignment was constructed using 612bps of this fragment and consisted of 212 individuals from 52 collections representing 15 countries. There were a total of eight polymorphic sites that separated the sequences into eight different haplotypes (Dcit-1 through Dcit-8). Phylogenetic network analysis using the statistical parsimony software, TCS, suggests two major haplotype groups with preliminary geographic bias between southwestern Asia (SWA) and southeastern Asia (SEA). The recent (within the last 15 to 25 years) invasion into the New World originated from only the SWA group in the northern hemisphere (USA and Mexico) and from both the SEA and SWA groups in the southern hemisphere (Brazil). In only one case, Reunion Island, did haplotypes from both the SEA and SWA group appear in the same location. In Brazil, both groups were present, but in separate locations. The Dcit-1 SWA haplotype was the most frequently encountered, including ~50% of the countries sampled and 87% of the total sequences obtained from India, Pakistan and Saudi Arabia. The second most frequently encountered haplotype, Dcit-2, the basis of the SEA group, represented ~50% of the countries and contained most of the sequences from Southeast Asia and China. Interestingly, only the Caribbean collections (Puerto Rico and Guadeloupe) represented a unique haplotype not found in other countries, indicating no relationship between the USA (Florida) and Caribbean introductions. There is no evidence for cryptic speciation for D. citri based on the COI region included in this study. PMID:22717059

  15. Haplotypes in the APOA1-C3-A4-A5 gene cluster affect plasma lipids in both humans and baboons

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Qian-fei; Liu, Xin; O' Connell, Jeff; Peng, Ze; Krauss, Ronald M.; Rainwater, David L.; VandeBerg, John L.; Rubin, Edward M.; Cheng, Jan-Fang; Pennacchio, Len A.

    2003-09-15

    Genetic studies in non-human primates serve as a potential strategy for identifying genomic intervals where polymorphisms impact upon human disease-related phenotypes. It remains unclear, however, whether independently arising polymorphisms in orthologous regions of non-human primates leads to similar variation in a quantitative trait found in both species. To explore this paradigm, we studied a baboon apolipoprotein gene cluster (APOA1/C3/A4/A5) for which the human gene orthologs have well established roles in influencing plasma HDL-cholesterol and triglyceride concentrations. Our extensive polymorphism analysis of this 68 kb gene cluster in 96 pedigreed baboons identified several haplotype blocks each with limited diversity, consistent with haplotype findings in humans. To determine whether baboons, like humans, also have particular haplotypes associated with lipid phenotypes, we genotyped 634 well characterized baboons using 16 haplotype tagging SNPs. Genetic analysis of single SNPs, as well as haplotypes, revealed an association of APOA5 and APOC3 variants with HDL cholesterol and triglyceride concentrations, respectively. Thus, independent variation in orthologous genomic intervals does associate with similar quantitative lipid traits in both species, supporting the possibility of uncovering human QTL genes in a highly controlled non-human primate model.

  16. Serpin peptidase inhibitor (SERPINB5) haplotypes are associated with susceptibility to hepatocellular carcinoma

    Science.gov (United States)

    Yang, Shun-Fa; Yeh, Chao-Bin; Chou, Ying-Erh; Lee, Hsiang-Lin; Liu, Yu-Fan

    2016-05-01

    Hepatocellular carcinoma (HCC) represents the second leading cause of cancer-related death worldwide. The serpin peptidase inhibitor SERPINB5 is a tumour-suppressor gene that promotes the development of various cancers in humans. However, whether SERPINB5 gene variants play a role in HCC susceptibility remains unknown. In this study, we genotyped 6 SNPs of the SERPINB5 gene in an independent cohort from a replicate population comprising 302 cases and 590 controls. Additionally, patients who had at least one rs2289520 C allele in SERPINB5 tended to exhibit better liver function than patients with genotype GG (Child-Pugh grade A vs. B or C; P = 0.047). Next, haplotype blocks were reconstructed according to the linkage disequilibrium structure of the SERPINB5 gene. A haplotype “C-C-C” (rs17071138 + rs3744941 + rs8089204) in SERPINB5-correlated promoter showed a significant association with an increased HCC risk (AOR = 1.450 P = 0.031). Haplotypes “T-C-A” and “C-C-C” (rs2289519 + rs2289520 + rs1455555) located in the SERPINB5 coding region had a decreased (AOR = 0.744 P = 0.031) and increased (AOR = 1.981 P = 0.001) HCC risk, respectively. Finally, an additional integrated in silico analysis confirmed that these SNPs affected SERPINB5 expression and protein stability, which significantly correlated with tumour expression and subsequently with tumour development and aggressiveness. Taken together, our findings regarding these biomarkers provide a prediction model for risk assessment.

  17. Worldwide genealogy of Entamoeba histolytica: an overview to understand haplotype distribution and infection outcome.

    Science.gov (United States)

    Zermeño, Valeria; Ximénez, Cecilia; Morán, Patricia; Valadez, Alicia; Valenzuela, Olivia; Rascón, Edgar; Diaz, Daniel; Cerritos, René

    2013-07-01

    Although Entamoeba histolytica is one of the most prevalent intestinal parasites, how the different strains of this species are distributed all over the world and how different genotypes are associated with the infection outcome are yet to be fully understood. Recently, the use of a number of molecular markers has made the characterization of several genotypes in those regions with high incidence of amoebiasis possible. This work proposes the first genealogy of E. histolytica, with an haplotype network based on two tRNA gene-linked array of Short Tandem Repeats (STRs) reported until today, and 47 sequences from 39 new isolates of Mexican Amoebic Liver Abscesses (ALA) samples. One hundred and three sequences were obtained from D-A locus, their information about the geographic region of isolation as well as clinical diagnosis were also collected. One hundred and five sequences from N-K2 locus were also obtained as well as the region of isolation, but the information about clinical diagnosis was not available in all cases. The most abundant and widely distributed haplotype in the world is the one of E. histolytica HM1:IMSS strain. This was found in Mexico, Bangladesh, Japan, China and USA and is associated to symptomatic patients as well as asymptomatic cyst passers. Many other haplotypes were found only in a single country. Both genealogies suggest that there are no lineages within the networks that may be related to a particular geographic region or infection outcome. A concatenated analysis of the two molecular markers revealed 12 different combinations, which suggests the possibility of genetic recombination events. The present study is the first to propose a global genealogy of this species and suggests that there are still many genotypes to be discovered. The genotyping of new isolates will help to understand the great diversity and genetic structure of this parasite. Copyright © 2013 Elsevier B.V. All rights reserved.

  18. Three-dimensional lithographically-defined organotypic tissue arrays for quantitative analysis of morphogenesis and neoplastic progression

    Energy Technology Data Exchange (ETDEWEB)

    Nelson, Celeste M.; Inman, Jamie L.; Bissell, Mina J.

    2008-02-13

    Here we describe a simple micromolding method to construct three-dimensional arrays of organotypic epithelial tissue structures that approximate in vivo histology. An elastomeric stamp containing an array of posts of defined geometry and spacing is used to mold microscale cavities into the surface of type I collagen gels. Epithelial cells are seeded into the cavities and covered with a second layer of collagen. The cells reorganize into hollow tissues corresponding to the geometry of the cavities. Patterned tissue arrays can be produced in 3-4 h and will undergo morphogenesis over the following one to three days. The protocol can easily be adapted to study a variety of tissues and aspects of normal and neoplastic development.

  19. Nucleotide polymorphisms and haplotype diversity of RTCS gene in China elite maize inbred lines.

    Directory of Open Access Journals (Sweden)

    Enying Zhang

    Full Text Available The maize RTCS gene, encoding a LOB domain transcription factor, plays important roles in the initiation of embryonic seminal and postembryonic shoot-borne root. In this study, the genomic sequences of this gene in 73 China elite inbred lines, including 63 lines from 5 temperate heteroric groups and 10 tropic germplasms, were obtained, and the nucleotide polymorphisms and haplotype diversity were detected. A total of 63 sequence variants, including 44 SNPs and 19 indels, were identified at this locus, and most of them were found to be located in the regions of UTR and intron. The coding region of this gene in all tested inbred lines carried 14 haplotypes, which encoding 7 deferring RTCS proteins. Analysis of the polymorphism sites revealed that at least 6 recombination events have occurred. Among all 6 groups tested, only the P heterotic group had a much lower nucleotide diversity than the whole set, and selection analysis also revealed that only this group was under strong negative selection. However, the set of Huangzaosi and its derived lines possessed a higher nucleotide diversity than the whole set, and no selection signal were identified.

  20. Rapid DNA haplotyping using a multiplex heteroduplex approach: Application to Duchenne muscula dystrophy carrier detection

    Energy Technology Data Exchange (ETDEWEB)

    Prior, T.W.; Wenger, G.D.; Moore, J. [Ohio State Univ., Columbus, OH (United States)] [and others

    1994-09-01

    A new strategy has been developed for rapid haplotype analysis. It is based on an initial multiplex amplification of several polymorphic sites, followed by heteroduplex detection. Heteroduplexes formed between two different alleles are detected because they migrate differently than the corresponding homoduplexes in Hydrolink-MDE gel. The method is simple, rapid, does not depend on specific sequences such as restriction enzyme sites or CA boxes and does not require the use of isotope. This approach has been tested using 12 commonly occurring polymorphisms spanning the dystrophin gene as a model. We describe the use of the method to assign the carrier status of females in Duchenne muscular dystrophy (DMD) pedigrees. As a result of expanding the number of detectable polymorphisms throughout the dystrophin gene, we show how the method can easily be combined with dinucleotide analysis to improve the accuracy of carrier detection in the nondeletion cases. The technique is also shown to be used as an effective screen for improving carrier detection in several families with deletions. The finding of heterozygosity within the deletion identifies the at-risk female as a noncarrier. Using this method, we have identified and incorporated 3 new dystrophin polymorphisms (one of which in exon 16 is unique to African Americans). The method may be used other genetic diseases when mutations are unknown, or there are few dinucleotide markers in the gene proximity, or for the identification of haplotype backgrounds of mutant alleles.

  1. Software Defined Cyberinfrastructure

    Energy Technology Data Exchange (ETDEWEB)

    Foster, Ian; Blaiszik, Ben; Chard, Kyle; Chard, Ryan

    2017-07-17

    Within and across thousands of science labs, researchers and students struggle to manage data produced in experiments, simulations, and analyses. Largely manual research data lifecycle management processes mean that much time is wasted, research results are often irreproducible, and data sharing and reuse remain rare. In response, we propose a new approach to data lifecycle management in which researchers are empowered to define the actions to be performed at individual storage systems when data are created or modified: actions such as analysis, transformation, copying, and publication. We term this approach software-defined cyberinfrastructure because users can implement powerful data management policies by deploying rules to local storage systems, much as software-defined networking allows users to configure networks by deploying rules to switches.We argue that this approach can enable a new class of responsive distributed storage infrastructure that will accelerate research innovation by allowing any researcher to associate data workflows with data sources, whether local or remote, for such purposes as data ingest, characterization, indexing, and sharing. We report on early experiments with this approach in the context of experimental science, in which a simple if-trigger-then-action (IFTA) notation is used to define rules.

  2. The Systemic Lupus Erythematosus IRF5 Risk Haplotype Is Associated with Systemic Sclerosis

    Science.gov (United States)

    Beretta, Lorenzo; Simeón, Carmen P.; Carreira, Patricia E.; Callejas, José Luis; Fernández-Castro, Mónica; Sáez-Comet, Luis; Beltrán, Emma; Camps, María Teresa; Egurbide, María Victoria; Airó, Paolo; Scorza, Raffaella; Lunardi, Claudio; Hunzelmann, Nicolas; Riemekasten, Gabriela; Witte, Torsten; Kreuter, Alexander; Distler, Jörg H. W.; Madhok, Rajan; Shiels, Paul; van Laar, Jacob M.; Fonseca, Carmen; Denton, Christopher; Herrick, Ariane; Worthington, Jane; Schuerwegh, Annemie J.; Vonk, Madelon C.; Voskuyl, Alexandre E.; Radstake, Timothy R. D. J.; Martín, Javier

    2013-01-01

    Systemic sclerosis (SSc) is a fibrotic autoimmune disease in which the genetic component plays an important role. One of the strongest SSc association signals outside the human leukocyte antigen (HLA) region corresponds to interferon (IFN) regulatory factor 5 (IRF5), a major regulator of the type I IFN pathway. In this study we aimed to evaluate whether three different haplotypic blocks within this locus, which have been shown to alter the protein function influencing systemic lupus erythematosus (SLE) susceptibility, are involved in SSc susceptibility and clinical phenotypes. For that purpose, we genotyped one representative single-nucleotide polymorphism (SNP) of each block (rs10488631, rs2004640, and rs4728142) in a total of 3,361 SSc patients and 4,012 unaffected controls of Caucasian origin from Spain, Germany, The Netherlands, Italy and United Kingdom. A meta-analysis of the allele frequencies was performed to analyse the overall effect of these IRF5 genetic variants on SSc. Allelic combination and dependency tests were also carried out. The three SNPs showed strong associations with the global disease (rs4728142: P  = 1.34×10−8, OR  = 1.22, CI 95%  = 1.14–1.30; rs2004640: P  = 4.60×10−7, OR  = 0.84, CI 95%  = 0.78–0.90; rs10488631: P  = 7.53×10−20, OR  = 1.63, CI 95%  = 1.47–1.81). However, the association of rs2004640 with SSc was not independent of rs4728142 (conditioned P  = 0.598). The haplotype containing the risk alleles (rs4728142*A-rs2004640*T-rs10488631*C: P  = 9.04×10−22, OR  = 1.75, CI 95%  = 1.56–1.97) better explained the observed association (likelihood P-value  = 1.48×10−4), suggesting an additive effect of the three haplotypic blocks. No statistical significance was observed in the comparisons amongst SSc patients with and without the main clinical characteristics. Our data clearly indicate that the SLE risk haplotype also influences SSc predisposition, and that

  3. Pros and cons of conjoint analysis of discrete choice experiments to define classification and response criteria in rheumatology.

    Science.gov (United States)

    Taylor, William J

    2016-03-01

    Conjoint analysis of choice or preference data has been used in marketing for over 40 years but has appeared in healthcare settings much more recently. It may be a useful technique for applications within the rheumatology field. Conjoint analysis in rheumatology contexts has mainly used the approaches implemented in 1000Minds Ltd, Dunedin, New Zealand, Sawtooth Software, Orem UT, USA. Examples include classification criteria, composite response criteria, service prioritization tools and utilities assessment. Limitations imposed by very many attributes can be managed using new techniques. Conjoint analysis studies of classification and response criteria suggest that the assumption of equal weighting of attributes cannot be met, which challenges traditional approaches to composite criteria construction. Weights elicited through choice experiments with experts can derive more accurate classification criteria, than unweighted criteria. Studies that find significant variation in attribute weights for composite response criteria for gout make construction of such criteria problematic. Better understanding of various multiattribute phenomena is likely to increase with increased use of conjoint analysis, especially when the attributes concern individual perceptions or opinions. In addition to classification criteria, some applications for conjoint analysis that are emerging in rheumatology include prioritization tools, remission criteria, and utilities for life areas.

  4. Decision analysis to define the optimal management of athletes with anomalous aortic origin of a coronary artery.

    Science.gov (United States)

    Mery, Carlos M; Lopez, Keila N; Molossi, Silvana; Sexson-Tejtel, S Kristen; Krishnamurthy, Rajesh; McKenzie, E Dean; Fraser, Charles D; Cantor, Scott B

    2016-11-01

    The goal of this study was to use decision analysis to evaluate the impact of varying uncertainties on the outcomes of patients with anomalous aortic origin of a coronary artery. Two separate decision analysis models were created: one for anomalous left coronary artery (ALCA) and one for anomalous right coronary artery (ARCA). Three strategies were compared: observation, exercise restriction, and surgery. Probabilities and health utilities were estimated on the basis of existing literature. Deterministic and probabilistic sensitivity analyses were performed. Surgery was the optimal management strategy for patients management in anomalous aortic origin of a coronary artery depends on multiple factors, including individual patient characteristics. Decision analysis provides a tool to understand how these characteristics affect the outcomes with each management strategy and thus may aid in the decision making process for a particular patient. Copyright © 2016 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

  5. Defining functioning levels in patients with schizophrenia: A combination of a novel clustering method and brain SPECT analysis.

    Science.gov (United States)

    Catherine, Faget-Agius; Aurélie, Vincenti; Eric, Guedj; Pierre, Michel; Raphaëlle, Richieri; Marine, Alessandrini; Pascal, Auquier; Christophe, Lançon; Laurent, Boyer

    2017-12-30

    This study aims to define functioning levels of patients with schizophrenia by using a method of interpretable clustering based on a specific functioning scale, the Functional Remission Of General Schizophrenia (FROGS) scale, and to test their validity regarding clinical and neuroimaging characterization. In this observational study, patients with schizophrenia have been classified using a hierarchical top-down method called clustering using unsupervised binary trees (CUBT). Socio-demographic, clinical, and neuroimaging SPECT perfusion data were compared between the different clusters to ensure their clinical relevance. A total of 242 patients were analyzed. A four-group functioning level structure has been identified: 54 are classified as "minimal", 81 as "low", 64 as "moderate", and 43 as "high". The clustering shows satisfactory statistical properties, including reproducibility and discriminancy. The 4 clusters consistently differentiate patients. "High" functioning level patients reported significantly the lowest scores on the PANSS and the CDSS, and the highest scores on the GAF, the MARS and S-QoL 18. Functioning levels were significantly associated with cerebral perfusion of two relevant areas: the left inferior parietal cortex and the anterior cingulate. Our study provides relevant functioning levels in schizophrenia, and may enhance the use of functioning scale. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. An Approach to Define the Heat Flow in Drilling with Different Cooling Systems Using Finite Element Analysis

    Directory of Open Access Journals (Sweden)

    Carlos Henrique Lauro

    2013-01-01

    Full Text Available The heat generated in the cutting zone with high-speed drilling causes damage in the machined part. The heat can affect the dimensions of the hole considering its diameter. Moreover, the heat reduces tool life of uncoated and coated tools. This paper shows experimental tests with high-speed drilling in hardened steel. Drilling was performed on AISI H13 steel with dimensions of 100 × 40 × 14 mm and 52 HRC. The work pieces were drilled with coated drills (TiAlN. A flooded lubricant system and the minimal quantity of lubricant (MQL were applied to investigate the ability to remove heat from the cutting zone and to compare with dry tests. FEM was applied to define the heat flow and the coefficient of convection for the cooling systems. A steepest descent method was employed to minimize the difference between empirical and simulation data. The results showed that the simulation technique used to find values for heat flow and the coefficient of convection were close to the literature reference. In addition, the adjustment errors of the simulated temperature curves were less than 10% when compared with trial curves. Furthermore, the MQL showed a capability of cooling 3.5 times higher than that of the flooded system.

  7. Modeling coverage gaps in haplotype frequencies via Bayesian inference to improve stem cell donor selection.

    Science.gov (United States)

    Louzoun, Yoram; Alter, Idan; Gragert, Loren; Albrecht, Mark; Maiers, Martin

    2018-05-01

    Regardless of sampling depth, accurate genotype imputation is limited in regions of high polymorphism which often have a heavy-tailed haplotype frequency distribution. Many rare haplotypes are thus unobserved. Statistical methods to improve imputation by extending reference haplotype distributions using linkage disequilibrium patterns that relate allele and haplotype frequencies have not yet been explored. In the field of unrelated stem cell transplantation, imputation of highly polymorphic human leukocyte antigen (HLA) genes has an important application in identifying the best-matched stem cell donor when searching large registries totaling over 28,000,000 donors worldwide. Despite these large registry sizes, a significant proportion of searched patients present novel HLA haplotypes. Supporting this observation, HLA population genetic models have indicated that many extant HLA haplotypes remain unobserved. The absent haplotypes are a significant cause of error in haplotype matching. We have applied a Bayesian inference methodology for extending haplotype frequency distributions, using a model where new haplotypes are created by recombination of observed alleles. Applications of this joint probability model offer significant improvement in frequency distribution estimates over the best existing alternative methods, as we illustrate using five-locus HLA frequency data from the National Marrow Donor Program registry. Transplant matching algorithms and disease association studies involving phasing and imputation of rare variants may benefit from this statistical inference framework.

  8. Mechanisms of haplotype divergence at the RGA08 nucleotide-binding leucine-rich repeat gene locus in wild banana (Musa balbisiana).

    Science.gov (United States)

    Baurens, Franc-Christophe; Bocs, Stéphanie; Rouard, Mathieu; Matsumoto, Takashi; Miller, Robert N G; Rodier-Goud, Marguerite; MBéguié-A-MBéguié, Didier; Yahiaoui, Nabila

    2010-07-16

    Comparative sequence analysis of complex loci such as resistance gene analog clusters allows estimating the degree of sequence conservation and mechanisms of divergence at the intraspecies level. In banana (Musa sp.), two diploid wild species Musa acuminata (A genome) and Musa balbisiana (B genome) contribute to the polyploid genome of many cultivars. The M. balbisiana species is associated with vigour and tolerance to pests and disease and little is known on the genome structure and haplotype diversity within this species. Here, we compare two genomic sequences of 253 and 223 kb corresponding to two haplotypes of the RGA08 resistance gene analog locus in M. balbisiana "Pisang Klutuk Wulung" (PKW). Sequence comparison revealed two regions of contrasting features. The first is a highly colinear gene-rich region where the two haplotypes diverge only by single nucleotide polymorphisms and two repetitive element insertions. The second corresponds to a large cluster of RGA08 genes, with 13 and 18 predicted RGA genes and pseudogenes spread over 131 and 152 kb respectively on each haplotype. The RGA08 cluster is enriched in repetitive element insertions, in duplicated non-coding intergenic sequences including low complexity regions and shows structural variations between haplotypes. Although some allelic relationships are retained, a large diversity of RGA08 genes occurs in this single M. balbisiana genotype, with several RGA08 paralogs specific to each haplotype. The RGA08 gene family has evolved by mechanisms of unequal recombination, intragenic sequence exchange and diversifying selection. An unequal recombination event taking place between duplicated non-coding intergenic sequences resulted in a different RGA08 gene content between haplotypes pointing out the role of such duplicated regions in the evolution of RGA clusters. Based on the synonymous substitution rate in coding sequences, we estimated a 1 million year divergence time for these M. balbisiana haplotypes. A

  9. Single-Cell Transcriptomic Analysis Defines Heterogeneity and Transcriptional Dynamics in the Adult Neural Stem Cell Lineage

    Directory of Open Access Journals (Sweden)

    Ben W. Dulken

    2017-01-01

    Full Text Available Neural stem cells (NSCs in the adult mammalian brain serve as a reservoir for the generation of new neurons, oligodendrocytes, and astrocytes. Here, we use single-cell RNA sequencing to characterize adult NSC populations and examine the molecular identities and heterogeneity of in vivo NSC populations. We find that cells in the NSC lineage exist on a continuum through the processes of activation and differentiation. Interestingly, rare intermediate states with distinct molecular profiles can be identified and experimentally validated, and our analysis identifies putative surface markers and key intracellular regulators for these subpopulations of NSCs. Finally, using the power of single-cell profiling, we conduct a meta-analysis to compare in vivo NSCs and in vitro cultures, distinct fluorescence-activated cell sorting strategies, and different neurogenic niches. These data provide a resource for the field and contribute to an integrative understanding of the adult NSC lineage.

  10. Intragenic haplotype analysis of common HFE mutations in the ...

    Indian Academy of Sciences (India)

    mutation <100 generations ago in the Celtic populations of mainland Europe, with a ... 0.9–5.8%, evidencing regional differences in distribution across the ..... and H63D alleles in the HFE gene among various Jewish ethnic groups in Israel: a ...

  11. SNP and haplotype mapping for genetic analysis in the rat

    Czech Academy of Sciences Publication Activity Database

    Saar, K.; Beck, A.; Bihoreau, M. T.; Birney, E.; Brocklebank, D.; Chen, Y.; Cuppen, E.; Demonchy, S.; Dopazo, J.; Flicek, P.; Foglio, M.; Fujiyama, A.; Gut, I. G.; Gauguier, D.; Guigo, R.; Guryev, V.; Heinig, M.; Hummel, O.; Jahn, N.; Klages, S.; Křen, Vladimír; Kube, M.; Kuhl, H.; Kuramoto, T.; Pravenec, Michal

    2008-01-01

    Roč. 40, č. 5 (2008), s. 560-566 ISSN 1061-4036 R&D Projects: GA MŠk(CZ) 1P05ME791; GA MŠk(CZ) 1M0520; GA MŠk(CZ) ME08006 Grant - others:HHMI(US) 55005624; -(XE) LSHG-CT-2005-019015 Institutional research plan: CEZ:AV0Z50110509 Source of funding: N - neverejné zdroje ; R - rámcový projekt EK Keywords : SNP * rat * complete map Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 30.259, year: 2008

  12. CFTR mutation analysis and haplotype associations in CF patients☆

    OpenAIRE

    Cordovado, S.K.; Hendrix, M.; Greene, C.N.; Mochal, S.; Earley, M.C.; Farrell, P.M.; Kharrazi, M.; Hannon, W.H.; Mueller, P.W.

    2011-01-01

    Most newborn screening (NBS) laboratories use second-tier molecular tests for cystic fibrosis (CF) using dried blood spots (DBS). The Centers for Disease Control and Prevention’s NBS Quality Assurance Program offers proficiency testing (PT) in DBS for CF transmembrane conductance regulator (CFTR) gene mutation detection. Extensive molecular characterization on 76 CF patients, family members or screen positive newborns was performed for quality assurance. The coding, regulatory regions and por...

  13. Compound haplotypes at Xp11.23 and human population growth in Eurasia.

    Science.gov (United States)

    Alonso, S; Armour, J A L

    2004-09-01

    To investigate patterns of diversity and the evolutionary history of Eurasians, we have sequenced a 2.8 kb region at Xp11.23 in a sample of African and Eurasian chromosomes. This region is in a long intron of CLCN5 and is immediately flanked by a highly variable minisatellite, DXS255, and a human-specific Ta0 LINE. Compared to Africans, Eurasians showed a marked reduction in sequence diversity. The main Euro-Asiatic haplotype seems to be the ancestral haplotype for the whole sample. Coalescent simulations, including recombination and exponential growth, indicate a median length of strong linkage disequilibrium, up to approximately 9 kb for this area. The Ka/Ks ratio between the coding sequence of human CLCN5 and its mouse orthologue is much less than 1. This implies that the region sequenced is unlikely to be under the strong influence of positive selective processes on CLCN5, mutations in which have been associated with disorders such as Dent's disease. In contrast, a scenario based on a population bottleneck and exponential growth seems a more likely explanation for the reduced diversity observed in Eurasians. Coalescent analysis and linked minisatellite diversity (which reaches a gene diversity value greater than 98% in Eurasians) suggest an estimated age of origin of the Euro-Asiatic diversity compatible with a recent out-of-Africa model for colonization of Eurasia by modern Homo sapiens.

  14. Trends in colorectal cancer incidence: a period and birth-cohort analysis in a well-defined French population.

    Science.gov (United States)

    Chauvenet, Marion; Cottet, Vanessa; Lepage, Côme; Jooste, Valérie; Faivre, Jean; Bouvier, Anne-Marie

    2011-06-30

    France stands among high-risk areas for colorectal cancer. Different trends in CRC incidence are reported around the world. The aim of this study was to provide temporal trends in CRC incidence over a 30-year period in a French well-defined population. Between 1976 and 2005, 17,028 new cases were registered by the Burgundy digestive cancer registry. The mean variations in age-standardized incidence rates were estimated using a Poisson regression adjusted for age for each gender and location. The cumulative risk by birth cohort of developing a cancer over the age range 0-74 years was estimated using an age-cohort model. Incidence rates for right and left colon cancers increased more rapidly in males (respectively +11.7% and +10.3% on average by 5-year period) than in females (respectively +5.9% and +6.1%). It remained stable for sigmoid cancers in males (-0.1%) and decreased in females (-5.2%). It also decreased for rectal cancers both in males (-2.7%) and in females (-2.0%). The cumulative risk increased from 3.9% for males born around 1900 to 4.9% for those born around 1930 and then slightly decreased (4.5% among those born around 1950). It remained at the same level for females born around 1900 (2.7%) as for those born around 1930 (2.7%) and then slightly increased (2.9%) for those born around 1950. For right colon cancers, the cumulative risk increased strikingly in successive birth cohorts from 0.53% to 1.2% in males and 0.55% to 0.77% in females. The corresponding cumulative risks for the left colon were 0.24% and 0.42% in males and 0.14% and 0.29% in females. For sigmoid cancer, they decreased from 1.59% to 1.08% in males, and 0.88% to 0.80% in females. Temporal variations in incidence rates of colorectal cancers differed according to subsite, suggesting different aetiological factors and implications for diagnosis and screening strategies. Total colonoscopy must be the preferred strategy in high-risk groups or after a positive faecal occult blood test.

  15. Trends in colorectal cancer incidence: a period and birth-cohort analysis in a well-defined French population

    Directory of Open Access Journals (Sweden)

    Faivre Jean

    2011-06-01

    Full Text Available Abstract Background France stands among high-risk areas for colorectal cancer. Different trends in CRC incidence are reported around the world. The aim of this study was to provide temporal trends in CRC incidence over a 30-year period in a French well-defined population. Methods Between 1976 and 2005, 17,028 new cases were registered by the Burgundy digestive cancer registry. The mean variations in age-standardized incidence rates were estimated using a Poisson regression adjusted for age for each gender and location. The cumulative risk by birth cohort of developing a cancer over the age range 0-74 years was estimated using an age-cohort model. Results Incidence rates for right and left colon cancers increased more rapidly in males (respectively +11.7% and +10.3% on average by 5-year period than in females (respectively +5.9% and +6.1%. It remained stable for sigmoid cancers in males (-0.1% and decreased in females (-5.2%. It also decreased for rectal cancers both in males (-2.7% and in females (-2.0%. The cumulative risk increased from 3.9% for males born around 1900 to 4.9% for those born around 1930 and then slightly decreased (4.5% among those born around 1950. It remained at the same level for females born around 1900 (2.7% as for those born around 1930 (2.7% and then slightly increased (2.9% for those born around 1950. For right colon cancers, the cumulative risk increased strikingly in successive birth cohorts from 0.53% to 1.2% in males and 0.55% to 0.77% in females. The corresponding cumulative risks for the left colon were 0.24% and 0.42% in males and 0.14% and 0.29% in females. For sigmoid cancer, they decreased from 1.59% to 1.08% in males, and 0.88% to 0.80% in females. Conclusion Temporal variations in incidence rates of colorectal cancers differed according to subsite, suggesting different aetiological factors and implications for diagnosis and screening strategies. Total colonoscopy must be the preferred strategy in high

  16. An individual urinary proteome analysis in normal human beings to define the minimal sample number to represent the normal urinary proteome

    Directory of Open Access Journals (Sweden)

    Liu Xuejiao

    2012-11-01

    Full Text Available Abstract Background The urinary proteome has been widely used for biomarker discovery. A urinary proteome database from normal humans can provide a background for discovery proteomics and candidate proteins/peptides for targeted proteomics. Therefore, it is necessary to define the minimum number of individuals required for sampling to represent the normal urinary proteome. Methods In this study, inter-individual and inter-gender variations of urinary proteome were taken into consideration to achieve a representative database. An individual analysis was performed on overnight urine samples from 20 normal volunteers (10 males and 10 females by 1DLC/MS/MS. To obtain a representative result of each sample, a replicate 1DLCMS/MS analysis was performed. The minimal sample number was estimated by statistical analysis. Results For qualitative analysis, less than 5% of new proteins/peptides were identified in a male/female normal group by adding a new sample when the sample number exceeded nine. In addition, in a normal group, the percentage of newly identified proteins/peptides was less than 5% upon adding a new sample when the sample number reached 10. Furthermore, a statistical analysis indicated that urinary proteomes from normal males and females showed different patterns. For quantitative analysis, the variation of protein abundance was defined by spectrum count and western blotting methods. And then the minimal sample number for quantitative proteomic analysis was identified. Conclusions For qualitative analysis, when considering the inter-individual and inter-gender variations, the minimum sample number is 10 and requires a balanced number of males and females in order to obtain a representative normal human urinary proteome. For quantitative analysis, the minimal sample number is much greater than that for qualitative analysis and depends on the experimental methods used for quantification.

  17. Reverse engineering of modified genes by Bayesian network analysis defines molecular determinants critical to the development of glioblastoma.

    Directory of Open Access Journals (Sweden)

    Brian W Kunkle

    Full Text Available In this study we have identified key genes that are critical in development of astrocytic tumors. Meta-analysis of microarray studies which compared normal tissue to astrocytoma revealed a set of 646 differentially expressed genes in the majority of astrocytoma. Reverse engineering of these 646 genes using Bayesian network analysis produced a gene network for each grade of astrocytoma (Grade I-IV, and 'key genes' within each grade were identified. Genes found to be most influential to development of the highest grade of astrocytoma, Glioblastoma multiforme were: COL4A1, EGFR, BTF3, MPP2, RAB31, CDK4, CD99, ANXA2, TOP2A, and SERBP1. All of these genes were up-regulated, except MPP2 (down regulated. These 10 genes were able to predict tumor status with 96-100% confidence when using logistic regression, cross validation, and the support vector machine analysis. Markov genes interact with NFkβ, ERK, MAPK, VEGF, growth hormone and collagen to produce a network whose top biological functions are cancer, neurological disease, and cellular movement. Three of the 10 genes - EGFR, COL4A1, and CDK4, in particular, seemed to be potential 'hubs of activity'. Modified expression of these 10 Markov Blanket genes increases lifetime risk of developing glioblastoma compared to the normal population. The glioblastoma risk estimates were dramatically increased with joint effects of 4 or more than 4 Markov Blanket genes. Joint interaction effects of 4, 5, 6, 7, 8, 9 or 10 Markov Blanket genes produced 9, 13, 20.9, 26.7, 52.8, 53.2, 78.1 or 85.9%, respectively, increase in lifetime risk of developing glioblastoma compared to normal population. In summary, it appears that modified expression of several 'key genes' may be required for the development of glioblastoma. Further studies are needed to validate these 'key genes' as useful tools for early detection and novel therapeutic options for these tumors.

  18. Quantitative trait loci and the relevance of phased haplotypes

    DEFF Research Database (Denmark)

    Gregersen, Vivi Raundahl

    Genetic control of different production traits and diseases within livestock has been of great interest since domenstication. SNPs have greatly facilitated the use of QTL studies in the search of genomic regions affecting different phenotypes. The studies have been conducted to identify regions...... underlying gentic control both as traditional linkage studies relying on genetic maps and as GWAS where an approach of phasing haplotypes within the QTL have been conducted to validate the regions. Overall, regions of interest have been identified for chronic pleuritis and osteochondrosis in addition to meat...... quality and boar taint in pigs, and for improved chees production within cows...

  19. Reverse Engineering of Modified Genes by Bayesian Network Analysis Defines Molecular Determinants Critical to the Development of Glioblastoma

    Science.gov (United States)

    Kunkle, Brian W.; Yoo, Changwon; Roy, Deodutta

    2013-01-01

    In this study we have identified key genes that are critical in development of astrocytic tumors. Meta-analysis of microarray studies which compared normal tissue to astrocytoma revealed a set of 646 differentially expressed genes in the majority of astrocytoma. Reverse engineering of these 646 genes using Bayesian network analysis produced a gene network for each grade of astrocytoma (Grade I–IV), and ‘key genes’ within each grade were identified. Genes found to be most influential to development of the highest grade of astrocytoma, Glioblastoma multiforme were: COL4A1, EGFR, BTF3, MPP2, RAB31, CDK4, CD99, ANXA2, TOP2A, and SERBP1. All of these genes were up-regulated, except MPP2 (down regulated). These 10 genes were able to predict tumor status with 96–100% confidence when using logistic regression, cross validation, and the support vector machine analysis. Markov genes interact with NFkβ, ERK, MAPK, VEGF, growth hormone and collagen to produce a network whose top biological functions are cancer, neurological disease, and cellular movement. Three of the 10 genes - EGFR, COL4A1, and CDK4, in particular, seemed to be potential ‘hubs of activity’. Modified expression of these 10 Markov Blanket genes increases lifetime risk of developing glioblastoma compared to the normal population. The glioblastoma risk estimates were dramatically increased with joint effects of 4 or more than 4 Markov Blanket genes. Joint interaction effects of 4, 5, 6, 7, 8, 9 or 10 Markov Blanket genes produced 9, 13, 20.9, 26.7, 52.8, 53.2, 78.1 or 85.9%, respectively, increase in lifetime risk of developing glioblastoma compared to normal population. In summary, it appears that modified expression of several ‘key genes’ may be required for the development of glioblastoma. Further studies are needed to validate these ‘key genes’ as useful tools for early detection and novel therapeutic options for these tumors. PMID:23737970

  20. Molecular characterisation and expression analysis of SEREX-defined antigen NUCB2 in gastric epithelium, gastritis and gastric cancer

    Directory of Open Access Journals (Sweden)

    A Line

    2009-03-01

    Full Text Available NUCB2 is an EF-hand Ca2+ binding protein that has been implicated in various physiological processes like calcium homeostasis, hypothalamic regulation of feeding and TNF receptor shedding. In our previous study we identified NUCB2 as a potential tumour antigen eliciting autoantibody responses in 5.4% of gastric cancer patients but not in the healthy individuals. The current study aimed to elucidate the molecular mechanism underlying NUCB2 immunogenicity and to gain an insight into the physiological functions of NUCB2 in the stomach. mRNA expression analysis demonstrated that NUCB2 is ubiquitously expressed in normal tissues, including lymphoid tissues, and downregulated in gastric tumours when compared with the adjacent relatively normal stomach tissues. The search for molecular alterations resulted in the identification of novel mRNA variants transcribed from an alternative promoter and expressed predominantly in gastric cancers. Western blot analysis demonstrated that the protein levels correspond to mRNA levels and revealed that NUCB2 is phosphorylated in gastric mucosa. Furthermore, a 55 kDa isoform, generated presumably by yet an unidentified post-translational modification was detected in gastric tumours and AGS gastric cancer cells but was absent in the relatively normal gastric mucosa and thereby might have served as a trigger for the immune response against NUCB2. Staining of stomach tissue microarray with anti-NUCB2 antibody revealed that it is expressed in the secretory granules of chief cells and in the cytoplasm of parietal cells in the functioning gastric glands which are lost in atrophic glands and tumour cells. Hence we propose that NUCB2 may be implicated in gastric secretion by establishing an agonist-releasable Ca2+ store in ER or Golgi apparatus, signalling via heterotrimeric Ga proteins and/or mediating the exocytosis of the secretory granules.

  1. Molecular characterisation and expression analysis of SEREX-defined antigen NUCB2 in gastric epithelium, gastritis and gastric cancer

    Directory of Open Access Journals (Sweden)

    Z Kalnina

    2009-08-01

    Full Text Available NUCB2 is an EF-hand Ca2+ binding protein that has been implicated in various physiological processes like calcium homeostasis, hypothalamic regulation of feeding and TNF receptor shedding. In our previous study we identified NUCB2 as a potential tumour antigen eliciting autoantibody responses in 5.4% of gastric cancer patients but not in the healthy individuals. The current study aimed to elucidate the molecular mechanism underlying NUCB2 immunogenicity and to gain an insight into the physiological functions of NUCB2 in the stomach. mRNA expression analysis demonstrated that NUCB2 is ubiquitously expressed in normal tissues, including lymphoid tissues, and downregulated in gastric tumours when compared with the adjacent relatively normal stomach tissues. The search for molecular alterations resulted in the identification of novel mRNA variants transcribed from an alternative promoter and expressed predominantly in gastric cancers. Western blot analysis demonstrated that the protein levels correspond to mRNA levels and revealed that NUCB2 is phosphorylated in gastric mucosa. Furthermore, a 55 kDa isoform, generated presumably by yet an unidentified post-translational modification was detected in gastric tumours and AGS gastric cancer cells but was absent in the relatively normal gastric mucosa and thereby might have served as a trigger for the immune response against NUCB2. Staining of stomach tissue microarray with anti-NUCB2 antibody revealed that it is expressed in the secretory granules of chief cells and in the cytoplasm of parietal cells in the functioning gastric glands which are lost in atrophic glands and tumour cells. Hence we propose that NUCB2 may be implicated in gastric secretion by establishing an agonist-releasable Ca2+ store in ER or Golgi apparatus, signalling via heterotrimeric Ga proteins and/or mediating the exocytosis of the secretory granules.

  2. An Analysis of Determinants of Under-5 Mortality across Countries: Defining Priorities to Achieve Targets in Sustainable Developmental Goals.

    Science.gov (United States)

    Acheampong, Michael; Ejiofor, Chukwudi; Salinas-Miranda, Abraham

    2017-06-01

    Objectives The end of the era of millennium development goals (MDGs) ushered in the sustainable development goals (SDGs) with a new target for the reduction of under-five mortality rates (U5MR). Although U5MR decreased globally, the reduction was insufficient to meet MDGs targets because significant socioeconomic inequities remain unaddressed across and within countries. Thus, further progress in achieving the new SDGs target will be hindered if there is no adequate prioritization of important socioeconomic, healthcare, and environmental factors. The objective of this study was to assess factors that account most for the differences in U5MR between countries around the globe. Methods We conducted an ordinary least squares (OLS) regression-based prioritization analysis of socioeconomic, healthcare, and environmental variables from 109 countries to understand which factors explain the differences in U5MR best. Results All indicators examined individually affected differences in U5MR between countries. However, the results of multivariate OLS regression showed that the most important factors that accounted for the differences were, in order: fertility rate, total health expenditure per capita, access to improved water and sanitation, and female employment rate. Conclusions To achieve the new global target for U5MR, policymakers must focus on certain priority areas, such as interventions that address access to affordable maternal healthcare services, educational programs for mothers, especially those who are adolescents, and safe drinking water and sanitation.

  3. Hepatic transcriptome analysis of hepatitis C virus infection in chimpanzees defines unique gene expression patterns associated with viral clearance.

    Directory of Open Access Journals (Sweden)

    Santosh Nanda

    Full Text Available Hepatitis C virus infection leads to a high rate of chronicity. Mechanisms of viral clearance and persistence are still poorly understood. In this study, hepatic gene expression analysis was performed to identify any molecular signature associated with the outcome of hepatitis C virus (HCV infection in chimpanzees. Acutely HCV-infected chimpanzees with self-limited infection or progression to chronicity were studied. Interferon stimulated genes were induced irrespective of the outcome of infection. Early induction of a set of genes associated with cell proliferation and immune activation was associated with subsequent viral clearance. Specifically, two of the genes: interleukin binding factor 3 (ILF3 and cytotoxic granule-associated RNA binding protein (TIA1, associated with robust T-cell response, were highly induced early in chimpanzees with self-limited infection. Up-regulation of genes associated with CD8+ T cell response was evident only during the clearance phase of the acute self-limited infection. The induction of these genes may represent an initial response of cellular injury and proliferation that successfully translates to a "danger signal" leading to induction of adaptive immunity to control viral infection. This primary difference in hepatic gene expression between self-limited and chronic infections supports the concept that successful activation of HCV-specific T-cell response is critical in clearance of acute HCV infection.

  4. Re-defining failure envelopes for silicon carbide composites based on damage process analysis by acoustic emission

    International Nuclear Information System (INIS)

    Nozawa, Takashi; Ozawa, Kazumi; Tanigawa, Hiroyasu

    2013-01-01

    A silicon carbide fiber reinforced silicon carbide matrix (SiC/SiC) composite is a promising candidate for a fusion DEMO blanket. To develop design codes in practical use of them, strength anisotropy is an important issue to be clarified and therefore this study aimed to evaluate the failure behavior of the SiC/SiC composites to provide a strength map. For this purpose, detailed tensile, compressive and in-plane shear failure behaviors were evaluated by the acoustic emission (AE) technique for a plain–weave (P/W) chemically vapor-infiltration (CVI) SiC/SiC composite. The AE results distinguished damage accumulation processes by separately discussing localized variations of power within a time series by wavelet analysis. Of particular emphasis is that matrix cracking occurred prior to the proportional limit stress (PLS) by both tensile and compressive tests. This is because the rough-surface of SiC fibers resulted in the strong frictional stress at the fiber/matrix (F/M) interface, showing linearity in the stress–strain curve beyond the actual matrix cracking stress (i.e., possibly no sliding of the fibers at the F/M interface). In this paper, an updated failure envelope was provided by referring the true matrix cracking stresses as more realistic and reasonable failure criteria

  5. Re-defining failure envelopes for silicon carbide composites based on damage process analysis by acoustic emission

    Energy Technology Data Exchange (ETDEWEB)

    Nozawa, Takashi, E-mail: nozawa.takashi67@jaea.go.jp; Ozawa, Kazumi; Tanigawa, Hiroyasu

    2013-10-15

    A silicon carbide fiber reinforced silicon carbide matrix (SiC/SiC) composite is a promising candidate for a fusion DEMO blanket. To develop design codes in practical use of them, strength anisotropy is an important issue to be clarified and therefore this study aimed to evaluate the failure behavior of the SiC/SiC composites to provide a strength map. For this purpose, detailed tensile, compressive and in-plane shear failure behaviors were evaluated by the acoustic emission (AE) technique for a plain–weave (P/W) chemically vapor-infiltration (CVI) SiC/SiC composite. The AE results distinguished damage accumulation processes by separately discussing localized variations of power within a time series by wavelet analysis. Of particular emphasis is that matrix cracking occurred prior to the proportional limit stress (PLS) by both tensile and compressive tests. This is because the rough-surface of SiC fibers resulted in the strong frictional stress at the fiber/matrix (F/M) interface, showing linearity in the stress–strain curve beyond the actual matrix cracking stress (i.e., possibly no sliding of the fibers at the F/M interface). In this paper, an updated failure envelope was provided by referring the true matrix cracking stresses as more realistic and reasonable failure criteria.

  6. Protecting the historic centre of Venice. A coordinated analysis of the physical and perceived wear processes to define mitigating actions

    Directory of Open Access Journals (Sweden)

    Renata Codello

    2014-05-01

    Full Text Available The research aims to identify "physical" and "perceptual" wear factors of the historic center of Venice (with particular attention to the effects of anthropogenic pressure related to the phenomenon of tourism and to assess the damages they could produce to identify criteria and tools of mitigation and control. Research is part of the Action Plan "Protection and conservation of the heritage", established by the Plan of Management for the UNESCO Site of Venice and its Lagoon. Through a systemic reading and analysis of the forces of change in place, this study identifies the " macro-emergencies", i.e. the main factors that adversely affect the site’s safeguarding. The research project "Evaluation of wear processes and critical factors of the City of Venice and its lagoon, and its impact on the site’s protection" is part of the actions set out by the Management Plan of the UNESCO site of Venice and its Lagoon. The main objective of the project is the identification of physical and perceptual factors of wear, which threaten the conservation of the historical and artistic heritage of the historic center of Venice, with a particular focus on the effects of anthropogenic pressure linked to tourism, and the evaluation of their level of danger. A further objective is the recognition of measurable parameters (indicators for monitoring and, subsequently, mitigation strategies for the most significant phenomena.

  7. Newly defined landmarks for a three-dimensionally based cephalometric analysis: a retrospective cone-beam computed tomography scan review.

    Science.gov (United States)

    Lee, Moonyoung; Kanavakis, Georgios; Miner, R Matthew

    2015-01-01

    To identify two novel three-dimensional (3D) cephalometric landmarks and create a novel three-dimensionally based anteroposterior skeletal measurement that can be compared with traditional two-dimensional (2D) cephalometric measurements in patients with Class I and Class II skeletal patterns. Full head cone-beam computed tomography (CBCT) scans of 100 patients with all first molars in occlusion were obtained from a private practice. InvivoDental 3D (version 5.1.6, Anatomage, San Jose, Calif) was used to analyze the CBCT scans in the sagittal and axial planes to create new landmarks and a linear 3D analysis (M measurement) based on maxillary and mandibular centroids. Independent samples t-test was used to compare the mean M measurement to traditional 2D cephalometric measurements, ANB and APDI. Interexaminer and intraexaminer reliability were evaluated using 2D and 3D scatterplots. The M measurement, ANB, and APDI could statistically differentiate between patients with Class I and Class II skeletal patterns (P < .001). The M measurement exhibited a correlation coefficient (r) of -0.79 and 0.88 with APDI and ANB, respectively. The overall centroid landmarks and the M measurement combine 2D and 3D methods of imaging; the measurement itself can distinguish between patients with Class I and Class II skeletal patterns and can serve as a potential substitute for ANB and APDI. The new three-dimensionally based landmarks and measurements are reliable, and there is great potential for future use of 3D analyses for diagnosis and research.

  8. Exploring climate niches of ponderosa pine (Pinus ponderosa Douglas ex Lawson) haplotypes in the western United States: implications for evolutionary history and conservation

    Science.gov (United States)

    Douglas J. Shinneman; Robert E. Means; Kevin M. Potter; Valerie D. Hipkins; Tzen-Yuh Chiang

    2016-01-01

    Ponderosa pine (Pinus ponderosa Douglas ex Lawson) occupies montane environments throughout western North America, where it is both an ecologically and economically important tree species. A recent study using mitochondrial DNA analysis demonstrated substantial genetic variation among ponderosa pine populations in the western U.S., identifying 10 haplotypes with unique...

  9. The evolutionary history of the DMRT3 'Gait keeper' haplotype.

    Science.gov (United States)

    Staiger, E A; Almén, M S; Promerová, M; Brooks, S; Cothran, E G; Imsland, F; Jäderkvist Fegraeus, K; Lindgren, G; Mehrabani Yeganeh, H; Mikko, S; Vega-Pla, J L; Tozaki, T; Rubin, C J; Andersson, L

    2017-10-01

    A previous study revealed a strong association between the DMRT3:Ser301STOP mutation in horses and alternate gaits as well as performance in harness racing. Several follow-up studies have confirmed a high frequency of the mutation in gaited horse breeds and an effect on gait quality. The aim of this study was to determine when and where the mutation arose, to identify additional potential causal mutations and to determine the coalescence time for contemporary haplotypes carrying the stop mutation. We utilized sequences from 89 horses representing 26 breeds to identify 102 SNPs encompassing the DMRT3 gene that are in strong linkage disequilibrium with the stop mutation. These 102 SNPs were genotyped in an additional 382 horses representing 72 breeds, and we identified 14 unique haplotypes. The results provided conclusive evidence that DMRT3:Ser301STOP is causal, as no other sequence polymorphisms showed an equally strong association to locomotion traits. The low sequence diversity among mutant chromosomes demonstrated that they must have diverged from a common ancestral sequence within the last 10 000 years. Thus, the mutation occurred either just before domestication or more likely some time after domestication and then spread across the world as a result of selection on locomotion traits. © 2017 Stichting International Foundation for Animal Genetics.

  10. HLA alleles and HLA-B27 haplotypes associated with susceptibility and severity of ankylosing spondylitis in a Portuguese population.

    Science.gov (United States)

    Pimentel-Santos, F M; Matos, M; Ligeiro, D; Mourão, A F; Ribeiro, C; Costa, J; Santos, H; Barcelos, A; Pinto, P; Cruz, M; Sousa, E; Santos, R A; Fonseca, J E; Trindade, H; Guedes-Pinto, H; Branco, J C

    2013-12-01

    Human leukocyte antigen (HLA)-B27 is the mostly known major histocompatibility complex (MHC) gene associated with ankylosing spondylitis (AS). Nonetheless, there is substantial evidence that other MHC genes appear to be associated with the disease, although it has not yet been established whether these associations are driven by direct associations or by linkage disequilibrium (LD) mechanisms. We aimed to investigate the contributions of HLA class I and II alleles and B27-haplotypes for AS in a case-control study. A total of 188 HLA-B27 AS cases and 189 HLA-B27 healthy controls were selected and typed for HLA class I and II by the Luminex polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSOP) method. Allelic and haplotypic distributions were estimated by maximum likelihood method using Arlequin v3.11 and statistical analysis were performed by Stata10.1. No associations were found between non-HLA-B27 loci and AS susceptibility, but several associations were observed for phenotypic features of the disease. DRB1*08 was identified as a risk factor for uveitis and DQB1*04 seems to provide protection for AS severity (functional, metrological and radiological indexes). A*02/B27/C*02/DRB1*01/DQB1*05 [P<0.0001; odds ratio (OR) = 39.06; 95% confidence interval (CI) (2.34-651)] is the only haplotype that seems to confer susceptibility to AS. Moreover, the haplotype A*02/B27/C*01/DRB1*08/DQB1*04 seems to provide protection for disease functional and radiological repercussions. Our findings are compatible with the hypothesis that other genes within the HLA region besides HLA-B27 might play some role in AS susceptibility and severity. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. A novel haplotype of low-frequency variants in the aldosterone synthase gene among northern Han Chinese with essential hypertension.

    Science.gov (United States)

    Zhang, Hao; Li, Xueyan; Zhou, Li; Zhang, Keyong; Zhang, Qi; Li, Jingping; Wang, Ningning; Jin, Ming; Wu, Nan; Cong, Mingyu; Qiu, Changchun

    2017-09-01

    Low-frequency variants showed that there is more power to detect risk variants than to detect protective variants in complex diseases. Aldosterone plays an important role in the renin-angiotensin-aldosterone system, and aldosterone synthase catalyzes the speed-controlled steps of aldosterone biosynthesis. Polymorphisms of the aldosterone synthase gene (CYP11B2) have been reported to be associated with essential hypertension (EH). CYP11B2 polymorphisms such as -344T/C, have been extensively reported, but others are less well known. This study aimed to assess the association between human CYP11B2 and EH using a haplotype-based case-control study. A total of 1024 EH patients and 956 normotensive controls, which consist of north Han population peasants, were enrolled. Seven single nucleotide polymorphisms (SNPs) (rs28659182, rs10087214, rs73715282, rs542092383, rs4543, rs28491316, and rs7463212) covering the entire human CYP11B2 gene were genotyped as markers using the MassARRAY system. The major allele G frequency of rs542092383 was found to be risk against hypertension [odds ratio (OR) 3.478, 95% confidence interval (95% CI) 1.407-8.597, P = .004]. The AG genotype frequency of SNP rs542092383 was significantly associated with an increased risk of hypertension (OR 4.513, 95% CI 1.426-14.287, P = .010). In the haplotype-based case-control analysis, the frequency of the T-G-T haplotype was higher for EH patients than for controls (OR 5.729, 95% CI 1.889-17.371, P = .000495). All |D'| values of the seven SNPs were >0.9, and r values for rs28659182- rs10087214-rs28491316-rs7463212 SNPs were >0.8 and showed strong linkage intensity. Haplotype T-G-T may therefore be a useful genetic marker for EH.

  12. Haplotype diversity of 17 Y-chromosomal STRs in three native Sarawak populations (Iban, Bidayuh and Melanau) in East Malaysia.

    Science.gov (United States)

    Chang, Yuet Meng; Swaran, Yuvaneswari; Phoon, Yoong Keat; Sothirasan, Kavin; Sim, Hang Thiew; Lim, Kong Boon; Kuehn, Daniel

    2009-06-01

    17 Y-STRs (DYS456, DYS389I, DYS390, DYS389II, DYS458, DYS19, DYS385a/b, DYS393, DYS391, DYS439, DYS635 or Y-GATA C4, DYS392, Y-GATA H4, DYS437, DYS438 and DYS448) have been analyzed in 320 male individuals from Sarawak, an eastern state of Malaysia on the Borneo island using the AmpFlSTR Y-filer (Applied Biosystems, Foster City, CA). These individuals were from three indigenous ethnic groups in Sarawak comprising of 103 Ibans, 113 Bidayuhs and 104 Melanaus. The observed 17-loci haplotypes and the individual allele frequencies for each locus were estimated, whilst the locus diversity, haplotype diversity and discrimination capacity were calculated in the three groups. Analysis of molecular variance (AMOVA) indicated that 87.6% of the haplotypic variation was found within population and 12.4% between populations (fixation index F(ST)=0.124, p=0.000). This study has revealed that the indigenous populations in Sarawak are distinctly different to each other, and to the three major ethnic groups in Malaysia (Malays, Chinese and Indians), with the Melanaus having a strikingly high degree of shared haplotypes within. There are rare unusual variants and microvariants that were not present in Malaysian Malay, Chinese or Indian groups. In addition, occurrences of DYS385 duplications which were only noticeably present in Chinese group previously was also observed in the Iban group whilst null alleles were detected at several Y-loci (namely DYS19, DYS392, DYS389II and DYS448) in the Iban and Melanau groups.

  13. Novel Tenascin-C Haplotype Modifies the Risk for a Failure to Heal After Rotator Cuff Repair.

    Science.gov (United States)

    Kluger, Rainer; Huber, Klaus R; Seely, Philipp G; Berger, Christian E; Frommlet, Florian

    2017-11-01

    Several single-nucleotide polymorphisms (SNPs) in the TNC gene have recently been found to be associated with degenerative rotator cuff tears. Exonic SNPs in the TNC gene are related to the risk for a failure to heal after rotator cuff repair. Case-control study; Level of evidence, 3. A total of 302 patients from the Vienna area and European Caucasian ancestry underwent mini-open rotator cuff repair for a full-thickness superior or posterosuperior tear and were assessed for the integrity of the repair 1 year postoperatively with a real-time 7.5- to 10-MHz ultrasound linear array transducer. Outcomes were classified as intact (complete footprint coverage), small (T] was protective for a large recurrent defect (odds ratio = 0.16; 95% CI, 0.09-0.31). The role of rs1138545 was further backed by haplotype analysis, which showed that the combination of the C allele at rs1138545 [C>T], the A allele at rs2104772 [A>T], and the G allele at rs10759752 [A>G] formed the risk-related haplotype [CAG]. The CAG haplotype was associated with large recurrent defects ( P rotator cuff repairs are clinically relevant, and a heritable component of the disorder is plausible on the basis of a genetic association with 8 TNC variants. Characterization of TNC sequences that favor tendon healing will help engineer new products in regenerative medicine.

  14. Haplotype diversity of 16 Y-chromosomal STRs in three main ethnic populations (Malays, Chinese and Indians) in Malaysia.

    Science.gov (United States)

    Chang, Yuet Meng; Perumal, Revathi; Keat, Phoon Yoong; Kuehn, Daniel L C

    2007-03-22

    We have analyzed 16 Y-STR loci (DYS456, DYS389I, DYS390, DYS389II, DYS458, DYS19, DYS385a/b, DYS393, DYS391, DYS439, DYS635 or Y-GATA C4, DYS392, Y-GATA H4, DYS437, DYS438 and DYS448) from the non-recombining region of the human Y-chromosome in 980 male individuals from three main ethnic populations in Malaysia (Malay, Chinese, Indian) using the AmpFlSTR((R)) Y-filertrade mark (Applied Biosystems, Foster City, CA). The observed 17-loci haplotypes and the individual allele frequencies for each locus were estimated, whilst the locus diversity, haplotype diversity and discrimination capacity were calculated in the three ethnic populations. Analysis of molecular variance indicated that 88.7% of the haplotypic variation is found within population and 11.3% is between populations (fixation index F(ST)=0.113, p=0.000). This study has revealed Y-chromosomes with null alleles at several Y-loci, namely DYS458, DYS392, DYS389I, DYS389II, DYS439, DYS448 and Y-GATA H4; and several occurrences of duplications at the highly polymorphic DYS385 loci. Some of these deleted loci were in regions of the Y(q) arm that have been implicated in the occurrence of male infertility.

  15. Antioxidant activity of yogurt made from milk characterized by different casein haplotypes and fortified with chestnut and sulla honeys.

    Science.gov (United States)

    Perna, Annamaria; Intaglietta, Immacolata; Simonetti, Amalia; Gambacorta, Emilio

    2014-11-01

    The aim of this work was to evaluate the antioxidant activity of yogurt made from milk characterized by different casein (CN) haplotypes (αs1-, β-, κ-CN) and fortified with chestnut and sulla honeys. The CN haplotype was determined by isoelectric focusing, whereas antioxidant activity of yogurt was measured using 2,2'-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid and ferric-reducing antioxidant power. The statistical analysis showed a significant effect of the studied factors. The results showed that chestnut honey presented the highest phenolic acid and flavonoid contents, which are closely associated with its high antioxidant activity. The antioxidant activity of fortified yogurt samples was affected both by different CN haplotypes and by type of honey added. Yogurts fortified with chestnut honey showed higher antioxidant activity than those fortified with sulla honey. The different behavior observed among the fortified yogurts led us to hypothesize that the effects of protein-polyphenol complex on antioxidant activity are interactive. The results suggest that milk proteins polymorphism and polyphenols play different roles in affecting the bioavailability and the antioxidant activity of yogurt. Copyright © 2014 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  16. Differences in meiotic recombination rates in childhood acute lymphoblastic leukemia at an MHC class II hotspot close to disease associated haplotypes.

    Directory of Open Access Journals (Sweden)

    Pamela Thompson

    Full Text Available Childhood Acute Lymphoblastic Leukemia (ALL is a malignant lymphoid disease of which B-cell precursor- (BCP and T-cell- (T ALL are subtypes. The role of alleles encoded by major histocompatibility loci (MHC have been examined in a number of previous studies and results indicating weak, multi-allele associations between the HLA-DPB1 locus and BCP-ALL suggested a role for immunosusceptibility and possibly infection. Two independent SNP association studies of ALL identified loci approximately 37 kb from one another and flanking a strong meiotic recombination hotspot (DNA3, adjacent to HLA-DOA and centromeric of HLA-DPB1. To determine the relationship between this observation and HLA-DPB1 associations, we constructed high density SNP haplotypes of the 316 kb region from HLA-DMB to COL11A2 in childhood ALL and controls using a UK GWAS data subset and the software PHASE. Of four haplotype blocks identified, predicted haplotypes in Block 1 (centromeric of DNA3 differed significantly between BCP-ALL and controls (P = 0.002 and in Block 4 (including HLA-DPB1 between T-ALL and controls (P = 0.049. Of specific common (>5% haplotypes in Block 1, two were less frequent in BCP-ALL, and in Block 4 a single haplotype was more frequent in T-ALL, compared to controls. Unexpectedly, we also observed apparent differences in ancestral meiotic recombination rates at DNA3, with BCP-ALL showing increased and T-ALL decreased levels compared to controls. In silico analysis using LDsplit sotware indicated that recombination rates at DNA3 are influenced by flanking loci, including SNPs identified in childhood ALL association studies. The observed differences in rates of meiotic recombination at this hotspot, and potentially others, may be a characteristic of childhood leukemia and contribute to disease susceptibility, alternatively they may reflect interactions between ALL-associated haplotypes in this region.

  17. Genotypes and haplotypes in the insulin-like growth factors, their receptors and binding proteins in relation to plasma metabolic levels and mammographic density

    Directory of Open Access Journals (Sweden)

    Chanock Stephen J

    2010-03-01

    Full Text Available Abstract Background Increased mammographic density is one of the strongest independent risk factors for breast cancer. It is believed that one third of breast cancers are derived from breasts with more than 50% density. Mammographic density is affected by age, BMI, parity, and genetic predisposition. It is also greatly influenced by hormonal and growth factor changes in a woman's life cycle, spanning from puberty through adult to menopause. Genetic variations in genes coding for hormones and growth factors involved in development of the breast are therefore of great interest. The associations between genetic polymorphisms in genes from the IGF pathway on mammographic density and circulating levels of IGF1, its binding protein IGFBP3, and their ratio in postmenopausal women are reported here. Methods Samples from 964 postmenopausal Norwegian women aged 55-71 years were collected as a part of the Tromsø Mammography and Breast Cancer Study. All samples were genotyped for 25 SNPs in IGF1, IGF2, IGF1R, IGF2R, IGFALS and IGFBP3 using Taqman (ABI. The main statistical analyses were conducted with the PROC HAPLOTYPE procedure within SAS/GENETICS™ (SAS 9.1.3. Results The haplotype analysis revealed six haploblocks within the studied genes. Of those, four had significant associations with circulating levels of IGF1 or IGFBP3 and/or mammographic density. One haplotype variant in the IGF1 gene was found to be associated with mammographic density. Within the IGF2 gene one haplotype variant was associated with levels of both IGF1 and IGFBP3. Two haplotype variants in the IGF2R were associated with the level of IGF1. Both variants of the IGFBP3 haplotype were associated with the IGFBP3 level and indicate regulation in cis. Conclusion Polymorphisms within the IGF1 gene and related genes were associated with plasma levels of IGF1, IGFBP3 and mammographic density in this study of postmenopausal women.

  18. Genomic association for sexual precocity in beef heifers using pre-selection of genes and haplotype reconstruction.

    Directory of Open Access Journals (Sweden)

    Luciana Takada

    Full Text Available Reproductive traits are of the utmost importance for any livestock farming, but are difficult to measure and to interpret since they are influenced by various factors. The objective of this study was to detect associations between known polymorphisms in candidate genes related to sexual precocity in Nellore heifers, which could be used in breeding programs. Records of 1,689 precocious and non-precocious heifers from farms participating in the Conexão Delta G breeding program were analyzed. A subset of single nucleotide polymorphisms (SNP located in the region of the candidate genes at a distance of up to 5 kb from the boundaries of each gene, were selected from the panel of 777,000 SNPs of the High-Density Bovine SNP BeadChip. Linear mixed models were used for statistical analysis of early heifer pregnancy, relating the trait with isolated SNPs or with haplotype groups. The model included the contemporary group (year and month of birth as fixed effect and parent of the animal (sire effect as random effect. The fastPHASE® and GenomeStudio® were used for reconstruction of the haplotypes and for analysis of linkage disequilibrium based on r2 statistics. A total of 125 candidate genes and 2,024 SNPs forming haplotypes were analyzed. Statistical analysis after Bonferroni correction showed that nine haplotypes exerted a significant effect (p<0.05 on sexual precocity. Four of these haplotypes were located in the Pregnancy-associated plasma protein-A2 gene (PAPP-A2, two in the Estrogen-related receptor gamma gene (ESRRG, and one each in the Pregnancy-associated plasma protein-A gene (PAPP-A, Kell blood group complex subunit-related family (XKR4 and mannose-binding lectin genes (MBL-1 genes. Although the present results indicate that the PAPP-A2, PAPP-A, XKR4, MBL-1 and ESRRG genes influence sexual precocity in Nellore heifers, further studies are needed to evaluate their possible use in breeding programs.

  19. Analysis of Stakeholder-Defined Needs in Northeast U.S. Coastal Communities to Determine Gaps in Research Informing Coastal Resilience Planning

    Science.gov (United States)

    Molino, G. D.; Kenney, M. A.; Sutton-Grier, A.; Penn, K.

    2017-12-01

    The impacts of climate change on our coastlines are increasing pressure on communities, ecosystems, infrastructure, and state-to-local economies in the northeastern United States (U.S.). As a result of current or imminent risk of acute and chronic hazards, local, state and regional entities have taken steps to identify and address vulnerabilities to climate change. Decisions to increase coastal infrastructure resilience and grey, green, and cultural infrastructure solutions requires physical, natural, and social science that is useful for decision-making and effective science translation mechanisms. Despite the desire to conduct or fund science that meets the needs of communities, there has been no comprehensive analysis to determine stakeholder-defined research needs. To address this gap, this study conducts a stakeholder needs analysis in northeast U.S. coastal communities to determine gaps in information and translation processes supporting coastal resilience planning. Documents were sourced from local, state, and regional organizations in both the public and private sectors, using the northeast region defined by the third National Climate Assessment. Modeled after Dilling et al. (2015), a deductive coding schema was developed that categorized documents using specific search terms such as "Location and condition of infrastructure" and "Proactive planning". A qualitative document analysis was then executed using NVivo to formally identify patterns and themes present in stakeholder surveys, workshop proceedings, and reports. Initial stakeholder priorities centered around incorporation of climate science into planning and decision making regarding vulnerabilities of infrastructure, enhanced emergency planning and response, and communication of key information.

  20. Genetic relationships among native americans based on beta-globin gene cluster haplotype frequencies

    Directory of Open Access Journals (Sweden)

    Rita de Cassia Mousinho-Ribeiro

    2003-01-01

    Full Text Available The distribution of b-globin gene haplotypes was studied in 209 Amerindians from eight tribes of the Brazilian Amazon: Asurini from Xingú, Awá-Guajá, Parakanã, Urubú-Kaapór, Zoé, Kayapó (Xikrin from the Bacajá village, Katuena, and Tiriyó. Nine different haplotypes were found, two of which (n. 11 and 13 had not been previously identified in Brazilian indigenous populations. Haplotype 2 (+ - - - - was the most common in all groups studied, with frequencies varying from 70% to 100%, followed by haplotype 6 (- + + - +, with frequencies between 7% and 18%. The frequency distribution of the b-globin gene haplotypes in the eighteen Brazilian Amerindian populations studied to date is characterized by a reduced number of haplotypes (average of 3.5 and low levels of heterozygosity and intrapopulational differentiation, with a single clearly predominant haplotype in most tribes (haplotype 2. The Parakanã, Urubú-Kaapór, Tiriyó and Xavante tribes constitute exceptions, presenting at least four haplotypes with relatively high frequencies. The closest genetic relationships were observed between the Brazilian and the Colombian Amerindians (Wayuu, Kamsa and Inga, and, to a lesser extent, with the Huichol of Mexico. North-American Amerindians are more differentiated and clearly separated from all other tribes, except the Xavante, from Brazil, and the Mapuche, from Argentina. A restricted pool of ancestral haplotypes may explain the low diversity observed among most present-day Brazilian and Colombian Amerindian groups, while interethnic admixture could be the most important factor to explain the high number of haplotypes and high levels of diversity observed in some South-American and most North-American tribes.

  1. Musical aptitude is associated with AVPR1A-haplotypes.

    Directory of Open Access Journals (Sweden)

    Liisa T Ukkola

    Full Text Available Artistic creativity forms the basis of music culture and music industry. Composing, improvising and arranging music are complex creative functions of the human brain, which biological value remains unknown. We hypothesized that practicing music is social communication that needs musical aptitude and even creativity in music. In order to understand the neurobiological basis of music in human evolution and communication we analyzed polymorphisms of the arginine vasopressin receptor 1A (AVPR1A, serotonin transporter (SLC6A4, catecol-O-methyltranferase (COMT, dopamin receptor D2 (DRD2 and tyrosine hydroxylase 1 (TPH1, genes associated with social bonding and cognitive functions in 19 Finnish families (n = 343 members with professional musicians and/or active amateurs. All family members were tested for musical aptitude using the auditory structuring ability test (Karma Music test; KMT and Carl Seashores tests for pitch (SP and for time (ST. Data on creativity in music (composing, improvising and/or arranging music was surveyed using a web-based questionnaire. Here we show for the first time that creative functions in music have a strong genetic component (h(2 = .84; composing h(2 = .40; arranging h(2 = .46; improvising h(2 = .62 in Finnish multigenerational families. We also show that high music test scores are significantly associated with creative functions in music (p<.0001. We discovered an overall haplotype association with AVPR1A gene (markers RS1 and RS3 and KMT (p = 0.0008; corrected p = 0.00002, SP (p = 0.0261; corrected p = 0.0072 and combined music test scores (COMB (p = 0.0056; corrected p = 0.0006. AVPR1A haplotype AVR+RS1 further suggested a positive association with ST (p = 0.0038; corrected p = 0.00184 and COMB (p = 0.0083; corrected p = 0.0040 using haplotype-based association test HBAT. The results suggest that the neurobiology of music perception and production is likely to be related to the pathways affecting intrinsic attachment

  2. Distribution of HLA-G extended haplotypes and one HLA-E polymorphism in a large-scale study of mother-child dyads with and without severe preeclampsia and eclampsia

    DEFF Research Database (Denmark)

    Nilsson, L. L.; Djurisic, S; Andersen, A.-M. N.

    2016-01-01

    was not associated with severe preeclampsia. Furthermore, the polymorphism (rs1264457) defining the two nonsynonymous HLA-E alleles, HLA-E*01:01:xx:xx and HLA-E*01:03:xx:xx, were not associated with severe preeclampsia. Finally, no specific HLA-G haplotypes were significantly associated with increased risk...

  3. Defining cyber warfare

    Directory of Open Access Journals (Sweden)

    Dragan D. Mladenović

    2012-04-01

    Full Text Available Cyber conflicts represent a new kind of warfare that is technologically developing very rapidly. Such development results in more frequent and more intensive cyber attacks undertaken by states against adversary targets, with a wide range of diverse operations, from information operations to physical destruction of targets. Nevertheless, cyber warfare is waged through the application of the same means, techniques and methods as those used in cyber criminal, terrorism and intelligence activities. Moreover, it has a very specific nature that enables states to covertly initiate attacks against their adversaries. The starting point in defining doctrines, procedures and standards in the area of cyber warfare is determining its true nature. In this paper, a contribution to this effort was made through the analysis of the existing state doctrines and international practice in the area of cyber warfare towards the determination of its nationally acceptable definition.

  4. Effects of the number of markers per haplotype and clustering of haplotypes on the accuracy of QTL mapping and prediction of genomic breeding values

    Directory of Open Access Journals (Sweden)

    Schrooten Chris

    2009-01-01

    Full Text Available Abstract The aim of this paper was to compare the effect of haplotype definition on the precision of QTL-mapping and on the accuracy of predicted genomic breeding values. In a multiple QTL model using identity-by-descent (IBD probabilities between haplotypes, various haplotype definitions were tested i.e. including 2, 6, 12 or 20 marker alleles and clustering base haplotypes related with an IBD probability of > 0.55, 0.75 or 0.95. Simulated data contained 1100 animals with known genotypes and phenotypes and 1000 animals with known genotypes and unknown phenotypes. Genomes comprising 3 Morgan were simulated and contained 74 polymorphic QTL and 383 polymorphic SNP markers with an average r2 value of 0.14 between adjacent markers. The total number of haplotypes decreased up to 50% when the window size was increased from two to 20 markers and decreased by at least 50% when haplotypes related with an IBD probability of > 0.55 instead of > 0.95 were clustered. An intermediate window size led to more precise QTL mapping. Window size and clustering had a limited effect on the accuracy of predicted total breeding values, ranging from 0.79 to 0.81. Our conclusion is that different optimal window sizes should be used in QTL-mapping versus genome-wide breeding value prediction.

  5. Discovery, evaluation and distribution of haplotypes of the wheat Ppd-D1 gene.

    Science.gov (United States)

    Guo, Zhiai; Song, Yanxia; Zhou, Ronghua; Ren, Zhenglong; Jia, Jizeng

    2010-02-01

    Ppd-D1 is one of the most potent genes affecting the photoperiod response of wheat (Triticum aestivum). Only two alleles, insensitive Ppd-D1a and sensitive Ppd-D1b, were known previously, and these did not adequately explain the broad adaptation of wheat to photoperiod variation. In this study, five diagnostic molecular markers were employed to identify Ppd-D1 haplotypes in 492 wheat varieties from diverse geographic locations and 55 accessions of Aegilops tauschii, the D genome donor species of wheat. Six Ppd-D1 haplotypes, designated I-VI, were identified. Types II, V and VI were considered to be more ancient and types I, III and IV were considered to be derived from type II. The transcript abundances of the Ppd-D1 haplotypes showed continuous variation, being highest for haplotype I, lowest for haplotype III, and correlating negatively with varietal differences in heading time. These haplotypes also significantly affected other agronomic traits. The distribution frequency of Ppd-D1 haplotypes showed partial correlations with both latitudes and altitudes of wheat cultivation regions. The evolution, expression and distribution of Ppd-D1 haplotypes were consistent evidentially with each other. What was regarded as a pair of alleles in the past can now be considered a series of alleles leading to continuous variation.

  6. Musical Aptitude Is Associated with AVPR1A-Haplotypes

    Science.gov (United States)

    Ukkola, Liisa T.; Onkamo, Päivi; Raijas, Pirre; Karma, Kai; Järvelä, Irma

    2009-01-01

    Artistic creativity forms the basis of music culture and music industry. Composing, improvising and arranging music are complex creative functions of the human brain, which biological value remains unknown. We hypothesized that practicing music is social communication that needs musical aptitude and even creativity in music. In order to understand the neurobiological basis of music in human evolution and communication we analyzed polymorphisms of the arginine vasopressin receptor 1A (AVPR1A), serotonin transporter (SLC6A4), catecol-O-methyltranferase (COMT), dopamin receptor D2 (DRD2) and tyrosine hydroxylase 1 (TPH1), genes associated with social bonding and cognitive functions in 19 Finnish families (n = 343 members) with professional musicians and/or active amateurs. All family members were tested for musical aptitude using the auditory structuring ability test (Karma Music test; KMT) and Carl Seashores tests for pitch (SP) and for time (ST). Data on creativity in music (composing, improvising and/or arranging music) was surveyed using a web-based questionnaire. Here we show for the first time that creative functions in music have a strong genetic component (h2 = .84; composing h2 = .40; arranging h2 = .46; improvising h2 = .62) in Finnish multigenerational families. We also show that high music test scores are significantly associated with creative functions in music (pmusic test scores (COMB) (p = 0.0056; corrected p = 0.0006). AVPR1A haplotype AVR+RS1 further suggested a positive association with ST (p = 0.0038; corrected p = 0.00184) and COMB (p = 0.0083; corrected p = 0.0040) using haplotype-based association test HBAT. The results suggest that the neurobiology of music perception and production is likely to be related to the pathways affecting intrinsic attachment behavior. PMID:19461995

  7. Musical aptitude is associated with AVPR1A-haplotypes.

    Science.gov (United States)

    Ukkola, Liisa T; Onkamo, Päivi; Raijas, Pirre; Karma, Kai; Järvelä, Irma

    2009-05-20

    Artistic creativity forms the basis of music culture and music industry. Composing, improvising and arranging music are complex creative functions of the human brain, which biological value remains unknown. We hypothesized that practicing music is social communication that needs musical aptitude and even creativity in music. In order to understand the neurobiological basis of music in human evolution and communication we analyzed polymorphisms of the arginine vasopressin receptor 1A (AVPR1A), serotonin transporter (SLC6A4), catecol-O-methyltranferase (COMT), dopamin receptor D2 (DRD2) and tyrosine hydroxylase 1 (TPH1), genes associated with social bonding and cognitive functions in 19 Finnish families (n = 343 members) with professional musicians and/or active amateurs. All family members were tested for musical aptitude using the auditory structuring ability test (Karma Music test; KMT) and Carl Seashores tests for pitch (SP) and for time (ST). Data on creativity in music (composing, improvising and/or arranging music) was surveyed using a web-based questionnaire. Here we show for the first time that creative functions in music have a strong genetic component (h(2) = .84; composing h(2) = .40; arranging h(2) = .46; improvising h(2) = .62) in Finnish multigenerational families. We also show that high music test scores are significantly associated with creative functions in music (pmusic test scores (COMB) (p = 0.0056; corrected p = 0.0006). AVPR1A haplotype AVR+RS1 further suggested a positive association with ST (p = 0.0038; corrected p = 0.00184) and COMB (p = 0.0083; corrected p = 0.0040) using haplotype-based association test HBAT. The results suggest that the neurobiology of music perception and production is likely to be related to the pathways affecting intrinsic attachment behavior.

  8. Haplotype assembly in polyploid genomes and identical by descent shared tracts.

    Science.gov (United States)

    Aguiar, Derek; Istrail, Sorin

    2013-07-01

    Genome-wide haplotype reconstruction from sequence data, or haplotype assembly, is at the center of major challenges in molecular biology and life sciences. For complex eukaryotic organisms like humans, the genome is vast and the population samples are growing so rapidly that algorithms processing high-throughput sequencing data must scale favorably in terms of both accuracy and computational efficiency. Furthermore, current models and methodologies for haplotype assembly (i) do not consider individuals sharing haplotypes jointly, which reduces the size and accuracy of assembled haplotypes, and (ii) are unable to model genomes having more than two sets of homologous chromosomes (polyploidy). Polyploid organisms are increasingly becoming the target of many research groups interested in the genomics of disease, phylogenetics, botany and evolution but there is an absence of theory and methods for polyploid haplotype reconstruction. In this work, we present a number of results, extensions and generalizations of compass graphs and our HapCompass framework. We prove the theoretical complexity of two haplotype assembly optimizations, thereby motivating the use of heuristics. Furthermore, we present graph theory-based algorithms for the problem of haplotype assembly using our previously developed HapCompass framework for (i) novel implementations of haplotype assembly optimizations (minimum error correction), (ii) assembly of a pair of individuals sharing a haplotype tract identical by descent and (iii) assembly of polyploid genomes. We evaluate our methods on 1000 Genomes Project, Pacific Biosciences and simulated sequence data. HapCompass is available for download at http://www.brown.edu/Research/Istrail_Lab/. Supplementary data are available at Bioinformatics online.

  9. Plasmodium falciparum isolates from Angola show the StctVMNT haplotype in the pfcrt gene

    Science.gov (United States)

    2010-01-01

    Background Effective treatment remains a mainstay of malaria control, but it is unfortunately strongly compromised by drug resistance, particularly in Plasmodium falciparum, the most important human malaria parasite. Although P. falciparum chemoresistance is well recognized all over the world, limited data are available on the distribution and prevalence of pfcrt and pfmdr1 haplotypes that mediate resistance to commonly used drugs and that show distinct geographic differences. Methods Plasmodium falciparum-infected blood samples collected in 2007 at four municipalities of Luanda, Angola, were genotyped using PCR and direct DNA sequencing. Single nucleotide polymorphisms in the P. falciparum pfcrt and pfmdr1 genes were assessed and haplotype prevalences were determined. Results and Discussion The most prevalent pfcrt haplotype was StctVMNT (representing amino acids at codons 72-76). This result was unexpected, since the StctVMNT haplotype has previously been seen mainly in parasites from South America and India. The CVIET, CVMNT and CVINT drug-resistance haplotypes were also found, and one previously undescribed haplotype (CVMDT) was detected. Regarding pfmdr1, the most prevalent haplotype was YEYSNVD (representing amino acids at codons 86, 130, 184, 1034, 1042, 1109 and 1246). Wild haplotypes for pfcrt and pfmdr1 were uncommon; 3% of field isolates harbored wild type pfcrt (CVMNK), whereas 21% had wild type pfmdr1 (NEYSNVD). The observed predominance of the StctVMNT haplotype in Angola could be a result of frequent travel between Brazil and Angola citizens in the context of selective pressure of heavy CQ use. Conclusions The high prevalence of the pfcrt SVMNT haplotype and the pfmdr1 86Y mutation confirm high-level chloroquine resistance and might suggest reduced efficacy of amodiaquine in Angola. Further studies must be encouraged to examine the in vitro sensitivity of pfcrt SVMNT parasites to artesunate and amodiaquine for better conclusive data. PMID:20565881

  10. Novel CYP2E1 haplotype identified in a South African cohort

    Directory of Open Access Journals (Sweden)

    Laura J. Heathfield

    2014-09-01

    Full Text Available Alcohol abuse accounts for approximately 2.5 million deaths annually and is the third highest risk factor for disease and disability. Alcohol is metabolised by polymorphic enzymes and the status of an individual with respect to alcohol metabolising enzymes may have forensic relevance in post-mortems. Baseline frequencies of gene variants involved in alcohol metabolism need to be established to aid the identification of suitable population-specific polymorphisms to genotype during molecular autopsies. The principal alcohol metabolising enzymes include alcohol dehydrogenase (ADH, aldehyde dehydrogenase (ALDH and cytochrome P450 2E1 (CYP2E1. Six single nucleotide polymorphisms (SNPs – rs1229984G>A and rs2066702C>T in ADH1B, rs671G>A in ALDH2, and rs3813867G>C, rs2031920C>T and rs6413432T>A in CYP2E1 – were genotyped in 150 individuals from four South African populations: Xhosa, Zulu, South African white and South African coloured. Allele frequencies for each SNP in the four population groups were 0–10% for rs1229984A, 2–12% for rs2066702T, 0–2% for rs671A, 1–4% for rs3813867C, 0–1% for rs2031920T and 3–15% for rs6413432A. Haplotype analysis revealed a novel combination of three SNPs in CYP2E1 whose effects on alcohol metabolism need further investigation. Establishment of baseline frequencies adds to our knowledge of genetic variation in alcohol metabolising enzymes and additional research is required to determine the functional significance of this novel CYP2E1 haplotype.

  11. The prognostic value of age for invasive lobular breast cancer depending on estrogen receptor and progesterone receptor-defined subtypes: A NCDB analysis.

    Science.gov (United States)

    Liu, Jieqiong; Chen, Kai; Mao, Kai; Su, Fengxi; Liu, Qiang; Jacobs, Lisa K

    2016-02-02

    We aimed to assess the effect of age on survival according to estrogen receptor (ER) and progesterone receptor (PR)-defined lobular breast cancer subtype in a wide age range. 43,230 invasive lobular breast cancer women without comorbidities diagnosed between 2004 and 2011 in the National Cancer Database (NCDB) were analyzed. The effects of age on overall survival (OS) among different age groups were evaluated by log-rank test and Cox proportional model. Multivariate analysis showed that patients diagnosed at both young ( 0.1); and in ER-PR+ subgroup, the HRs were similar in patients younger than 70 (P > 0.1); thus, the plots of HRs in these three subtypes remained steady until the age of 60 or 70. Our findings identified that the effect of age on OS in lobular breast cancer varied with ER/PR-defined subtypes. Personalized treatment strategies should be developed to improve outcomes of breast cancer patients with different ages and ER/PR statuses.

  12. Modeling and E-M estimation of haplotype-specific relative risks from genotype data for a case-control study of unrelated individuals.

    Science.gov (United States)

    Stram, Daniel O; Leigh Pearce, Celeste; Bretsky, Phillip; Freedman, Matthew; Hirschhorn, Joel N; Altshuler, David; Kolonel, Laurence N; Henderson, Brian E; Thomas, Duncan C

    2003-01-01

    The US National Cancer Institute has recently sponsored the formation of a Cohort Consortium (http://2002.cancer.gov/scpgenes.htm) to facilitate the pooling of data on very large numbers of people, concerning the effects of genes and environment on cancer incidence. One likely goal of these efforts will be generate a large population-based case-control series for which a number of candidate genes will be investigated using SNP haplotype as well as genotype analysis. The goal of this paper is to outline the issues involved in choosing a method of estimating haplotype-specific risk estimates for such data that is technically appropriate and yet attractive to epidemiologists who are already comfortable with odds ratios and logistic regression. Our interest is to develop and evaluate extensions of methods, based on haplotype imputation, that have been recently described (Schaid et al., Am J Hum Genet, 2002, and Zaykin et al., Hum Hered, 2002) as providing score tests of the null hypothesis of no effect of SNP haplotypes upon risk, which may be used for more complex tasks, such as providing confidence intervals, and tests of equivalence of haplotype-specific risks in two or more separate populations. In order to do so we (1) develop a cohort approach towards odds ratio analysis by expanding the E-M algorithm to provide maximum likelihood estimates of haplotype-specific odds ratios as well as genotype frequencies; (2) show how to correct the cohort approach, to give essentially unbiased estimates for population-based or nested case-control studies by incorporating the probability of selection as a case or control into the likelihood, based on a simplified model of case and control selection, and (3) finally, in an example data set (CYP17 and breast cancer, from the Multiethnic Cohort Study) we compare likelihood-based confidence interval estimates from the two methods with each other, and with the use of the single-imputation approach of Zaykin et al. applied under both

  13. Haplotype Study in SCA10 Families Provides Further Evidence for a Common Ancestral Origin of the Mutation.

    Science.gov (United States)

    Bampi, Giovana B; Bisso-Machado, Rafael; Hünemeier, Tábita; Gheno, Tailise C; Furtado, Gabriel V; Veliz-Otani, Diego; Cornejo-Olivas, Mario; Mazzeti, Pillar; Bortolini, Maria Cátira; Jardim, Laura B; Saraiva-Pereira, Maria Luiza

    2017-12-01

    Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant neurodegenerative disorder characterized by progressive cerebellar ataxia and epilepsy. The disease is caused by a pentanucleotide ATTCT expansion in intron 9 of the ATXN10 gene on chromosome 22q13.3. SCA10 has shown a geographical distribution throughout America with a likely degree of Amerindian ancestry from different countries so far. Currently available data suggest that SCA10 mutation might have spread out early during the peopling of the Americas. However, the ancestral origin of SCA10 mutation remains under speculation. Samples of SCA10 patients from two Latin American countries were analysed, being 16 families from Brazil (29 patients) and 21 families from Peru (27 patients) as well as 49 healthy individuals from Indigenous Quechua population and 51 healthy Brazilian individuals. Four polymorphic markers spanning a region of 5.2 cM harbouring the ATTCT expansion were used to define the haplotypes, which were genotyped by different approaches. Our data have shown that 19-CGGC-14 shared haplotype was found in 47% of Brazilian and in 63% of Peruvian families. Frequencies from both groups are not statistically different from Quechua controls (57%), but they are statistically different from Brazilian controls (12%) (p Quechuas, 19-15-CGGC-14-10, is found in 50% of Brazilian and in 65% of Peruvian patients with SCA10. These findings bring valuable evidence that ATTCT expansion may have arisen in a Native American chromosome.

  14. HLA-G regulatory haplotypes and implantation outcome in couples who underwent assisted reproduction treatment.

    Science.gov (United States)

    Costa, Cynthia Hernandes; Gelmini, Georgia Fernanda; Wowk, Pryscilla Fanini; Mattar, Sibelle Botogosque; Vargas, Rafael Gustavo; Roxo, Valéria Maria Munhoz Sperandio; Schuffner, Alessandro; Bicalho, Maria da Graça

    2012-09-01

    The role of HLA-G in several clinical conditions related to reproduction has been investigated. Important polymorphisms have been found within the 5'URR and 3'UTR regions of the HLA-G promoter. The aim of the present study was to investigate 16 SNPs in the 5'URR and 14-bp insertion/deletion (ins/del) polymorphism located in the 3'UTR region of the HLA-G gene and its possible association with the implantation outcome in couples who underwent assisted reproduction treatments (ART). The case group was composed of 25 ART couples. Ninety-four couples with two or more term pregnancies composed the control group. Polymorphism haplotype frequencies of the HLA-G were determined for both groups. The Haplotype 5, Haplotype 8 and Haplotype 11 were absolute absence in ART couples. The HLA-G*01:01:02a, HLA-G*01:01:02b alleles and the 14-bp ins polymorphism, Haplotype 2, showed an increased frequency in case women and similar distribution between case and control men. However, this susceptibility haplotype is significantly presented in case women and in couple with failure implantation after treatment, which led us to suggest a maternal effect, associated with this haplotype, once their presence in women is related to a higher number of couples who underwent ART. Copyright © 2012. Published by Elsevier Inc.

  15. Mineralocorticoid receptor haplotype moderates the effects of oral contraceptives and menstrual cycle on emotional information processing.

    Science.gov (United States)

    Hamstra, Danielle A; de Kloet, E Ronald; Tollenaar, Marieke; Verkuil, Bart; Manai, Meriem; Putman, Peter; Van der Does, Willem

    2016-10-01

    The processing of emotional information is affected by menstrual cycle phase and by the use of oral contraceptives (OCs). The stress hormone cortisol is known to affect emotional information processing via the limbic mineralocorticoid receptor (MR). We investigated in an exploratory study whether the MR-genotype moderates the effect of both OC-use and menstrual cycle phase on emotional cognition. Healthy premenopausal volunteers (n=93) of West-European descent completed a battery of emotional cognition tests. Forty-nine participants were OC users and 44 naturally cycling, 21 of whom were tested in the early follicular (EF) and 23 in the mid-luteal (ML) phase of the menstrual cycle. In MR-haplotype 1/3 carriers, ML women gambled more than EF women when their risk to lose was relatively small. In MR-haplotype 2, ML women gambled more than EF women, regardless of their odds of winning. OC-users with MR-haplotype 1/3 recognised fewer facial expressions than ML women with MR-haplotype 1/3. MR-haplotype 1/3 carriers may be more sensitive to the influence of their female hormonal status. MR-haplotype 2 carriers showed more risky decision-making. As this may reflect optimistic expectations, this finding may support previous observations in female carriers of MR-haplotype 2 in a naturalistic cohort study. © The Author(s) 2016.

  16. Fetal hemoglobin in sickle cell anemia: The Arab-Indian haplotype and new therapeutic agents.

    Science.gov (United States)

    Habara, Alawi H; Shaikho, Elmutaz M; Steinberg, Martin H

    2017-11-01

    Fetal hemoglobin (HbF) has well-known tempering effects on the symptoms of sickle cell disease and its levels vary among patients with different haplotypes of the sickle hemoglobin gene. Compared with sickle cell anemia haplotypes found in patients of African descent, HbF levels in Saudi and Indian patients with the Arab-Indian (AI) haplotype exceed that in any other haplotype by nearly twofold. Genetic association studies have identified some loci associated with high HbF in the AI haplotype but these observations require functional confirmation. Saudi patients with the Benin haplotype have HbF levels almost twice as high as African patients with this haplotype but this difference is unexplained. Hydroxyurea is still the only FDA approved drug for HbF induction in sickle cell disease. While most patients treated with hydroxyurea have an increase in HbF and some clinical improvement, 10 to 20% of adults show little response to this agent. We review the genetic basis of HbF regulation focusing on sickle cell anemia in Saudi Arabia and discuss new drugs that can induce increased levels of HbF. © 2017 Wiley Periodicals, Inc.

  17. Defining Quantum Control Flow

    OpenAIRE

    Ying, Mingsheng; Yu, Nengkun; Feng, Yuan

    2012-01-01

    A remarkable difference between quantum and classical programs is that the control flow of the former can be either classical or quantum. One of the key issues in the theory of quantum programming languages is defining and understanding quantum control flow. A functional language with quantum control flow was defined by Altenkirch and Grattage [\\textit{Proc. LICS'05}, pp. 249-258]. This paper extends their work, and we introduce a general quantum control structure by defining three new quantu...

  18. Can play be defined?

    DEFF Research Database (Denmark)

    Eichberg, Henning

    2015-01-01

    Can play be defined? There is reason to raise critical questions about the established academic demand that at phenomenon – also in humanist studies – should first of all be defined, i.e. de-lineated and by neat lines limited to a “little box” that can be handled. The following chapter develops....... Human beings can very well understand play – or whatever phenomenon in human life – without defining it....

  19. Annexin A5 Promoter Haplotype M2 Is Not a Risk Factor for Recurrent Pregnancy Loss in Northern Europe

    DEFF Research Database (Denmark)

    Nagirnaja, Liina; Nõmmemees, Diana; Rull, Kristiina

    2015-01-01

    and recurrent pregnancy loss (RPL), however with inconclusive results. STUDY SUBJECTS AND METHODS: A retrospective case-control study combining resequencing and restriction fragment length polymorphism (RFLP) analysis was undertaken in 313 women with unexplained RPL and 214 fertile women from Estonia...... compared to controls both in Estonia (8.1% vs 15.2%, respectively) and Denmark (9.7% vs 12.6%). The high M2 prevalence in fertile controls was consistent with estimations for European and East Asian populations (9.6%-16.0%). CONCLUSIONS: This study cautions to consider the M2 haplotype as a deterministic...

  20. Genetic and molecular characterization of three novel S-haplotypes in sour cherry (Prunus cerasus L.).

    Science.gov (United States)

    Tsukamoto, Tatsuya; Potter, Daniel; Tao, Ryutaro; Vieira, Cristina P; Vieira, Jorge; Iezzoni, Amy F

    2008-01-01

    Tetraploid sour cherry (Prunus cerasus L.) exhibits gametophytic self-incompatibility (GSI) whereby the specificity of self-pollen rejection is controlled by alleles of the stylar and pollen specificity genes, S-RNase and SFB (S haplotype-specific F-box protein gene), respectively. As sour cherry selections can be either self-compatible (SC) or self-incompatible (SI), polyploidy per se does not result in SC. Instead the genotype-dependent loss of SI in sour cherry is due to the accumulation of non-functional S-haplotypes. The presence of two or more non-functional S-haplotypes within sour cherry 2x pollen renders that pollen SC. Two new S-haplotypes from sour cherry, S(33) and S(34), that are presumed to be contributed by the P. fruticosa species parent, the complete S-RNase and SFB sequences of a third S-haplotype, S(35), plus the presence of two previously identified sweet cherry S-haplotypes, S(14) and S(16) are described here. Genetic segregation data demonstrated that the S(16)-, S(33)-, S(34)-, and S(35)-haplotypes present in sour cherry are fully functional. This result is consistent with our previous finding that 'hetero-allelic' pollen is incompatible in sour cherry. Phylogenetic analyses of the SFB and S-RNase sequences from available Prunus species reveal that the relationships among S-haplotypes show no correspondence to known organismal relationships at any taxonomic level within Prunus, indicating that polymorphisms at the S-locus have been maintained throughout the evolution of the genus. Furthermore, the phylogenetic relationships among SFB sequences are generally incongruent with those among S-RNase sequences for the same S-haplotypes. Hypotheses compatible with these results are discussed.

  1. Effects of Single Nucleotide Polymorphism Marker Density on Haplotype Block Partition

    Directory of Open Access Journals (Sweden)

    Sun Ah Kim

    2016-12-01

    Full Text Available Many researchers have found that one of the most important characteristics of the structure of linkage disequilibrium is that the human genome can be divided into non-overlapping block partitions in which only a small number of haplotypes are observed. The location and distribution of haplotype blocks can be seen as a population property influenced by population genetic events such as selection, mutation, recombination and population structure. In this study, we investigate the effects of the density of markers relative to the full set of all polymorphisms in the region on the results of haplotype partitioning for five popular haplotype block partition methods: three methods in Haploview (confidence interval, four gamete test, and solid spine, MIG++ implemented in PLINK 1.9 and S-MIG++. We used several experimental datasets obtained by sampling subsets of single nucleotide polymorphism (SNP markers of chromosome 22 region in the 1000 Genomes Project data and also the HapMap phase 3 data to compare the results of haplotype block partitions by five methods. With decreasing sampling ratio down to 20% of the original SNP markers, the total number of haplotype blocks decreases and the length of haplotype blocks increases for all algorithms. When we examined the marker-independence of the haplotype block locations constructed from the datasets of different density, the results using below 50% of the entire SNP markers were very different from the results using the entire SNP markers. We conclude that the haplotype block construction results should be used and interpreted carefully depending on the selection of markers and the purpose of the study.

  2. Mapping of HLA- DQ haplotypes in a group of Danish patients with celiac disease

    DEFF Research Database (Denmark)

    Lund, Flemming; Hermansen, Mette N; Pedersen, Merete F

    2015-01-01

    BACKGROUND: A cost-effective identification of HLA- DQ risk haplotypes using the single nucleotide polymorphism (SNP) technique has recently been applied in the diagnosis of celiac disease (CD) in four European populations. The objective of the study was to map risk HLA- DQ haplotypes in a group...... of Danish CD patients using the SNP technique. METHODS: Cohort A: Among 65 patients with gastrointestinal symptoms we compared the HLA- DQ2 and HLA- DQ8 risk haplotypes obtained by the SNP technique (method 1) with results based on a sequence specific primer amplification technique (method 2...

  3. Genetic relationships among native americans based on b-globin gene cluster haplotype frequencies

    OpenAIRE

    Mousinho-Ribeiro Rita de Cassia; Pante-de-Sousa Gabriella; Santos Eduardo José Melo dos; Guerreiro João Farias

    2003-01-01

    The distribution of b-globin gene haplotypes was studied in 209 Amerindians from eight tribes of the Brazilian Amazon: Asurini from Xingú, Awá-Guajá, Parakanã, Urubú-Kaapór, Zoé, Kayapó (Xikrin from the Bacajá village), Katuena, and Tiriyó. Nine different haplotypes were found, two of which (n. 11 and 13) had not been previously identified in Brazilian indigenous populations. Haplotype 2 (+ - - - -) was the most common in all groups studied, with frequencies varying from 70% to 100%, followed...

  4. The Prognostic Value of Haplotypes in the Vascular Endothelial Growth Factor

    DEFF Research Database (Denmark)

    Hansen, Torben Frøstrup; Spindler, Karen-Lise Garm; Andersen, Rikke Fredslund

    2010-01-01

    Abstract: New prognostic markers in patients with colorectal cancer (CRC) are a prerequisite for individualized treatment. Prognostic importance of single nucleotide polymorphisms (SNPs) in the vascular endothelial growth factor A (VEGF-A) gene has been proposed. The objective of the present study...... using the PHASE program. The prognostic influence was evaluated using Kaplan-Meir plots and log rank tests. Cox regression method was used to analyze the independent prognostic importance of different markers. All three SNPs were significantly related to survival. A haplotype combination, responsible...... findings in a second and independent cohort. Haplotype combinations call for further investigation. Keywords: colorectal neoplasm; single nucleotide polymorphisms; haplotypes; vascular endothelial growth factor A; survival...

  5. Population-specific haplotype association of the postsynaptic density gene DLG4 with schizophrenia, in family-based association studies.

    Directory of Open Access Journals (Sweden)

    Shabeesh Balan

    Full Text Available The post-synaptic density (PSD of glutamatergic synapses harbors a multitude of proteins critical for maintaining synaptic dynamics. Alteration of protein expression levels in this matrix is a marked phenomenon of neuropsychiatric disorders including schizophrenia, where cognitive functions are impaired. To investigate the genetic relationship of genes expressed in the PSD with schizophrenia, a family-based association analysis of genetic variants in PSD genes such as DLG4, DLG1, PICK1 and MDM2, was performed, using Japanese samples (124 pedigrees, n = 376 subjects. Results showed a significant association of the rs17203281 variant from the DLG4 gene, with preferential transmission of the C allele (p = 0.02, although significance disappeared after correction for multiple testing. Replication analysis of this variant, found no association in a Chinese schizophrenia cohort (293 pedigrees, n = 1163 subjects or in a Japanese case-control sample (n = 4182 subjects. The DLG4 expression levels between postmortem brain samples from schizophrenia patients showed no significant changes from controls. Interestingly, a five marker haplotype in DLG4, involving rs2242449, rs17203281, rs390200, rs222853 and rs222837, was enriched in a population specific manner, where the sequences A-C-C-C-A and G-C-C-C-A accumulated in Japanese (p = 0.0009 and Chinese (p = 0.0007 schizophrenia pedigree samples, respectively. However, this could not be replicated in case-control samples. None of the variants in other examined candidate genes showed any significant association in these samples. The current study highlights a putative role for DLG4 in schizophrenia pathogenesis, evidenced by haplotype association, and warrants further dense screening for variants within these haplotypes.

  6. Recovery of native genetic background in admixed populations using haplotypes, phenotypes, and pedigree information--using Cika cattle as a case breed.

    Directory of Open Access Journals (Sweden)

    Mojca Simčič

    Full Text Available The aim of this study was to obtain unbiased estimates of the diversity parameters, the population history, and the degree of admixture in Cika cattle which represents the local admixed breeds at risk of extinction undergoing challenging conservation programs. Genetic analyses were performed on the genome-wide Single Nucleotide Polymorphism (SNP Illumina Bovine SNP50 array data of 76 Cika animals and 531 animals from 14 reference populations. To obtain unbiased estimates we used short haplotypes spanning four markers instead of single SNPs to avoid an ascertainment bias of the BovineSNP50 array. Genome-wide haplotypes combined with partial pedigree and type trait classification show the potential to improve identification of purebred animals with a low degree of admixture. Phylogenetic analyses demonstrated unique genetic identity of Cika animals. Genetic distance matrix presented by rooted Neighbour-Net suggested long and broad phylogenetic connection between Cika and Pinzgauer. Unsupervised clustering performed by the admixture analysis and two-dimensional presentation of the genetic distances between individuals also suggest Cika is a distinct breed despite being similar in appearance to Pinzgauer. Animals identified as the most purebred could be used as a nucleus for a recovery of the native genetic background in the current admixed population. The results show that local well-adapted strains, which have never been intensively managed and differentiated into specific breeds, exhibit large haplotype diversity. They suggest a conservation and recovery approach that does not rely exclusively on the search for the original native genetic background but rather on the identification and removal of common introgressed haplotypes would be more powerful. Successful implementation of such an approach should be based on combining phenotype, pedigree, and genome-wide haplotype data of the breed of interest and a spectrum of reference breeds which

  7. Globin haplotypes of human T-cell lymphotropic virus type I-infected individuals in Salvador, Bahia, Brazil, suggest a post-Columbian African origin of this virus.

    Science.gov (United States)

    Alcantara, Luiz Carlos; Van Dooren, Sonia; Gonçalves, Marilda Souza; Kashima, Simone; Costa, Maria Cristina Ramos; Santos, Fred Luciano Neves; Bittencourt, Achilea Lisboa; Dourado, Inês; Filho, Antonio Andrade; Covas, Dimas Tadeu; Vandamme, Anne-Mieke; Galvão-Castro, Bernardo

    2003-08-01

    The city of Salvador, Bahia, Brazil, has sociodemographic characteristics similar to some African cities. Up to now, it has had the highest prevalence of human T-cell lymphotropic virus type I (HTLV-I) infection (1.74%) in the country. To investigate which strains of HTLV-I are circulating in Salvador, we studied isolates from 82 patients infected with HTLV-I: 19 from the general population, 21 from pregnant women, 16 from intravenous drug users, and 26 from patients and their family attending a neurologic clinic. Phylogenetic analysis from part of the LTR fragments showed that most of these isolates belonged to the Transcontinental subgroup of the Cosmopolitan subtype (HTLV-Ia). Only one sample from a pregnant woman was closely related to the Japanese subgroup, suggesting recent introduction of a Japanese HTLV-I lineage into Salvador. betaA-Globin haplotypes were examined in 34 infected individuals and found to be atypical, confirming the racial heterogeneity of this population. A total of 20 chromosomes were characterized as Central African Republic (CAR) haplotype (29.4%), 31 (45.6%) were characterized as Benin (BEN) haplotype, and 17 (25%) were characterized as Senegal (SEN) haplotype. Five patients' genotypes (14.7%) were CAR/CAR; 10 (29,4%), BEN/BEN; 9 (26.5%), CAR/BEN; 2 (5.9%), BEN/SEN; and 7 (20.6%), SEN/SEN. One patient's genotype (2.9%) was CAR/SEN. The betaA-globin haplotype distribution in Salvador is unusual compared with other Brazilian states. Our data support the hypothesis of multiple post-Columbian introductions of African HTLV-Ia strains in Salvador, Bahia, Brazil.

  8. Strong association between a splice mutation (IVS12+5G{r_arrow}A) and haplotype 6 in hereditary tyrosinemia type I

    Energy Technology Data Exchange (ETDEWEB)

    Tanguay, R.M.; St-Louis, M.; Gibson, K. [Universite Laval, Ste-Foy (Canada)] [and others

    1994-09-01

    Hereditary tyrosinemia type I (HT I; McKusick 276700) is a severe inborn error of tyrosine catabolism pathway caused by a deficiency of fumarylacetoacetate hydrolase (FAH). The highest frequency reported is the one in Saguenay-Lac St-Jean (Quebec, Canada) where 1:1,846 births are affected. The FAH gene has been cloned and several mutations have been described. Allele specific oligonucleotide (ASO) hybridization was used to examine the frequency of a splice (IVS12-5G{r_arrow}A) mutation recently reported and RFLP analysis was done to identify haplotypes related to HT I. The splice mutation was found on 45/50 alleles (90%) in patients from SLSJ and 12/66 (18%) alleles from patients world-wide. All 25 patients from the SLSJ region were positive with 20 being homozygous, indicating that this mutation is the major cause of HT I in French Canada. Of these 25 patients, 96% were positive for one haplotype called no 6 which is these 25 patients, 96% were positive for one haplotype called no 6 which is identified by TaqI, RsaI, BglII, MspI and KpnI digestions. These data show a really strong association between the mutation (IVS12+5G{r_arrow}A) and haplotype 6. Among our patients from around the world, {approximately}52% were positive for haplotype 6 indicating its strong relation with HT I. These results provide the rationale for DNA-based carrier testing for HT I in the F-C population at risk as well as in HT I patients in general.

  9. MDR1 haplotypes conferring an increased expression of intestinal CYP3A4 rather than MDR1 in female living-donor liver transplant patients.

    Science.gov (United States)

    Hosohata, Keiko; Masuda, Satohiro; Yonezawa, Atsushi; Katsura, Toshiya; Oike, Fumitaka; Ogura, Yasuhiro; Takada, Yasutsugu; Egawa, Hiroto; Uemoto, Shinji; Inui, Ken-Ichi

    2009-07-01

    This study investigated whether haplotypes in the multidrug resistance 1 (MDR1) gene had effects on mRNA expression levels of MDR1 and cytochrome P450 (CYP) 3A4, and on the pharmacokinetics of tacrolimus in living-donor liver transplant (LDLT) patients, considering the gender difference. Haplotype analysis of MDR1 with G2677T/A and C3435T was performed in 63 de novo Japanese LDLT patients (17 to 55 years; 44.4% women). The expression levels of MDR1 and CYP3A4 mRNAs in jejunal biopsy specimens were quantified by real-time PCR. Intestinal CYP3A4 mRNA expression levels (amol/microg total RNA) showed significantly higher values in women carrying the 2677TT-3435TT haplotype (median, 10.7; range, 5.92-15.2) than those with 2677GG-3435CC (3.03; range 1.38-4.68) and 2677GT-3435CT (median, 4.31; range, 0.07-9.42) (P = 0.022), but not in men (P = 0.81). However, MDR1 haplotype did not influence mRNA expression levels of MDR1 nor the concentration/dose ratio [(ng/mL)/(mg/day)] of oral tacrolimus for the postoperative 7 days, irrespective of gender. MDR1 haplotype may have a minor association with the tacrolimus pharmacokinetics after LDLT, but could be a good predictor of the inter-individual variation of intestinal expression of CYP3A4 in women.

  10. Exploring climate niches of ponderosa pine (Pinus ponderosa Douglas ex Lawson) haplotypes in the western United States: Implications for evolutionary history and conservation

    Science.gov (United States)

    Shinneman, Douglas; Means, Robert E.; Potter, Kevin M.; Hipkins, Valerie D.

    2016-01-01

    Ponderosa pine (Pinus ponderosa Douglas ex Lawson) occupies montane environments throughout western North America, where it is both an ecologically and economically important tree species. A recent study using mitochondrial DNA analysis demonstrated substantial genetic variation among ponderosa pine populations in the western U.S., identifying 10 haplotypes with unique evolutionary lineages that generally correspond spatially with distributions of the Pacific (P. p. var. ponderosa) and Rocky Mountain (P. p. var. scopulorum) varieties. To elucidate the role of climate in shaping the phylogeographic history of ponderosa pine, we used nonparametric multiplicative regression to develop predictive climate niche models for two varieties and 10 haplotypes and to hindcast potential distribution of the varieties during the last glacial maximum (LGM), ~22,000 yr BP. Our climate niche models performed well for the varieties, but haplotype models were constrained in some cases by small datasets and unmeasured microclimate influences. The models suggest strong relationships between genetic lineages and climate. Particularly evident was the role of seasonal precipitation balance in most models, with winter- and summer-dominated precipitation regimes strongly associated with P. p. vars. ponderosa and scopulorum, respectively. Indeed, where present-day climate niches overlap between the varieties, introgression of two haplotypes also occurs along a steep clinal divide in western Montana. Reconstructed climate niches for the LGM suggest potentially suitable climate existed for the Pacific variety in the California Floristic province, the Great Basin, and Arizona highlands, while suitable climate for the Rocky Mountain variety may have existed across the southwestern interior highlands. These findings underscore potentially unique phylogeographic origins of modern ponderosa pine evolutionary lineages, including potential adaptations to Pleistocene climates associated with

  11. Exploring Climate Niches of Ponderosa Pine (Pinus ponderosa Douglas ex Lawson) Haplotypes in the Western United States: Implications for Evolutionary History and Conservation.

    Science.gov (United States)

    Shinneman, Douglas J; Means, Robert E; Potter, Kevin M; Hipkins, Valerie D

    2016-01-01

    Ponderosa pine (Pinus ponderosa Douglas ex Lawson) occupies montane environments throughout western North America, where it is both an ecologically and economically important tree species. A recent study using mitochondrial DNA analysis demonstrated substantial genetic variation among ponderosa pine populations in the western U.S., identifying 10 haplotypes with unique evolutionary lineages that generally correspond spatially with distributions of the Pacific (P. p. var. ponderosa) and Rocky Mountain (P. p. var. scopulorum) varieties. To elucidate the role of climate in shaping the phylogeographic history of ponderosa pine, we used nonparametric multiplicative regression to develop predictive climate niche models for two varieties and 10 haplotypes and to hindcast potential distribution of the varieties during the last glacial maximum (LGM), ~22,000 yr BP. Our climate niche models performed well for the varieties, but haplotype models were constrained in some cases by small datasets and unmeasured microclimate influences. The models suggest strong relationships between genetic lineages and climate. Particularly evident was the role of seasonal precipitation balance in most models, with winter- and summer-dominated precipitation regimes strongly associated with P. p. vars. ponderosa and scopulorum, respectively. Indeed, where present-day climate niches overlap between the varieties, introgression of two haplotypes also occurs along a steep clinal divide in western Montana. Reconstructed climate niches for the LGM suggest potentially suitable climate existed for the Pacific variety in the California Floristic province, the Great Basin, and Arizona highlands, while suitable climate for the Rocky Mountain variety may have existed across the southwestern interior highlands. These findings underscore potentially unique phylogeographic origins of modern ponderosa pine evolutionary lineages, including potential adaptations to Pleistocene climates associated with discrete

  12. Exploring Climate Niches of Ponderosa Pine (Pinus ponderosa Douglas ex Lawson Haplotypes in the Western United States: Implications for Evolutionary History and Conservation.

    Directory of Open Access Journals (Sweden)

    Douglas J Shinneman

    Full Text Available Ponderosa pine (Pinus ponderosa Douglas ex Lawson occupies montane environments throughout western North America, where it is both an ecologically and economically important tree species. A recent study using mitochondrial DNA analysis demonstrated substantial genetic variation among ponderosa pine populations in the western U.S., identifying 10 haplotypes with unique evolutionary lineages that generally correspond spatially with distributions of the Pacific (P. p. var. ponderosa and Rocky Mountain (P. p. var. scopulorum varieties. To elucidate the role of climate in shaping the phylogeographic history of ponderosa pine, we used nonparametric multiplicative regression to develop predictive climate niche models for two varieties and 10 haplotypes and to hindcast potential distribution of the varieties during the last glacial maximum (LGM, ~22,000 yr BP. Our climate niche models performed well for the varieties, but haplotype models were constrained in some cases by small datasets and unmeasured microclimate influences. The models suggest strong relationships between genetic lineages and climate. Particularly evident was the role of seasonal precipitation balance in most models, with winter- and summer-dominated precipitation regimes strongly associated with P. p. vars. ponderosa and scopulorum, respectively. Indeed, where present-day climate niches overlap between the varieties, introgression of two haplotypes also occurs along a steep clinal divide in western Montana. Reconstructed climate niches for the LGM suggest potentially suitable climate existed for the Pacific variety in the California Floristic province, the Great Basin, and Arizona highlands, while suitable climate for the Rocky Mountain variety may have existed across the southwestern interior highlands. These findings underscore potentially unique phylogeographic origins of modern ponderosa pine evolutionary lineages, including potential adaptations to Pleistocene climates associated

  13. Haplotype-based case-control study on human apurinic/apyrimidinic endonuclease 1/redox effector factor-1 gene and essential hypertension.

    Science.gov (United States)

    Naganuma, Takahiro; Nakayama, Tomohiro; Sato, Naoyuki; Fu, Zhenyan; Soma, Masayoshi; Yamaguchi, Mai; Shimodaira, Masanori; Aoi, Noriko; Usami, Ron

    2010-02-01

    Oxidative DNA damage is involved in the pathophysiology of essential hypertension (EH), which is a multifactorial disorder. Apurinic/apyrimidinic endonuclease 1/redox effector factor-1 (APE1/REF-1) is an essential endonuclease in the base excision repair pathway of oxidatively damaged DNA, in addition to having reducing properties that promote the binding of redox-sensitive transcription factors. Blood pressure in APE1/REF-1-knockout mice is reported to be significantly higher than in wild-type mice. The aim of this study was to investigate the relationship between EH and the human APE1/REF-1 gene through a haplotype-based case-control study using single-nucleotide polymorphisms (SNPs). We selected five SNPs in the human APE1/REF-1 gene (rs1760944, rs3136814, rs17111967, rs3136817, and rs1130409), and performed case-control studies in 265 EH patients and 266 age-matched normotensive (NT) subjects. rs17111967 was found to show nonheterogeneity among Japanese subjects. There were no significant differences in the overall distribution of genotypes or alleles for each SNP between EH and NT groups. In the overall distribution of the haplotype-based case-control study constructed based on rs1760944, rs3136817, and rs1130409, the frequency of the G-T-T haplotype was significantly higher in the EH group than in the NT group (2.1% vs. 0.0%, P = 0.001). Multiple logistic regression analysis also revealed significant differences for the G-T-T haplotype, even after adjustment for confounding factors (OR = 8.600, 95% CI: 1.073-68.951, P = 0.043). Based on the present results, the G-T-T haplotype appears to be a genetic marker of EH, and the APE1/REF-1 gene appears to be a susceptibility gene for EH.

  14. Effects of defined mixtures of persistent organic pollutants (POPs) on multiple cellular responses in the human hepatocarcinoma cell line, HepG2, using high content analysis screening

    Energy Technology Data Exchange (ETDEWEB)

    Wilson, Jodie [Institute for Global Food Security, School of Biological Sciences, Queen' s University Belfast, Northern Ireland (United Kingdom); Berntsen, Hanne Friis; Zimmer, Karin Elisabeth [Norwegian University of Life Sciences, Oslo (Norway); Frizzell, Caroline [Institute for Global Food Security, School of Biological Sciences, Queen' s University Belfast, Northern Ireland (United Kingdom); Verhaegen, Steven; Ropstad, Erik [Norwegian University of Life Sciences, Oslo (Norway); Connolly, Lisa, E-mail: l.connolly@qub.ac.uk [Institute for Global Food Security, School of Biological Sciences, Queen' s University Belfast, Northern Ireland (United Kingdom)

    2016-03-01

    Persistent organic pollutants (POPs) are toxic substances, highly resistant to environmental degradation, which can bio-accumulate and have long-range atmospheric transport potential. Most studies focus on single compound effects, however as humans are exposed to several POPs simultaneously, investigating exposure effects of real life POP mixtures on human health is necessary. A defined mixture of POPs was used, where the compound concentration reflected its contribution to the levels seen in Scandinavian human serum (total mix). Several sub mixtures representing different classes of POPs were also constructed. The perfluorinated (PFC) mixture contained six perfluorinated compounds, brominated (Br) mixture contained seven brominated compounds, chlorinated (Cl) mixture contained polychlorinated biphenyls and also p,p’-dichlorodiphenyldichloroethylene, hexachlorobenzene, three chlordanes, three hexachlorocyclohexanes and dieldrin. Human hepatocarcinoma (HepG2) cells were used for 2 h and 48 h exposures to the seven mixtures and analysis on a CellInsight™ NXT High Content Screening platform. Multiple cytotoxic endpoints were investigated: cell number, nuclear intensity and area, mitochondrial mass and membrane potential (MMP) and reactive oxygen species (ROS). Both the Br and Cl mixtures induced ROS production but did not lead to apoptosis. The PFC mixture induced ROS production and likely induced cell apoptosis accompanied by the dissipation of MMP. Synergistic effects were evident for ROS induction when cells were exposed to the PFC + Br mixture in comparison to the effects of the individual mixtures. No significant effects were detected in the Br + Cl, PFC + Cl or total mixtures, which contain the same concentrations of chlorinated compounds as the Cl mixture plus additional compounds; highlighting the need for further exploration of POP mixtures in risk assessment. - Highlights: • High content analysis (HCA) is a novel approach for determining toxicity of

  15. Effects of defined mixtures of persistent organic pollutants (POPs) on multiple cellular responses in the human hepatocarcinoma cell line, HepG2, using high content analysis screening

    International Nuclear Information System (INIS)

    Wilson, Jodie; Berntsen, Hanne Friis; Zimmer, Karin Elisabeth; Frizzell, Caroline; Verhaegen, Steven; Ropstad, Erik; Connolly, Lisa

    2016-01-01

    Persistent organic pollutants (POPs) are toxic substances, highly resistant to environmental degradation, which can bio-accumulate and have long-range atmospheric transport potential. Most studies focus on single compound effects, however as humans are exposed to several POPs simultaneously, investigating exposure effects of real life POP mixtures on human health is necessary. A defined mixture of POPs was used, where the compound concentration reflected its contribution to the levels seen in Scandinavian human serum (total mix). Several sub mixtures representing different classes of POPs were also constructed. The perfluorinated (PFC) mixture contained six perfluorinated compounds, brominated (Br) mixture contained seven brominated compounds, chlorinated (Cl) mixture contained polychlorinated biphenyls and also p,p’-dichlorodiphenyldichloroethylene, hexachlorobenzene, three chlordanes, three hexachlorocyclohexanes and dieldrin. Human hepatocarcinoma (HepG2) cells were used for 2 h and 48 h exposures to the seven mixtures and analysis on a CellInsight™ NXT High Content Screening platform. Multiple cytotoxic endpoints were investigated: cell number, nuclear intensity and area, mitochondrial mass and membrane potential (MMP) and reactive oxygen species (ROS). Both the Br and Cl mixtures induced ROS production but did not lead to apoptosis. The PFC mixture induced ROS production and likely induced cell apoptosis accompanied by the dissipation of MMP. Synergistic effects were evident for ROS induction when cells were exposed to the PFC + Br mixture in comparison to the effects of the individual mixtures. No significant effects were detected in the Br + Cl, PFC + Cl or total mixtures, which contain the same concentrations of chlorinated compounds as the Cl mixture plus additional compounds; highlighting the need for further exploration of POP mixtures in risk assessment. - Highlights: • High content analysis (HCA) is a novel approach for determining toxicity of

  16. On detecting incomplete soft or hard selective sweeps using haplotype structure

    DEFF Research Database (Denmark)

    Ferrer-Admetlla, Anna; Liang, Mason; Korneliussen, Thorfinn Sand

    2014-01-01

    We present a new haplotype-based statistic (nSL) for detecting both soft and hard sweeps in population genomic data from a single population. We compare our new method with classic single-population haplotype and site frequency spectrum (SFS)-based methods and show that it is more robust, particu......We present a new haplotype-based statistic (nSL) for detecting both soft and hard sweeps in population genomic data from a single population. We compare our new method with classic single-population haplotype and site frequency spectrum (SFS)-based methods and show that it is more robust......, particularly to recombination rate variation. However, all statistics show some sensitivity to the assumptions of the demographic model. Additionally, we show that nSL has at least as much power as other methods under a number of different selection scenarios, most notably in the cases of sweeps from standing...

  17. Y-STR haplotypes of Native American populations from the Brazilian Amazon region.

    Science.gov (United States)

    Palha, Teresinha Jesus Brabo Ferreira; Rodrigues, Elzemar Martins Ribeiro; dos Santos, Sidney Emanuel Batista

    2010-10-01

    The allele and haplotype frequencies of nine Y-STRs (DYS19, DYS389 I, DYS389 II, DYS390, DYS391, DYS392, DYS393, DYS385 I/II) were determined in a sample of six native tribes from the Brazilian Amazon (Tiriyó, Awa-Guajá, Waiãpi, Urubu-Kaapor, Zoé and Parakanã). Forty-eight different haplotypes were identified, 28 of which unique. Five haplotypes are very frequent and were shared by over 10 individuals. The estimated haplotype diversity (0.9114) was very low compared to other geographic groups, including Africans, Europeans and Asians. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  18. Association of serotonin receptor 2a haplotypes with obsessive-compulsive disorder and its treatment response in Iranian patients: a genetic and pharmacogenetic study.

    Science.gov (United States)

    Sina, Marzie; Ahmadiani, Abolhassan; Asadi, Sareh; Shams, Jamal

    2018-01-01

    Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder causing intrusive thoughts or repetitive behaviors. Serotonin reuptake inhibitors are used for OCD treatment, but 40%-60% of patients do not respond to them adequately. In this study, the associations of serotonin receptor 2a polymorphisms rs6311 and rs6313 with OCD, its familial form and fluvoxamine treatment response in Iranian population were investigated. Association analyses were conducted in 293 OCD cases fulfilling the Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV-TR and 245 controls. Pharmacotherapy was defined as 12 weeks of treatment with fluvoxamine (150-300 mg). Treatment response was considered as >25% reduction in Yale-Brown Obsessive Compulsive Scale score. Genotyping was performed by means of PCR-RFLP. The results showed no association of rs6311 or rs6313 with OCD, but their haplotypes had different distribution patterns in cases and controls. Moreover, rs6313 was associated with the familial form of OCD in females significantly ( P =0.005) under the recessive genetic model. Moreover, rs6311-rs6313 haplotypes were associated with fluvoxamine treatment response in OCD patients with more AC and less AT in responders. HTR2A haplotypes are associated with OCD and its treatment response with a fluvoxamine in Iranian patients. Furthermore, the observed association of rs6313 with the familial form of OCD in females suggests different genetic background of OCD familial and non-familial forms, which needs further investigation.

  19. Defining Overweight and Obesity

    Science.gov (United States)

    ... Micronutrient Malnutrition State and Local Programs Defining Adult Overweight and Obesity Recommend on Facebook Tweet Share Compartir ... weight for a given height is described as overweight or obese. Body Mass Index, or BMI, is ...

  20. Drinking Levels Defined

    Science.gov (United States)

    ... of Alcohol Consumption Alcohol's Effects on the Body Alcohol Use Disorder Fetal Alcohol Exposure Support & Treatment Alcohol Policy Special ... Definition of Drinking at Low Risk for Developing Alcohol Use Disorder (AUD): For women, low-risk drinking is defined ...

  1. Haplotypes of the porcine peroxisome proliferator-activated receptor delta gene are associated with backfat thickness

    Directory of Open Access Journals (Sweden)

    Blöcker Helmut

    2009-11-01

    Full Text Available Abstract Background Peroxisome proliferator-activated receptor delta belongs to the nuclear receptor superfamily of ligand-inducible transcription factors. It is a key regulator of lipid metabolism. The peroxisome proliferator-activated receptor delta gene (PPARD has been assigned to a region on porcine chromosome 7, which harbours a quantitative trait locus for backfat. Thus, PPARD is considered a functional and positional candidate gene for backfat thickness. The purpose of this study was to test this candidate gene hypothesis in a cross of breeds that were highly divergent in lipid deposition characteristics. Results Screening for genetic variation in porcine PPARD revealed only silent mutations. Nevertheless, significant associations between PPARD haplotypes and backfat thickness were observed in the F2 generation of the Mangalitsa × Piétrain cross as well as a commercial German Landrace population. Haplotype 5 is associated with increased backfat in F2 Mangalitsa × Piétrain pigs, whereas haplotype 4 is associated with lower backfat thickness in the German Landrace population. Haplotype 4 and 5 carry the same alleles at all but one SNP. Interestingly, the opposite effects of PPARD haplotypes 4 and 5 on backfat thickness are reflected by opposite effects of these two haplotypes on PPAR-δ mRNA levels. Haplotype 4 significantly increases PPAR-δ mRNA levels, whereas haplotype 5 decreases mRNA levels of PPAR-δ. Conclusion This study provides evidence for an association between PPARD and backfat thickness. The association is substantiated by mRNA quantification. Further studies are required to clarify, whether the observed associations are caused by PPARD or are the result of linkage disequilibrium with a causal variant in a neighbouring gene.

  2. Prognostic importance of VEGF-A haplotype combinations in a stage II colon cancer population

    DEFF Research Database (Denmark)

    Kjaer-Frifeldt, Sanne; Fredslund, Rikke; Lindebjerg, Jan

    2012-01-01

    To investigate the prognostic effect of three VEGF-A SNPs, -2578, -460 and 405, as well as the corresponding haplotype combinations, in a unique population of stage II colon cancer patients.......To investigate the prognostic effect of three VEGF-A SNPs, -2578, -460 and 405, as well as the corresponding haplotype combinations, in a unique population of stage II colon cancer patients....

  3. Interrelationships between Amerindian tribes of lower Amazonia as manifest by HLA haplotype disequilibria.

    OpenAIRE

    Black, F L

    1984-01-01

    HLA B-C haplotypes exhibit common disequilibria in populations drawn from four continents, indicating that they are subject to broadly active selective forces. However, the A-B and A-C associations we have examined show no consistent disequilibrium pattern, leaving open the possibility that these disequilibria are due to descent from common progenitors. By examining HLA haplotype distributions, I have explored the implications that would follow from the hypothesis that biological selection pl...

  4. Mitochondrial and Y chromosome haplotype motifs as diagnostic markers of Jewish ancestry: a reconsideration.

    Directory of Open Access Journals (Sweden)

    Sergio eTofanelli

    2014-11-01

    Full Text Available Several authors have proposed haplotype motifs based on site variants at the mitochondrial genome (mtDNA and the non-recombining portion of the Y chromosome (NRY to trace the genealogies of Jewish people. Here, we analyzed their main approaches and test the feasibility of adopting motifs as ancestry markers through construction of a large database of mtDNA and NRY haplotypes from public genetic genealogical repositories. We verified the reliability of Jewish ancestry prediction based on the Cohen and Levite Modal Haplotypes in their classical 6 STR marker format or in the extended 12 STR format, as well as four founder mtDNA lineages (HVS-I segments accounting for about 40% of the current population of Ashkenazi Jews. For this purpose we compared haplotype composition in individuals of self-reported Jewish ancestry with the rest of European, African or Middle Eastern samples, to test for non-random association of ethno-geographic groups and haplotypes. Overall, NRY and mtDNA based motifs, previously reported to differentiate between groups, were found to be more represented in Jewish compared to non-Jewish groups. However, this seems to stem from common ancestors of Jewish lineages being rather recent respect to ancestors of non-Jewish lineages with the same haplotype signatures. Moreover, the polyphyly of haplotypes which contain the proposed motifs and the misuse of constant mutation rates heavily affected previous attempts to correctly dating the origin of common ancestries. Accordingly, our results stress the limitations of using the above haplotype motifs as reliable Jewish ancestry predictors and show its inadequacy for forensic or genealogical purposes.

  5. Haplotypes in the Dystrophin DNA Segment Point to a Mosaic Origin of Modern Human Diversity

    OpenAIRE

    Ziętkiewicz, Ewa; Yotova, Vania; Gehl, Dominik; Wambach, Tina; Arrieta, Isabel; Batzer, Mark; Cole, David E.C.; Hechtman, Peter; Kaplan, Feige; Modiano, David; Moisan, Jean-Paul; Michalski, Roman; Labuda, Damian

    2003-01-01

    Although Africa has played a central role in human evolutionary history, certain studies have suggested that not all contemporary human genetic diversity is of recent African origin. We investigated 35 simple polymorphic sites and one Tn microsatellite in an 8-kb segment of the dystrophin gene. We found 86 haplotypes in 1,343 chromosomes from around the world. Although a classical out-of-Africa topology was observed in trees based on the variant frequencies, the tree of haplotype sequences re...

  6. Defining Documentary Film

    DEFF Research Database (Denmark)

    Juel, Henrik

    2006-01-01

    A discussion of various attemts at defining documentary film regarding form, content, truth, stile, genre or reception - and a propoposal of a positive list of essential, but non-exclusive characteristica of documentary film......A discussion of various attemts at defining documentary film regarding form, content, truth, stile, genre or reception - and a propoposal of a positive list of essential, but non-exclusive characteristica of documentary film...

  7. Minimum description length block finder, a method to identify haplotype blocks and to compare the strength of block boundaries.

    Science.gov (United States)

    Mannila, H; Koivisto, M; Perola, M; Varilo, T; Hennah, W; Ekelund, J; Lukk, M; Peltonen, L; Ukkonen, E

    2003-07-01

    We describe a new probabilistic method for finding haplotype blocks that is based on the use of the minimum description length (MDL) principle. We give a rigorous definition of the quality of a segmentation of a genomic region into blocks and describe a dynamic programming algorithm for finding the optimal segmentation with respect to this measure. We also describe a method for finding the probability of a block boundary for each pair of adjacent markers: this gives a tool for evaluating the significance of each block boundary. We have applied the method to the published data of Daly and colleagues. The results expose some problems that exist in the current methods for the evaluation of the significance of predicted block boundaries. Our method, MDL block finder, can be used to compare block borders in different sample sets, and we demonstrate this by applying the MDL-based method to define the block structure in chromosomes from population isolates.

  8. A Costa Rican family affected with Charcot-Marie-Tooth disease due to the myelin protein zero (MPZ p.Thr124Met mutation shares the Belgian haplotype

    Directory of Open Access Journals (Sweden)

    Alejandro Leal

    2014-12-01

    Full Text Available The p.Thr124Met mutation in the myelin protein zero (MPZ causes the Charcot-Marie-Tooth disease type 2J, a peripheral neuropathy with additional symptoms as pupillary alterations and deafness. It was observed in several families around the world originating e. g. from Germany, Belgium, Japan, Italy and North America. Here we report Central American patients originating from a family in Costa Rica carrying this mutation. Clinical, electrophysiological and molecular analysis of patients and controls were performed, including gene and linked markers´ sequencing. Carriers share almost the entire haplotype with two non related Belgian CMT patients. As a result of the haplotype analysis, based on ten markers (seven SNPs, two microsatellites and an intronic polyA stretch, the founder effect hypothesis for this allele migration is suggestive. Rev. Biol. Trop. 62 (4: 1285-1293. Epub 2014 December 01.

  9. Analyses of 123 Peripheral Human Immune Cell Subsets: Defining Differences with Age and between Healthy Donors and Cancer Patients Not Detected in Analysis of Standard Immune Cell Types

    Directory of Open Access Journals (Sweden)

    Lauren M. Lepone

    2016-03-01

    Full Text Available Recent advances in human immunology have led to the identification of novel immune cell subsets and the biological function of many of these subsets has now been identified. The recent US Food and Drug Administration approval of several immunotherapeutics for the treatment of a variety of cancer types and the results of ongoing immunotherapy clinical studies requires a more thorough interrogation of the immune system. We report here the use of flow cytometry-based analyses to identify 123 immune cell subsets of peripheral blood mononuclear cells. The use of these panels defines multiple differences in younger (< 40 years vs. older (≥ 40 years individuals and between aged-matched apparently healthy individuals and metastatic cancer patients, aspects not seen in the analysis of the following standard immune cell types: CD8, CD4, natural killer, natural killer-T, regulatory T, myeloid derived suppressor cells, conventional dendritic cells (DCs, plasmacytoid DCs and B cells. The use of these panels identifying 123 immune cell subsets may aid in the identification of patients who may benefit from immunotherapy, either prior to therapy or early in the immunotherapeutic regimen, for the treatment of cancer or other chronic or infectious diseases.

  10. How to use current practice, risk analysis and standards to define hospital-wide policies on the safe use of infusion technology.

    Science.gov (United States)

    Timmerman, Annemoon M; Oliveira-Martens, Suzanne M; Snijder, Roland A; Nieman, Anders K; Egberts, Toine C

    2015-08-01

    Infusion therapy is widely used in hospitals. It is well known that medication errors constitute one of the highest risks to patient safety, leading to numerous adverse events concerning incorrect application of infusion technology. Both clinical practice and in vitro studies show that infusion of multiple medications via one access point induces unwanted phenomena such as backflow and an incorrect system response to interventions. Within the Metrology for Drug Delivery project, we addressed the role of infusion devices in drug delivery. We surveyed current practices for application in hospitals to provide input to standards and quality norms for the materials used in infusion technology. Furthermore, we organized meetings with clinicians and other relevant stakeholders to set up a risk analysis-based infusion policy, accompanied by easy to access operating procedures on infusion technology. It was found difficult to establish clear-cut infusion safety guidelines based on quantitative data because of the many different application areas and stakeholders. However, both the expert team and the survey indicated the value of multidisciplinary qualitative discussion for defining best practices. We advise to incorporate specific requirements on infusion devices in protocols and standards, adjusted to specific applications, to ensure safe use of infusion technology.

  11. Genetic variability and haplotypes of Echinococcus isolates from Tunisia.

    Science.gov (United States)

    Boufana, Belgees; Lahmar, Samia; Rebaï, Waël; Ben Safta, Zoubeir; Jebabli, Leïla; Ammar, Adel; Kachti, Mahmoud; Aouadi, Soufia; Craig, Philip S

    2014-11-01

    The species/genotypes of Echinococcus infecting a range of intermediate, canid and human hosts were examined as well as the intraspecific variation and population structure of Echinococcus granulosus sensu lato (s.l.) within these hosts. A total of 174 Echinococcus isolates from humans and ungulate intermediate hosts and adult tapeworms from dogs and jackals were used. Genomic DNA was used to amplify a fragment within a mitochondrial gene and a nuclear gene, coding for cytochrome c oxidase subunit 1 (cox1; 828 bp) and elongation factor 1-alpha (ef1a; 656 bp), respectively. E. granulosus sensu stricto was identified from all host species examined, E. canadensis (G6) in a camel and, for the first time, fertile cysts of E. granulosus (s.s.) and E. equinus in equids (donkeys) and E. granulosus (s.s.) from wild boars and goats. Considerable genetic variation was seen only for the cox1 sequences of E. granulosus (s.s.). The pairwise fixation index (Fst) for cox1 E. granulosus (s.s.) sequences from donkeys was high and was statistically significant compared with that of E. granulosus populations from other intermediate hosts. A single haplotype (EqTu01) was identified for the cox1 nucleotide sequences of E. equinus. The role of donkeys in the epidemiology of echinococcosis in Tunisia requires further investigation. © The Author 2014. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  12. Single-cell systems level analysis of human Toll-Like-Receptor activation defines a chemokine signature in Systemic Lupus Erythematosus

    Science.gov (United States)

    O'Gorman, William E.; Hsieh, Elena W.Y.; Savig, Erica S.; Gherardini, Pier Federico; Hernandez, Joseph D.; Hansmann, Leo; Balboni, Imelda M.; Utz, Paul J.; Bendall, Sean C.; Fantl, Wendy J.; Lewis, David B.; Nolan, Garry P.; Davis, Mark M.

    2015-01-01

    Background Activation of Toll-Like Receptors (TLRs) induces inflammatory responses involved in immunity to pathogens and autoimmune pathogenesis, such as in Systemic Lupus Erythematosus (SLE). Although TLRs are differentially expressed across the immune system, a comprehensive analysis of how multiple immune cell subsets respond in a system-wide manner has previously not been described. Objective To characterize TLR activation across multiple immune cell subsets and individuals, with the goal of establishing a reference framework against which to compare pathological processes. Methods Peripheral whole blood samples were stimulated with TLR ligands, and analyzed by mass cytometry simultaneously for surface marker expression, activation states of intracellular signaling proteins, and cytokine production. We developed a novel data visualization tool to provide an integrated view of TLR signaling networks with single-cell resolution. We studied seventeen healthy volunteer donors and eight newly diagnosed untreated SLE patients. Results Our data revealed the diversity of TLR-induced responses within cell types, with TLR ligand specificity. Subsets of NK and T cells selectively induced NF-κB in response to TLR2 ligands. CD14hi monocytes exhibited the most polyfunctional cytokine expression patterns, with over 80 distinct cytokine combinations. Monocytic TLR-induced cytokine patterns were shared amongst a group of healthy donors, with minimal intra- and inter- individual variability. Furthermore, autoimmune disease altered baseline cytokine production, as newly diagnosed untreated SLE patients shared a distinct monocytic chemokine signature, despite clinical heterogeneity. Conclusion Mass cytometry analysis defined a systems-level reference framework for human TLR activation, which can be applied to study perturbations in inflammatory disease, such as SLE. PMID:26037552

  13. Vitamin D Receptor Gene Polymorphisms and Haplotypes in Hungarian Patients with Idiopathic Inflammatory Myopathy

    Directory of Open Access Journals (Sweden)

    Levente Bodoki

    2015-01-01

    Full Text Available Idiopathic inflammatory myopathies are autoimmune diseases characterized by symmetrical proximal muscle weakness. Our aim was to identify a correlation between VDR polymorphisms or haplotypes and myositis. We studied VDR-BsmI, VDR-ApaI, VDR-TaqI, and VDR-FokI polymorphisms and haplotypes in 89 Hungarian poly-/dermatomyositis patients (69 females and 93 controls (52 females. We did not obtain any significant differences for VDR-FokI, BsmI, ApaI, and TaqI genotypes and allele frequencies between patients with myositis and healthy individuals. There was no association of VDR polymorphisms with clinical manifestations and laboratory profiles in myositis patients. Men with myositis had a significantly different distribution of BB, Bb, and bb genotypes than female patients, control male individuals, and the entire control group. Distribution of TT, Tt, and tt genotypes was significantly different in males than in females in patient group. According to four-marker haplotype prevalence, frequencies of sixteen possible haplotypes showed significant differences between patient and control groups. The three most frequent haplotypes in patients were the fbAt, FBaT, and fbAT. Our findings may reveal that there is a significant association: Bb and Tt genotypes can be associated with myositis in the Hungarian population we studied. We underline the importance of our result in the estimated prevalence of four-marker haplotypes.

  14. The JAK2 GGCC (46/1 Haplotype in Myeloproliferative Neoplasms: Causal or Random?

    Directory of Open Access Journals (Sweden)

    Luisa Anelli

    2018-04-01

    Full Text Available The germline JAK2 haplotype known as “GGCC or 46/1 haplotype” (haplotypeGGCC_46/1 consists of a combination of single nucleotide polymorphisms (SNPs mapping in a region of about 250 kb, extending from the JAK2 intron 10 to the Insulin-like 4 (INLS4 gene. Four main SNPs (rs3780367, rs10974944, rs12343867, and rs1159782 generating a “GGCC” combination are more frequently indicated to represent the JAK2 haplotype. These SNPs are inherited together and are frequently associated with the onset of myeloproliferative neoplasms (MPN positive for both JAK2 V617 and exon 12 mutations. The association between the JAK2 haplotypeGGCC_46/1 and mutations in other genes, such as thrombopoietin receptor (MPL and calreticulin (CALR, or the association with triple negative MPN, is still controversial. This review provides an overview of the frequency and the role of the JAK2 haplotypeGGCC_46/1 in the pathogenesis of different myeloid neoplasms and describes the hypothetical mechanisms at the basis of the association with JAK2 gene mutations. Moreover, possible clinical implications are discussed, as different papers reported contrasting data about the correlation between the JAK2 haplotypeGGCC_46/1 and blood cell count, survival, or disease progression.

  15. Interrelationships between Amerindian tribes of lower Amazonia as manifest by HLA haplotype disequilibria.

    Science.gov (United States)

    Black, F L

    1984-11-01

    HLA B-C haplotypes exhibit common disequilibria in populations drawn from four continents, indicating that they are subject to broadly active selective forces. However, the A-B and A-C associations we have examined show no consistent disequilibrium pattern, leaving open the possibility that these disequilibria are due to descent from common progenitors. By examining HLA haplotype distributions, I have explored the implications that would follow from the hypothesis that biological selection played no role in determining A-C disequilibria in 10 diverse tribes of the lower Amazon Basin. Certain haplotypes are in strong positive disequilibria across a broad geographic area, suggesting that members of diverse tribes descend from common ancestors. On the basis of the extent of diffusion of the components of these haplotypes, one can estimate that the progenitors lived less than 6,000 years ago. One widely encountered lineage entered the area within the last 1,200 years. When haplotype frequencies are used in genetic distance measurements, they give a pattern of relationships very similar to that obtained by conventional chord measurements based on several genetic markers; but more than that, when individual haplotype disequilibria in the several tribes are compared, multiple origins of a single tribe are discernible and relationships are revealed that correlate more closely to geographic and linguistic patterns than do the genetic distance measurements.

  16. An accurate clone-based haplotyping method by overlapping pool sequencing.

    Science.gov (United States)

    Li, Cheng; Cao, Changchang; Tu, Jing; Sun, Xiao

    2016-07-08

    Chromosome-long haplotyping of human genomes is important to identify genetic variants with differing gene expression, in human evolution studies, clinical diagnosis, and other biological and medical fields. Although several methods have realized haplotyping based on sequencing technologies or population statistics, accuracy and cost are factors that prohibit their wide use. Borrowing ideas from group testing theories, we proposed a clone-based haplotyping method by overlapping pool sequencing. The clones from a single individual were pooled combinatorially and then sequenced. According to the distinct pooling pattern for each clone in the overlapping pool sequencing, alleles for the recovered variants could be assigned to their original clones precisely. Subsequently, the clone sequences could be reconstructed by linking these alleles accordingly and assembling them into haplotypes with high accuracy. To verify the utility of our method, we constructed 130 110 clones in silico for the individual NA12878 and simulated the pooling and sequencing process. Ultimately, 99.9% of variants on chromosome 1 that were covered by clones from both parental chromosomes were recovered correctly, and 112 haplotype contigs were assembled with an N50 length of 3.4 Mb and no switch errors. A comparison with current clone-based haplotyping methods indicated our method was more accurate. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

  17. Role of the extended MAPT haplotype in the worsening of psychotic symptoms and treatment response in Alzheimer disease.

    Science.gov (United States)

    Creese, Byron; Corbett, Anne; Jones, Emma; Fox, Chris; Ballard, Clive

    2014-12-01

    There is evidence that neurofibrillary tangle (NFT) burden is associated with psychotic symptoms in Alzheimer disease (AD). However, it is not clear whether this association is direct or mediated through the increased cognitive impairment associated with NFTs. We sought to determine whether the extended MAPT haplotype was associated with the worsening of delusions and hallucinations in a combined cohort of 95 patients who participated in 2 clinical trials of treatment with memantine. After controlling for baseline dementia severity, exposure to memantine, and antipsychotics, analysis shows that carriers of at least one H2 allele had a 5.4-fold (P = .03) increased risk of worsening hallucinations. There was some evidence of association with worsening delusions but only in analysis by allele. These results are the first to indicate that the H2 allele of the extended MAPT haplotype negatively affects the course of psychotic symptoms in AD independently of disease severity. It will be important for future research to examine MAPT transcription in people with AD with and without psychotic symptoms to understand the exact mechanisms underlying these findings. Copyright © 2014 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.

  18. A mixed integer linear programming model to reconstruct phylogenies from single nucleotide polymorphism haplotypes under the maximum parsimony criterion

    Science.gov (United States)

    2013-01-01

    Background Phylogeny estimation from aligned haplotype sequences has attracted more and more attention in the recent years due to its importance in analysis of many fine-scale genetic data. Its application fields range from medical research, to drug discovery, to epidemiology, to population dynamics. The literature on molecular phylogenetics proposes a number of criteria for selecting a phylogeny from among plausible alternatives. Usually, such criteria can be expressed by means of objective functions, and the phylogenies that optimize them are referred to as optimal. One of the most important estimation criteria is the parsimony which states that the optimal phylogeny T∗for a set H of n haplotype sequences over a common set of variable loci is the one that satisfies the following requirements: (i) it has the shortest length and (ii) it is such that, for each pair of distinct haplotypes hi,hj∈H, the sum of the edge weights belonging to the path from hi to hj in T∗ is not smaller than the observed number of changes between hi and hj. Finding the most parsimonious phylogeny for H involves solving an optimization problem, called the Most Parsimonious Phylogeny Estimation Problem (MPPEP), which is NP-hard in many of its versions. Results In this article we investigate a recent version of the MPPEP that arises when input data consist of single nucleotide polymorphism haplotypes extracted from a population of individuals on a common genomic region. Specifically, we explore the prospects for improving on the implicit enumeration strategy of implicit enumeration strategy used in previous work using a novel problem formulation and a series of strengthening valid inequalities and preliminary symmetry breaking constraints to more precisely bound the solution space and accelerate implicit enumeration of possible optimal phylogenies. We present the basic formulation and then introduce a series of provable valid constraints to reduce the solution space. We then prove

  19. Exploring Climate Niches of Ponderosa Pine (Pinus ponderosa Douglas ex Lawson) Haplotypes in the Western United States: Implications for Evolutionary History and Conservation

    OpenAIRE

    Shinneman, Douglas J.; Means, Robert E.; Potter, Kevin M.; Hipkins, Valerie D.

    2016-01-01

    Ponderosa pine (Pinus ponderosa Douglas ex Lawson) occupies montane environments throughout western North America, where it is both an ecologically and economically important tree species. A recent study using mitochondrial DNA analysis demonstrated substantial genetic variation among ponderosa pine populations in the western U.S., identifying 10 haplotypes with unique evolutionary lineages that generally correspond spatially with distributions of the Pacific (P. p. var. ponderosa) and Rocky ...

  20. Identification of a two-marker-haplotype on Bos taurus autosome 18 associated with somatic cell score in German Holstein cattle

    Directory of Open Access Journals (Sweden)

    Reinsch Norbert

    2009-09-01

    Full Text Available Abstract Background The somatic cell score (SCS is implemented in routine sire evaluations in many countries as an indicator trait for udder health. Somatic cell score is highly correlated with clinical mastitis, and in the German Holstein population quantitative trait loci (QTL for SCS have been repeatedly mapped on Bos taurus autosome 18 (BTA18. In the present study, we report a refined analysis of previously detected QTL regions on BTA18 with the aim of identifying marker and marker haplotypes in linkage disequilibrium with SCS. A combined linkage and linkage disequilibrium approach was implemented, and association analyses of marker genotypes and maternally inherited two-marker-haplotypes were conducted to identify marker and haplotypes in linkage disequilibrium with a locus affecting SCS in the German Holstein population. Results We detected a genome-wide significant QTL within marker interval 9 (HAMP_c.366+109G>A - BMS833 in the middle to telomeric region on BTA18 and a second putative QTL in marker interval 12-13 (BB710 - PVRL2_c.392G>A. Association analyses with genotypes of markers flanking the most likely QTL positions revealed the microsatellite marker BMS833 (interval 9 to be associated with a locus affecting SCS within the families investigated. A further analysis of maternally inherited two-marker haplotypes and effects of maternally inherited two-marker-interval gametes indicated haplotype 249-G in marker interval 12-13 (BB710 - PVRL2_c.392G>A to be associated with SCS in the German Holstein population. Conclusion Our results confirmed previous QTL mapping results for SCS and support the hypothesis that more than one locus presumably affects udder health in the middle to telomeric region of BTA18. However, a subsequent investigation of the reported QTL regions is necessary to verify the two-QTL hypothesis and confirm the association of two-marker-haplotype 249-G in marker interval 12-13 (BB710 - PVRL2_c.392G>A with SCS. For this

  1. Definably compact groups definable in real closed fields. I

    OpenAIRE

    Barriga, Eliana

    2017-01-01

    We study definably compact definably connected groups definable in a sufficiently saturated real closed field $R$. We introduce the notion of group-generic point for $\\bigvee$-definable groups and show the existence of group-generic points for definably compact groups definable in a sufficiently saturated o-minimal expansion of a real closed field. We use this notion along with some properties of generic sets to prove that for every definably compact definably connected group $G$ definable in...

  2. A haplotype of polymorphisms in ASE-1, RAI and ERCC1 and the effects of tobacco smoking and alcohol consumption on risk of colorectal cancer: a danish prospective case-cohort study

    International Nuclear Information System (INIS)

    Hansen, Rikke D; Sørensen, Mette; Tjønneland, Anne; Overvad, Kim; Wallin, Håkan; Raaschou-Nielsen, Ole; Vogel, Ulla

    2008-01-01

    Single nucleotide polymorphisms (SNPs) are the most frequent type of genetic variation in the human genome, and are of interest for the study of susceptibility to and protection from diseases. The haplotype at chromosome 19q13.2-3 encompassing the three SNPs ASE-1 G-21A, RAI IVS1 A4364G and ERCC1 Asn118Asn have been associated with risk of breast cancer and lung cancer. Haplotype carriers are defined as the homozygous carriers of RAI IVS1 A4364G A , ERCC1 Asn118Asn T and ASE-1 G-21A G . We aimed to evaluate whether the three polymorphisms and the haplotype are associated to risk of colorectal cancer, and investigated gene-environment associations between the polymorphisms and the haplotype and smoking status at enrolment, smoking duration, average smoking intensity and alcohol consumption, respectively, in relation to risk of colorectal cancer. Associations between the three individual polymorphisms, the haplotype and risk of colorectal cancer were examined, as well as gene-environment interaction, in a Danish case-cohort study including 405 cases and a comparison group of 810 persons. Incidence rate ratio (IRR) were estimated by the Cox proportional hazards model stratified according to gender, and two-sided 95% confidence intervals (CI) and p-values were calculated based on robust estimates of the variance-covariance matrix and Wald's test of the Cox regression parameter. No consistent associations between the three individual polymorphisms, the haplotype and risk of colorectal cancer were found. No statistically significant interactions between the genotypes and the lifestyle exposures smoking or alcohol consumption were observed. Our results suggest that the ASE-1 G-21A, RAI IVS1 A4364G and ERCC1 Asn118Asn polymorphisms and the previously identified haplotype are not associated with risk of colorectal cancer. We found no evidence of gene-environment interaction between the three polymorphisms and the haplotype and smoking intensity and alcohol consumption

  3. Modal Logics and Definability

    OpenAIRE

    Kuusisto, Antti

    2013-01-01

    In recent years, research into the mathematical foundations of modal logic has become increasingly popular. One of the main reasons for this is the fact that modal logic seems to adapt well to the requirements of a wide range of different fields of application. This paper is a summary of some of the author’s contributions to the understanding of modal definability theory.

  4. Defining Abnormally Low Tenders

    DEFF Research Database (Denmark)

    Ølykke, Grith Skovgaard; Nyström, Johan

    2017-01-01

    The concept of an abnormally low tender is not defined in EU public procurement law. This article takes an interdisciplinary law and economics approach to examine a dataset consisting of Swedish and Danish judgments and verdicts concerning the concept of an abnormally low tender. The purpose...

  5. Software Defined Coded Networking

    DEFF Research Database (Denmark)

    Di Paola, Carla; Roetter, Daniel Enrique Lucani; Palazzo, Sergio

    2017-01-01

    the quality of each link and even across neighbouring links and using simulations to show that an additional reduction of packet transmission in the order of 40% is possible. Second, to advocate for the use of network coding (NC) jointly with software defined networking (SDN) providing an implementation...

  6. Defining depth of anesthesia.

    Science.gov (United States)

    Shafer, S L; Stanski, D R

    2008-01-01

    In this chapter, drawn largely from the synthesis of material that we first presented in the sixth edition of Miller's Anesthesia, Chap 31 (Stanski and Shafer 2005; used by permission of the publisher), we have defined anesthetic depth as the probability of non-response to stimulation, calibrated against the strength of the stimulus, the difficulty of suppressing the response, and the drug-induced probability of non-responsiveness at defined effect site concentrations. This definition requires measurement of multiple different stimuli and responses at well-defined drug concentrations. There is no one stimulus and response measurement that will capture depth of anesthesia in a clinically or scientifically meaningful manner. The "clinical art" of anesthesia requires calibration of these observations of stimuli and responses (verbal responses, movement, tachycardia) against the dose and concentration of anesthetic drugs used to reduce the probability of response, constantly adjusting the administered dose to achieve the desired anesthetic depth. In our definition of "depth of anesthesia" we define the need for two components to create the anesthetic state: hypnosis created with drugs such as propofol or the inhalational anesthetics and analgesia created with the opioids or nitrous oxide. We demonstrate the scientific evidence that profound degrees of hypnosis in the absence of analgesia will not prevent the hemodynamic responses to profoundly noxious stimuli. Also, profound degrees of analgesia do not guarantee unconsciousness. However, the combination of hypnosis and analgesia suppresses hemodynamic response to noxious stimuli and guarantees unconsciousness.

  7. Defining and classifying syncope

    NARCIS (Netherlands)

    Thijs, Roland D.; Wieling, Wouter; Kaufmann, Horacio; van Dijk, Gert

    2004-01-01

    There is no widely adopted definition or classification of syncope and related disorders. This lack of uniformity harms patient care, research, and medical education. In this article, syncope is defined as a form of transient loss of consciousness (TLOC) due to cerebral hypoperfusion. Differences

  8. Assessment of M2/ANXA5 haplotype as a risk factor in couples with placenta-mediated pregnancy complications.

    Science.gov (United States)

    Rogenhofer, Nina; Nienaber, Lara R M; Amshoff, Lea C; Bogdanova, Nadia; Petroff, David; Wieacker, Peter; Thaler, Christian J; Markoff, Arseni

    2018-01-01

    The aim of this study was to confirm the associated M2/ANXA5 carrier risk in women with placenta-mediated pregnancy complications (PMPC) and to test their male partners for such association. Further analysis evaluated the influence of maternal vs. paternal M2 alleles on miscarriage. Two hundred eighty-eight couples with preeclampsia (PE), intrauterine growth restriction (IUGR), or premature birth (PB) were recruited (n = 96 of each phenotype). The prevalence of the M2 haplotype was compared to two control cohorts. They included a group of women with a history of normal pregnancy without gestational pathology (Munich controls, n = 94) and a random population sample (PopGen controls, n = 533). Significant association of M2 haplotype and pregnancy complications was confirmed for women and for couples, where prevalence was elevated from 15.4 to 23.8% (p pregnancy complication. M2/ANXA5 appears to be a risk factor for adverse pregnancy outcomes related, but not limited to miscarriages, with similar prevalence in women and their male partners. These findings support the proposed physiological function of ANXA5 as an embryonic anticoagulant that appears deficient in contiguous specter of thrombophilia-related pregnancy complications culminating more frequently in miscarriage in a maternal M2 carrier background.

  9. Decreased calcium pump expression in human erythrocytes is connected to a minor haplotype in the ATP2B4 gene.

    Science.gov (United States)

    Zámbó, Boglárka; Várady, György; Padányi, Rita; Szabó, Edit; Németh, Adrienn; Langó, Tamás; Enyedi, Ágnes; Sarkadi, Balázs

    2017-07-01

    Plasma membrane Ca 2+ -ATPases are key calcium exporter proteins in most tissues, and PMCA4b is the main calcium transporter in the human red blood cells (RBCs). In order to assess the expression level of PMCA4b, we have developed a flow cytometry and specific antibody binding method to quantitatively detect this protein in the erythrocyte membrane. Interestingly, we found several healthy volunteers showing significantly reduced expression of RBC-PMCA4b. Western blot analysis of isolated RBC membranes confirmed this observation, and indicated that there are no compensatory alterations in other PMCA isoforms. In addition, reduced PMCA4b levels correlated with a lower calcium extrusion capacity in these erythrocytes. When exploring the potential genetic background of the reduced PMCA4b levels, we found no missense mutations in the ATP2B4 coding regions, while a formerly unrecognized minor haplotype in the predicted second promoter region closely correlated with lower erythrocyte PMCA4b protein levels. In recent GWA studies, SNPs in this ATP2B4 haplotype have been linked to reduced mean corpuscular hemoglobin concentrations (MCHC), and to protection against malaria infection. Our data suggest that an altered regulation of gene expression is responsible for the reduced RBC-PMCA4b levels that is probably linked to the development of human disease-related phenotypes. Copyright © 2017 Elsevier Ltd. All rights reserved.

  10. Inference of haplotypic phase and missing genotypes in polyploid organisms and variable copy number genomic regions

    Directory of Open Access Journals (Sweden)

    Balding David J

    2008-12-01

    Full Text Available Abstract Background The power of haplotype-based methods for association studies, identification of regions under selection, and ancestral inference, is well-established for diploid organisms. For polyploids, however, the difficulty of determining phase has limited such approaches. Polyploidy is common in plants and is also observed in animals. Partial polyploidy is sometimes observed in humans (e.g. trisomy 21; Down's syndrome, and it arises more frequently in some human tissues. Local changes in ploidy, known as copy number variations (CNV, arise throughout the genome. Here we present a method, implemented in the software polyHap, for the inference of haplotype phase and missing observations from polyploid genotypes. PolyHap allows each individual to have a different ploidy, but ploidy cannot vary over the genomic region analysed. It employs a hidden Markov model (HMM and a sampling algorithm to infer haplotypes jointly in multiple individuals and to obtain a measure of uncertainty in its inferences. Results In the simulation study, we combine real haplotype data to create artificial diploid, triploid, and tetraploid genotypes, and use these to demonstrate that polyHap performs well, in terms of both switch error rate in recovering phase and imputation error rate for missing genotypes. To our knowledge, there is no comparable software for phasing a large, densely genotyped region of chromosome from triploids and tetraploids, while for diploids we found polyHap to be more accurate than fastPhase. We also compare the results of polyHap to SATlotyper on an experimentally haplotyped tetraploid dataset of 12 SNPs, and show that polyHap is more accurate. Conclusion With the availability of large SNP data in polyploids and CNV regions, we believe that polyHap, our proposed method for inferring haplotypic phase from genotype data, will be useful in enabling researchers analysing such data to exploit the power of haplotype-based analyses.

  11. Identification of the Mislabeled Breast Cancer Samples by Mitochondrial DNA Haplotyping

    Directory of Open Access Journals (Sweden)

    Xiaogang Chen

    2015-01-01

    Full Text Available The task to identify whether an archival malignant tumor specimen had been mislabeled or interchanged is a challenging one for forensic genetics. The nuclear DNA (nDNA markers were affected by the aberration of tumor cells, so they were not suitable for personal identification when the tumor tissues were tested. In this study, we focused on a new solution - mitochondrial single nucleotide polymorphism (mtSNP haplotyping by a multiplex SNaPshot assay. To validate our strategy of haplotyping with 25 mtSNPs, we analyzed 15 pairs of cancerous/healthy tissues taken from patients with ductal breast carcinoma. The haplotypes of all the fifteen breast cancer tissues were matched with their paired breast tissues. The heteroplasmy at 2 sites, 14783A/G and 16519C/T was observed in one breast tissue, which indicated a mixture of related mitochondrial haplotypes. However, only one haplotype was retained in the paired breast cancer tissue, which could be considered the result of proliferation of tumor subclone. The allele drop-out and allele drop-in were observed when 39 STRs and 20 tri-allelic SNPs of nDNA were applied. Compared to nDNA markers applied, 25 mtSNPs were more stable without interference from aberrance of breast cancer. Also, two cases were presented where the investigation of haplotype with 25 mtSNPs was used to prove the origin of biopsy specimen with breast cancer. The mislabeling of biopsy specimen with breast cancer could be certified in one case but could not be supported in the other case. We highlight the importance of stability of mtSNP haplotype in breast cancer. It was implied that our multiplex SNaPshot assay with 25 mtSNPs was a useful strategy to identify mislabeled breast cancer specimen.

  12. Three Novel Haplotypes of Theileria bicornis in Black and White Rhinoceros in Kenya.

    Science.gov (United States)

    Otiende, M Y; Kivata, M W; Jowers, M J; Makumi, J N; Runo, S; Obanda, V; Gakuya, F; Mutinda, M; Kariuki, L; Alasaad, S

    2016-02-01

    Piroplasms, especially those in the genera Babesia and Theileria, have been found to naturally infect rhinoceros. Due to natural or human-induced stress factors such as capture and translocations, animals often develop fatal clinical piroplasmosis, which causes death if not treated. This study examines the genetic diversity and occurrence of novel Theileria species infecting both black and white rhinoceros in Kenya. Samples collected opportunistically during routine translocations and clinical interventions from 15 rhinoceros were analysed by polymerase chain reaction (PCR) using a nested amplification of the small subunit ribosomal RNA (18S rRNA) gene fragments of Babesia and Theileria. Our study revealed for the first time in Kenya the presence of Theileria bicornis in white (Ceratotherium simum simum) and black (Diceros bicornis michaeli) rhinoceros and the existence of three new haplotypes: haplotypes H1 and H3 were present in white rhinoceros, while H2 was present in black rhinoceros. No specific haplotype was correlated to any specific geographical location. The Bayesian inference 50% consensus phylogram recovered the three haplotypes monophyleticly, and Theileria bicornis had very high support (BPP: 0.98). Furthermore, the genetic p-uncorrected distances and substitutions between T. bicornis and the three haplotypes were the same in all three haplotypes, indicating a very close genetic affinity. This is the first report of the occurrence of Theileria species in white and black rhinoceros from Kenya. The three new haplotypes reported here for the first time have important ecological and conservational implications, especially for population management and translocation programs and as a means of avoiding the transport of infected animals into non-affected areas. © 2014 Blackwell Verlag GmbH.

  13. Refined candidate region specified by haplotype sharing for Escherichia coli F4ab/F4ac susceptibility alleles in pigs

    DEFF Research Database (Denmark)

    Jacobsen, Mette Juul; Kracht, Steffen Skaarup; Esteso, G.

    2009-01-01

    Infection of the small intestine by enterotoxigenic Escherichia coli F4ab/ac is a major welfare problem and financial burden for the pig industry. Natural resistance to this infection is inherited as a Mendelian recessive trait, and a polymorphism in the MUC4 gene segregating for susceptibility....../resistance is presently used in a selection programme by the Danish pig breeding industry. To elucidate the genetic background involved in E. coli F4ab/ac susceptibility in pigs, a detailed haplotype map of the porcine candidate region was established. This region covers approximately 3.7 Mb. The material used...... for the study is a three generation family, where the founders are two Wild boars and eight Large White sows. All pigs have been phenotyped for susceptibility to F4ab/ac using an adhesion assay. Their haplotypes are known from segregation analysis using flanking markes. By a targeted approach, the candidate...

  14. Determination of βS haplotypes in patients with sickle-cell anemia in the state of Rio Grande do Norte, Brazil

    Directory of Open Access Journals (Sweden)

    Cynthia Hatsue Kitayama Cabral

    2011-01-01

    Full Text Available βS haplotypes were studied in 47 non-related patients with sickle-cell anemia from the state of Rio Grande do Norte, Brazil. Molecular analysis was conducted by PCR/RFLP using restriction endonucleases XmnI, HindIII, HincII and HinfI to analyze six polymorphic sites from the beta cluster. Twenty-seven patients (57.5% were identified with genotype CAR/CAR, 9 (19.1% CAR/BEN, 6 (12.8% CAR/CAM, 1 (2.1% BEN/BEN, 2 (4.3% CAR/Atp, 1 (2.1% BEN/Atp and 1 (2.1% with genotype Atp/Atp. The greater frequency of Cameroon haplotypes compared to other Brazilian states suggests the existence of a peculiarity of African origin in the state of Rio Grande do Norte.

  15. β2-Adrenergic receptor promoter haplotype influences the severity of acute viral respiratory tract infection during infancy: a prospective cohort study.

    Science.gov (United States)

    Wu, Pingsheng; Larkin, Emma K; Reiss, Sara S; Carroll, Kecia N; Summar, Marshall L; Minton, Patricia A; Woodward, Kimberly B; Liu, Zhouwen; Islam, Jessica Y; Hartert, Tina V; Moore, Paul E

    2015-09-14

    Despite the significant interest in β2-Adrenergic receptor (ADRB2) polymorphisms related to asthma, whether ADRB2 genetic variants are similarly associated with acute respiratory tract infections have not been studied. We hypothesized that genetic variants in ADRB2 associated with a response to asthma therapy during an asthma exacerbation were also associated with severity of acute respiratory tract infections. To test this hypothesis, we genotyped 5 common polymorphisms in the promoter region and coding block of the ADRB2 gene (loci -2387, -2274, -1343, +46, and +79) from 374 Caucasian and African American term infants who were enrolled at the time of acute respiratory illness over four respiratory viral seasons. Severity of respiratory tract infections was measured using a bronchiolitis severity score (BSS; range = 0-12, clinically significant difference = 0.5) with a higher score indicating more severe disease. We assigned the promoter, coding and combined promoter and coding haplotypes to the unphased genotype data. The associations between each of these five single-nucleotide polymorphisms (SNPs) as well as the haplotypes and infant BSS were analyzed using nonparametric univariate analysis and multivariable proportional odds model separately in Caucasians and African Americans. There was no significant association between infant BSS and each of the SNPs in both Caucasians and African Americans. However, promoter haplotype CCA was associated with a decreased BSS in African Americans in a dose dependent manner. The median (interquartile range) BSS of infants with no copies of the CCA haplotype, one copy, and two copies of the CCA haplotype were 5.5 (2.0, 8.0), 4.0 (1.0, 7.5), and 3.0 (1.0, 4.0), respectively. This dose dependent relationship persisted after adjusting for infant age, gender, daycare exposure, secondhand smoke exposure, prior history of breastfeeding, siblings at home, and enrollment season (adjusted odds ratio: 0.59, 95% confidence

  16. Direct sequencing of mitochondrial DNA detects highly divergent haplotypes in blue marlin (Makaira nigricans).

    Science.gov (United States)

    Finnerty, J R; Block, B A

    1992-06-01

    We were able to differentiate between species of billfish (Istiophoridae family) and to detect considerable intraspecific variation in the blue marlin (Makaira nigricans) by directly sequencing a polymerase chain reaction (PCR)-amplified, 612-bp fragment of the mitochondrial cytochrome b gene. Thirteen variable nucleotide sites separated blue marlin (n = 26) into 7 genotypes. On average, these genotypes differed by 5.7 base substitutions. A smaller sample of swordfish from an equally broad geographic distribution displayed relatively little intraspecific variation, with an average of 1.3 substitutions separating different genotypes. A cladistic analysis of blue marlin cytochrome b variants indicates two major divergent evolutionary lines within the species. The frequencies of these two major evolutionary lines differ significantly between Atlantic and Pacific ocean basins. This finding is important given that the Atlantic stocks of blue marlin are considered endangered. Migration from the Pacific can help replenish the numbers of blue marlin in the Atlantic, but the loss of certain mitochondrial DNA haplotypes in the Atlantic due to overfishing probably could not be remedied by an influx of Pacific fish because of their absence in the Pacific population. Fishery management strategies should attempt to preserve the genetic diversity within the species. The detection of DNA sequence polymorphism indicates the utility of PCR technology in pelagic fishery genetics.

  17. Defining Legal Moralism

    DEFF Research Database (Denmark)

    Thaysen, Jens Damgaard

    2015-01-01

    This paper discusses how legal moralism should be defined. It is argued that legal moralism should be defined as the position that “For any X, it is always a pro tanto reason for justifiably imposing legal regulation on X that X is morally wrong (where “morally wrong” is not conceptually equivalent...... to “harmful”)”. Furthermore, a distinction between six types of legal moralism is made. The six types are grouped according to whether they are concerned with the enforcement of positive or critical morality, and whether they are concerned with criminalising, legally restricting, or refraining from legally...... protecting morally wrong behaviour. This is interesting because not all types of legal moralism are equally vulnerable to the different critiques of legal moralism that have been put forth. Indeed, I show that some interesting types of legal moralism have not been criticised at all....

  18. Defining local food

    DEFF Research Database (Denmark)

    Eriksen, Safania Normann

    2013-01-01

    Despite evolving local food research, there is no consistent definition of “local food.” Various understandings are utilized, which have resulted in a diverse landscape of meaning. The main purpose of this paper is to examine how researchers within the local food systems literature define local...... food, and how these definitions can be used as a starting point to identify a new taxonomy of local food based on three domains of proximity....

  19. Effects of alteplase for acute stroke according to criteria defining the European Union and United States marketing authorizations: Individual-patient-data meta-analysis of randomized trials.

    Science.gov (United States)

    Hacke, Werner; Lyden, Patrick; Emberson, Jonathan; Baigent, Colin; Blackwell, Lisa; Albers, Gregory; Bluhmki, Erich; Brott, Thomas; Cohen, Geoffrey; Davis, Stephen M; Donnan, Geoffrey A; Grotta, James C; Howard, George; Kaste, Markku; Koga, Masatoshi; von Kummer, Rüdiger; Lansberg, Maarten G; Lindley, Richard I; Olivot, Jean-Marc; Parsons, Mark; Sandercock, Peter Ag; Toni, Danilo; Toyoda, Kazunori; Wahlgren, Nils; Wardlaw, Joanna M; Whiteley, William N; Del Zoppo, Gregory; Lees, Kennedy R

    2018-02-01

    Background The recommended maximum age and time window for intravenous alteplase treatment of acute ischemic stroke differs between the Europe Union and United States. Aims We compared the effects of alteplase in cohorts defined by the current Europe Union or United States marketing approval labels, and by hypothetical revisions of the labels that would remove the Europe Union upper age limit or extend the United States treatment time window to 4.5 h. Methods We assessed outcomes in an individual-patient-data meta-analysis of eight randomized trials of intravenous alteplase (0.9 mg/kg) versus control for acute ischemic stroke. Outcomes included: excellent outcome (modified Rankin score 0-1) at 3-6 months, the distribution of modified Rankin score, symptomatic intracerebral hemorrhage, and 90-day mortality. Results Alteplase increased the odds of modified Rankin score 0-1 among 2449/6136 (40%) patients who met the current European Union label and 3491 (57%) patients who met the age-revised label (odds ratio 1.42, 95% CI 1.21-1.68 and 1.43, 1.23-1.65, respectively), but not in those outside the age-revised label (1.06, 0.90-1.26). By 90 days, there was no increased mortality in the current and age-revised cohorts (hazard ratios 0.98, 95% CI 0.76-1.25 and 1.01, 0.86-1.19, respectively) but mortality remained higher outside the age-revised label (1.19, 0.99-1.42). Similarly, alteplase increased the odds of modified Rankin score 0-1 among 1174/6136 (19%) patients who met the current US approval and 3326 (54%) who met a 4.5-h revised approval (odds ratio 1.55, 1.19-2.01 and 1.37, 1.17-1.59, respectively), but not for those outside the 4.5-h revised approval (1.14, 0.97-1.34). By 90 days, no increased mortality remained for the current and 4.5-h revised label cohorts (hazard ratios 0.99, 0.77-1.26 and 1.02, 0.87-1.20, respectively) but mortality remained higher outside the 4.5-h revised approval (1.17, 0.98-1.41). Conclusions An age-revised European Union label or 4

  20. Measurement of circulating transcripts and gene cluster analysis predicts and defines therapeutic efficacy of peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors

    International Nuclear Information System (INIS)

    Bodei, L.; Kidd, M.; Modlin, I.M.; Severi, S.; Nicolini, S.; Paganelli, G.; Drozdov, I.; Kwekkeboom, D.J.; Krenning, E.P.; Baum, R.P.

    2016-01-01

    Peptide receptor radionuclide therapy (PRRT) is an effective method for treating neuroendocrine tumors (NETs). It is limited, however, in the prediction of individual tumor response and the precise and early identification of changes in tumor size. Currently, response prediction is based on somatostatin receptor expression and efficacy by morphological imaging and/or chromogranin A (CgA) measurement. The aim of this study was to assess the accuracy of circulating NET transcripts as a measure of PRRT efficacy, and moreover to identify prognostic gene clusters in pretreatment blood that could be interpolated with relevant clinical features in order to define a biological index for the tumor and a predictive quotient for PRRT efficacy. NET patients (n = 54), M: F 37:17, median age 66, bronchial: n = 13, GEP-NET: n = 35, CUP: n = 6 were treated with 177 Lu-based-PRRT (cumulative activity: 6.5-27.8 GBq, median 18.5). At baseline: 47/54 low-grade (G1/G2; bronchial typical/atypical), 31/49 18 FDG positive and 39/54 progressive. Disease status was assessed by RECIST1.1. Transcripts were measured by real-time quantitative reverse transcription PCR (qRT-PCR) and multianalyte algorithmic analysis (NETest); CgA by enzyme-linked immunosorbent assay (ELISA). Gene cluster (GC) derivations: regulatory network, protein:protein interactome analyses. Statistical analyses: chi-square, non-parametric measurements, multiple regression, receiver operating characteristic and Kaplan-Meier survival. The disease control rate was 72 %. Median PFS was not achieved (follow-up: 1-33 months, median: 16). Only grading was associated with response (p < 0.01). At baseline, 94 % of patients were NETest-positive, while CgA was elevated in 59 %. NETest accurately (89 %, χ 2 = 27.4; p = 1.2 x 10 -7 ) correlated with treatment response, while CgA was 24 % accurate. Gene cluster expression (growth-factor signalome and metabolome) had an AUC of 0.74 ± 0.08 (z-statistic = 2.92, p < 0.004) for predicting

  1. Measurement of circulating transcripts and gene cluster analysis predicts and defines therapeutic efficacy of peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors

    Energy Technology Data Exchange (ETDEWEB)

    Bodei, L. [European Institute of Oncology, Division of Nuclear Medicine, Milan (Italy); LuGenIum Consortium, Milan, Rotterdam, Bad Berka, London, Italy, Netherlands, Germany (Country Unknown); Kidd, M. [Wren Laboratories, Branford, CT (United States); Modlin, I.M. [LuGenIum Consortium, Milan, Rotterdam, Bad Berka, London, Italy, Netherlands, Germany (Country Unknown); Yale School of Medicine, New Haven, CT (United States); Severi, S.; Nicolini, S.; Paganelli, G. [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Nuclear Medicine and Radiometabolic Units, Meldola (Italy); Drozdov, I. [Bering Limited, London (United Kingdom); Kwekkeboom, D.J.; Krenning, E.P. [LuGenIum Consortium, Milan, Rotterdam, Bad Berka, London, Italy, Netherlands, Germany (Country Unknown); Erasmus Medical Center, Nuclear Medicine Department, Rotterdam (Netherlands); Baum, R.P. [LuGenIum Consortium, Milan, Rotterdam, Bad Berka, London, Italy, Netherlands, Germany (Country Unknown); Zentralklinik Bad Berka, Theranostics Center for Molecular Radiotherapy and Imaging, Bad Berka (Germany)

    2016-05-15

    Peptide receptor radionuclide therapy (PRRT) is an effective method for treating neuroendocrine tumors (NETs). It is limited, however, in the prediction of individual tumor response and the precise and early identification of changes in tumor size. Currently, response prediction is based on somatostatin receptor expression and efficacy by morphological imaging and/or chromogranin A (CgA) measurement. The aim of this study was to assess the accuracy of circulating NET transcripts as a measure of PRRT efficacy, and moreover to identify prognostic gene clusters in pretreatment blood that could be interpolated with relevant clinical features in order to define a biological index for the tumor and a predictive quotient for PRRT efficacy. NET patients (n = 54), M: F 37:17, median age 66, bronchial: n = 13, GEP-NET: n = 35, CUP: n = 6 were treated with {sup 177}Lu-based-PRRT (cumulative activity: 6.5-27.8 GBq, median 18.5). At baseline: 47/54 low-grade (G1/G2; bronchial typical/atypical), 31/49 {sup 18}FDG positive and 39/54 progressive. Disease status was assessed by RECIST1.1. Transcripts were measured by real-time quantitative reverse transcription PCR (qRT-PCR) and multianalyte algorithmic analysis (NETest); CgA by enzyme-linked immunosorbent assay (ELISA). Gene cluster (GC) derivations: regulatory network, protein:protein interactome analyses. Statistical analyses: chi-square, non-parametric measurements, multiple regression, receiver operating characteristic and Kaplan-Meier survival. The disease control rate was 72 %. Median PFS was not achieved (follow-up: 1-33 months, median: 16). Only grading was associated with response (p < 0.01). At baseline, 94 % of patients were NETest-positive, while CgA was elevated in 59 %. NETest accurately (89 %, χ{sup 2} = 27.4; p = 1.2 x 10{sup -7}) correlated with treatment response, while CgA was 24 % accurate. Gene cluster expression (growth-factor signalome and metabolome) had an AUC of 0.74 ± 0.08 (z-statistic = 2.92, p < 0

  2. PADI4 Haplotypes in Association with RA Mexican Patients, a New Prospect for Antigen Modulation

    Directory of Open Access Journals (Sweden)

    Maria Guadalupe Zavala-Cerna

    2013-01-01

    Full Text Available Peptidyl arginine deiminase IV (PAD 4 is the responsible enzyme for a posttranslational modification called citrullination, originating the antigenic determinant recognized by anti-cyclic citrullinated peptide antibodies (ACPA. Four SNPs (single nucleotide polymorphisms have been described in PADI4 gene to form a susceptibility haplotype for rheumatoid arthritis (RA; nevertheless, results in association studies appear contradictory in different populations. The aim of the study was to analyze if the presence of three SNPs in PADI4 gene susceptibility haplotype (GTG is associated with ACPA positivity in patients with RA. This was a cross-sectional study that included 86 RA patients and 98 healthy controls. Polymorphisms PADI4_89, PADI4_90, and PADI4_92 in the PADI4 gene were genotyped. The susceptibility haplotype (GTG was more frequent in RA patients; interestingly, we found a new haplotype associated with RA with a higher frequency (GTC. There were no associations between polymorphisms and high scores in Spanish HAQ-DI and DAS-28, but we did find an association between RARBIS index and PADI4_89, PADI4_90 polymorphisms. We could not confirm an association between susceptibility haplotype presence and ACPA positivity. Further evidence about proteomic expression of this gene will determine its participation in antigenic generation and autoimmunity.

  3. The impact of sample size and marker selection on the study of haplotype structures

    Directory of Open Access Journals (Sweden)

    Sun Xiao

    2004-03-01

    Full Text Available Abstract Several studies of haplotype structures in the human genome in various populations have found that the human chromosomes are structured such that each chromosome can be divided into many blocks, within which there is limited haplotype diversity. In addition, only a few genetic markers in a putative block are needed to capture most of the diversity within a block. There has been no systematic empirical study of the effects of sample size and marker set on the identified block structures and representative marker sets, however. The purpose of this study was to conduct a detailed empirical study to examine such impacts. Towards this goal, we have analysed three representative autosomal regions from a large genome-wide study of haplotypes with samples consisting of African-Americans and samples consisting of Japanese and Chinese individuals. For both populations, we have found that the sample size and marker set have significant impact on the number of blocks and the total number of representative markers identified. The marker set in particular has very strong impacts, and our results indicate that the marker density in the original datasets may not be adequate to allow a meaningful characterisation of haplotype structures. In general, we conclude that we need a relatively large sample size and a very dense marker panel in the study of haplotype structures in human populations.

  4. The performance of phylogenetic algorithms in estimating haplotype genealogies with migration.

    Science.gov (United States)

    Salzburger, Walter; Ewing, Greg B; Von Haeseler, Arndt

    2011-05-01

    Genealogies estimated from haplotypic genetic data play a prominent role in various biological disciplines in general and in phylogenetics, population genetics and phylogeography in particular. Several software packages have specifically been developed for the purpose of reconstructing genealogies from closely related, and hence, highly similar haplotype sequence data. Here, we use simulated data sets to test the performance of traditional phylogenetic algorithms, neighbour-joining, maximum parsimony and maximum likelihood in estimating genealogies from nonrecombining haplotypic genetic data. We demonstrate that these methods are suitable for constructing genealogies from sets of closely related DNA sequences with or without migration. As genealogies based on phylogenetic reconstructions are fully resolved, but not necessarily bifurcating, and without reticulations, these approaches outperform widespread 'network' constructing methods. In our simulations of coalescent scenarios involving panmictic, symmetric and asymmetric migration, we found that phylogenetic reconstruction methods performed well, while the statistical parsimony approach as implemented in TCS performed poorly. Overall, parsimony as implemented in the PHYLIP package performed slightly better than other methods. We further point out that we are not making the case that widespread 'network' constructing methods are bad, but that traditional phylogenetic tree finding methods are applicable to haplotypic data and exhibit reasonable performance with respect to accuracy and robustness. We also discuss some of the problems of converting a tree to a haplotype genealogy, in particular that it is nonunique. © 2011 Blackwell Publishing Ltd.

  5. Haplotypes in the dystrophin DNA segment point to a mosaic origin of modern human diversity.

    Science.gov (United States)

    Zietkiewicz, Ewa; Yotova, Vania; Gehl, Dominik; Wambach, Tina; Arrieta, Isabel; Batzer, Mark; Cole, David E C; Hechtman, Peter; Kaplan, Feige; Modiano, David; Moisan, Jean-Paul; Michalski, Roman; Labuda, Damian

    2003-11-01

    Although Africa has played a central role in human evolutionary history, certain studies have suggested that not all contemporary human genetic diversity is of recent African origin. We investigated 35 simple polymorphic sites and one T(n) microsatellite in an 8-kb segment of the dystrophin gene. We found 86 haplotypes in 1,343 chromosomes from around the world. Although a classical out-of-Africa topology was observed in trees based on the variant frequencies, the tree of haplotype sequences reveals three lineages accounting for present-day diversity. The proportion of new recombinants and the diversity of the T(n) microsatellite were used to estimate the age of haplotype lineages and the time of colonization events. The lineage that underwent the great expansion originated in Africa prior to the Upper Paleolithic (27,000-56,000 years ago). A second group, of structurally distinct haplotypes that occupy a central position on the tree, has never left Africa. The third lineage is represented by the haplotype that lies closest to the root, is virtually absent in Africa, and appears older than the recent out-of-Africa expansion. We propose that this lineage could have left Africa before the expansion (as early as 160,000 years ago) and admixed, outside of Africa, with the expanding lineage. Contemporary human diversity, although dominated by the recently expanded African lineage, thus represents a mosaic of different contributions.

  6. Climate Clever Clovers: New Paradigm to Reduce the Environmental Footprint of Ruminants by Breeding Low Methanogenic Forages Utilizing Haplotype Variation

    Directory of Open Access Journals (Sweden)

    Parwinder Kaur

    2017-09-01

    Full Text Available Mitigating methane production by ruminants is a significant challenge to global livestock production. This research offers a new paradigm to reduce methane emissions from ruminants by breeding climate-clever clovers. We demonstrate wide genetic diversity for the trait methanogenic potential in Australia’s key pasture legume, subterranean clover (Trifolium subterraneum L.. In a bi-parental population the broadsense heritability in methanogenic potential was moderate (H2 = 0.4 and allelic variation in a region of Chr 8 accounted for 7.8% of phenotypic variation. In a genome-wide association study we identified four loci controlling methanogenic potential assessed by an in vitro fermentation system. Significantly, the discovery of a single nucleotide polymorphism (SNP on Chr 5 in a defined haplotype block with an upstream putative candidate gene from a plant peroxidase-like superfamily (TSub_g18548 and a downstream lectin receptor protein kinase (TSub_g18549 provides valuable candidates for an assay for this complex trait. In this way haplotype variation can be tracked to breed pastures with reduced methanogenic potential. Of the quantitative trait loci candidates, the DNA-damage-repair/toleration DRT100-like protein (TSub_g26967, linked to avoid the severity of DNA damage induced by secondary metabolites, is considered central to enteric methane production, as are disease resistance (TSub_g26971, TSub_g26972, and TSub_g18549 and ribonuclease proteins (TSub_g26974, TSub_g26975. These proteins are good pointers to elucidate the genetic basis of in vitro microbial fermentability and enteric methanogenic potential in subterranean clover. The genes identified allow the design of a suite of markers for marker-assisted selection to reduce rumen methane emission in selected pasture legumes. We demonstrate the feasibility of a plant breeding approach without compromising animal productivity to mitigate enteric methane emissions, which is one of the most

  7. Defining Glaucomatous Optic Neuropathy from a Continuous Measure of Optic Nerve Damage - The Optimal Cut-off Point for Risk-factor Analysis in Population-based Epidemiology

    NARCIS (Netherlands)

    Ramdas, Wishal D.; Rizopoulos, Dimitris; Wolfs, Roger C. W.; Hofman, Albert; de Jong, Paulus T. V. M.; Vingerling, Johannes R.; Jansonius, Nomdo M.

    2011-01-01

    Purpose: Diseases characterized by a continuous trait can be defined by setting a cut-off point for the disease measure in question, accepting some misclassification. The 97.5th percentile is commonly used as a cut-off point. However, it is unclear whether this percentile is the optimal cut-off

  8. Linkage disequilibrium with HLA-DRB1-DQB1 haplotypes explains the association of TNF-308G>A variant with type 1 diabetes in a Brazilian cohort.

    Science.gov (United States)

    Patente, Thiago A; Monteiro, Maria B; Vieira, Suzana M; Rossi da Silva, Maria E; Nery, Márcia; Queiroz, Márcia; Azevedo, Mirela J; Canani, Luis H; Parisi, Maria C; Pavin, Elizabeth J; Mainardi, Débora; Javor, Juraj; Velho, Gilberto; Coimbra, Cássio N; Corrêa-Giannella, Maria Lúcia

    2015-08-15

    A functional variant in the promoter region of the gene encoding tumor necrosis factor (TNF; rs1800629, -308G>A) showed to confer susceptibility to T1D. However, TNF rs1800629 was found, in several populations, to be in linkage disequilibrium with HLA susceptibility haplotypes to T1D. We evaluated the association of TNF rs1800629 with T1D in a cohort of Brazilian subjects, and assessed the impact of HLA susceptibility haplotypes in this association. 659 subjects with T1D and 539 control subjects were genotyped for TNF-308G>A variant. HLA-DRB1 and HLA-DQB1 genes were genotyped in a subset of 313 subjects with T1D and 139 control subjects. Associations with T1D were observed for the A-allele of rs1800629 (OR 1.69, 95% CI 1.33-2.15, p<0.0001, in a codominant model) and for 3 HLA haplotypes: DRB1*03:01-DQB1*02:01 (OR 5.37, 95% CI 3.23-8.59, p<0.0001), DRB1*04:01-DQB1*03:02 (OR 2.95, 95% CI 1.21-7.21, p=0.01) and DRB1*04:02-DQB1*03:02 (OR 2.14, 95% CI 1.02-4.50, p=0.04). Linkage disequilibrium was observed between TNF rs1800629 and HLA-DRB1 and HLA-DQB1 alleles. In a stepwise regression analysis HLA haplotypes, but not TNF rs1800629, remained independently associated with T1D. Our results do not support an independent effect of allelic variations of TNF in the genetic susceptibility to T1D. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. Association between VEGF polymorphisms (936c/t, -460t/c and -634g/c) with haplotypes and coronary heart disease susceptibility.

    Science.gov (United States)

    Han, Xia; Liu, Lili; Niu, Jiamin; Yang, Jun; Zhang, Zengtang; Zhang, Zhiqiang

    2015-01-01

    Our aim was to investigate the association between single nucleotide polymorphisms (SNPs) of vascular endothelial growth factor (VEGF) and coronary heart disease (CHD) susceptibility in Chinese Han population. 144 CHD patients and 150 healthy individuals were enrolled in the study. Three SNPs (936C/T, -460T/C and -634G/C) of VEGF were chose and then were genotyped with Sequenom time-of-flight mass spectrometry (TOFMS). Odds ratio (OR) with 95% confidence interval (CI) were used to evaluate the association of genotypes and haplotypes and CHD susceptibility. The frequencies of -460T/C CC genotype (13.6%) was found higher in the case group than that of control group (6.7%), which indicated that CC genotype was a risk factor for CHD (OR=2.50, 95% CI=1.10-5.68). Correspondently, the C allele appeared to increase the risk of CHD (OR=1.54, 95% CI=1.07-2.22). For -634G/C polymorphism, the risk of the CC genotype carrier for CHD increased 2.24 fold compared to the wild genotype. Moreover, -634G/CC allele was significantly associated with CHD susceptibility (OR=1.65, 95% CI=1.15-2.36). In addition, +936C/T CT genotype and C allele appeared to be a genetic-susceptibility factors for CHD (OR=2.43, 95% CI=1.44-4.10; OR=1.95, 95% CI=1.26-3.02). The haplotype analysis showed that T-C-T, C-C-C and C-G-C haplotypes all could increase the risk for CHD (OR: 2.43, 2.77 and 2.33). we concluded VEGF polymorphisms were associated with CHD susceptibility. Moreover, the haplotypes of T-C-T, C-C-C and C-G-C all could increase the risk for CHD.

  10. Association between SLC19A1 Gene Polymorphism and High Dose Methotrexate Toxicity in Childhood Acute Lymphoblastic Leukaemia and Non Hodgkin Malignant Lymphoma: Introducing a Haplotype based Approach

    Science.gov (United States)

    Kotnik, Barbara Faganel; Jazbec, Janez; Grabar, Petra Bohanec; Rodriguez-Antona, Cristina

    2017-01-01

    Abstract Background We investigated the clinical relevance of SLC 19A1 genetic variability for high dose methotrexate (HD-MTX) related toxicities in children and adolescents with acute lymphoblastic leukaemia (ALL) and non Hodgkin malignant lymphoma (NHML). Patients and methods Eighty-eight children and adolescents with ALL/NHML were investigated for the influence of SLC 19A1 single nucleotide polymorphisms (SNPs) and haplotypes on HD-MTX induced toxicities. Results Patients with rs2838958 TT genotype had higher probability for mucositis development as compared to carriers of at least one rs2838958 C allele (OR 0.226 (0.071–0.725), p < 0.009). Haplotype TGTTCCG (H4) statistically significantly reduced the risk for the occurrence of adverse events during treatment with HD-MTX (OR 0.143 (0.023–0.852), p = 0.030). Conclusions SLC 19A1 SNP and haplotype analysis could provide additional information in a personalized HD-MTX therapy for children with ALL/NHML in order to achieve better treatment outcome. However further studies are needed to validate the results. PMID:29333125

  11. HLA alleles and haplotypes in Burmese (Myanmarese) and Karen in Thailand.

    Science.gov (United States)

    Kongmaroeng, C; Romphruk, A; Puapairoj, C; Leelayuwat, C; Kulski, J K; Inoko, H; Dunn, D S; Romphruk, A V

    2015-09-01

    This is the first report on human leukocyte antigen (HLA) allele and haplotype frequencies at three class I loci and two class II loci in unrelated healthy individuals from two ethnic groups, 170 Burmese and 200 Karen, originally from Burma (Myanmar), but sampled while residing in Thailand. Overall, the HLA allele and haplotype frequencies detected by polymerase chain reaction sequence-specific primer (PCR-SSP) at five loci (A, B, C, DRB1 and DRQB1) at low resolution showed distinct differences between the Burmese and Karen. In Burmese, five HLA-B*15 haplotypes with different HLA-A and HLA-DR/DQ combinations were detected with three of these not previously reported in other Asian populations. The data are important in the fields of anthropology, transplantation and disease-association studies. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. Casein haplotypes and their association with milk production traits in Norwegian Red cattle

    Directory of Open Access Journals (Sweden)

    Nome Torfinn

    2009-02-01

    Full Text Available Abstract A high resolution SNP map was constructed for the bovine casein region to identify haplotype structures and study associations with milk traits in Norwegian Red cattle. Our analyses suggest separation of the casein cluster into two haplotype blocks, one consisting of the CSN1S1, CSN2 and CSN1S2 genes and another one consisting of the CSN3 gene. Highly significant associations with both protein and milk yield were found for both single SNPs and haplotypes within the CSN1S1-CSN2-CSN1S2 haplotype block. In contrast, no significant association was found for single SNPs or haplotypes within the CSN3 block. Our results point towards CSN2 and CSN1S2 as the most likely loci harbouring the underlying causative DNA variation. In our study, the most significant results were found for the SNP CSN2_67 with the C allele consistently associated with both higher protein and milk yields. CSN2_67 calls a C to an A substitution at codon 67 in β-casein gene resulting in histidine replacing proline in the amino acid sequence. This polymorphism determines the protein variants A1/B (CSN2_67 A allele versus A2/A3 (CSN2_67 C allele. Other studies have suggested that a high consumption of A1/B milk may affect human health by increasing the risk of diabetes and heart diseases. Altogether these results argue for an increase in the frequency of the CSN2_67 C allele or haplotypes containing this allele in the Norwegian Red cattle population by selective breeding.

  13. Fundamental problem of forensic mathematics--the evidential value of a rare haplotype.

    Science.gov (United States)

    Brenner, Charles H

    2010-10-01

    Y-chromosomal and mitochondrial haplotyping offer special advantages for criminal (and other) identification. For different reasons, each of them is sometimes detectable in a crime stain for which autosomal typing fails. But they also present special problems, including a fundamental mathematical one: When a rare haplotype is shared between suspect and crime scene, how strong is the evidence linking the two? Assume a reference population sample is available which contains n-1 haplotypes. The most interesting situation as well as the most common one is that the crime scene haplotype was never observed in the population sample. The traditional tools of product rule and sample frequency are not useful when there are no components to multiply and the sample frequency is zero. A useful statistic is the fraction κ of the population sample that consists of "singletons" - of once-observed types. A simple argument shows that the probability for a random innocent suspect to match a previously unobserved crime scene type is (1-κ)/n - distinctly less than 1/n, likely ten times less. The robust validity of this model is confirmed by testing it against a range of population models. This paper hinges above all on one key insight: probability is not frequency. The common but erroneous "frequency" approach adopts population frequency as a surrogate for matching probability and attempts the intractable problem of guessing how many instances exist of the specific haplotype at a certain crime. Probability, by contrast, depends by definition only on the available data. Hence if different haplotypes but with the same data occur in two different crimes, although the frequencies are different (and are hopelessly elusive), the matching probabilities are the same, and are not hard to find. Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.

  14. HLA haplotype map of river valley populations with hemochromatosis traced through five centuries in Central Sweden.

    Science.gov (United States)

    Olsson, K Sigvard; Ritter, Bernd; Hansson, Norbeth; Chowdhury, Ruma R

    2008-07-01

    The hemochromatosis mutation, C282Y of the HFE gene, seems to have originated from a single event which once occurred in a person living in the north west of Europe carrying human leukocyte antigen (HLA)-A3-B7. In descendants of this ancestor also other haplotypes appear probably caused by local recombinations and founder effects. The background of these associations is unknown. Isolated river valley populations may be fruitful for the mapping of genetic disorders such as hemochromatosis. In this study, we try to test this hypothesis in a study from central Sweden where the haplotyope A1-B8 was common. HLA haplotypes and HFE mutations were studied in hemochromatosis patients with present or past parental origin in a sparsely populated (1/km(2)) rural district (n = 8366 in the year of 2005), in central Sweden. Pedigrees were constructed from the Swedish church book registry. Extended haplotypes were studied to evaluate origin of recombinations. There were 87 original probands, 36 females and 51 males identified during 30 yr, of whom 86% carried C282Y/C282Y and 14% C282Y/H63D. Of 32 different HLA haplotypes A1-B8 was the most common (34%), followed by A3-B7 (16%), both in strong linkage disequilibrium with controls, (P females. River valley populations may contain HLA haplotypes reflecting their demographic history. This study has demonstrated that the resistance against recombinations between HLA-A and HFE make HLA haplotypes excellent markers for population movements. Founder effects and genetic drift from bottleneck populations (surviving the plague?) may explain the commonness of the mutation in central Scandinavia. The intergenerational time difference >30 yr was greater than expected and means that the age of the original mutation may be underestimated.

  15. The clinical application of single-sperm-based SNP haplotyping for PGD of osteogenesis imperfecta.

    Science.gov (United States)

    Chen, Linjun; Diao, Zhenyu; Xu, Zhipeng; Zhou, Jianjun; Yan, Guijun; Sun, Haixiang

    2018-05-15

    Osteogenesis imperfecta (OI) is a genetically heterogeneous disorder, presenting either autosomal dominant, autosomal recessive or X-linked inheritance patterns. The majority of OI cases are autosomal dominant and are caused by heterozygous mutations in either the COL1A1 or COL1A2 gene. In these dominant disorders, allele dropout (ADO) can lead to misdiagnosis in preimplantation genetic diagnosis (PGD). Polymorphic markers linked to the mutated genes have been used to establish haplotypes for identifying ADO and ensuring the accuracy of PGD. However, the haplotype of male patients cannot be determined without data from affected relatives. Here, we developed a method for single-sperm-based single-nucleotide polymorphism (SNP) haplotyping via next-generation sequencing (NGS) for the PGD of OI. After NGS, 10 informative polymorphic SNP markers located upstream and downstream of the COL1A1 gene and its pathogenic mutation site were linked to individual alleles in a single sperm from an affected male. After haplotyping, a normal blastocyst was transferred to the uterus for a subsequent frozen embryo transfer cycle. The accuracy of PGD was confirmed by amniocentesis at 19 weeks of gestation. A healthy infant weighing 4,250 g was born via vaginal delivery at the 40th week of gestation. Single-sperm-based SNP haplotyping can be applied for PGD of any monogenic disorders or de novo mutations in males in whom the haplotype of paternal mutations cannot be determined due to a lack of affected relatives. ADO: allele dropout; DI: dentinogenesis imperfect; ESHRE: European Society of Human Reproduction and Embryology; FET: frozen embryo transfer; gDNA: genomic DNA; ICSI: intracytoplasmic sperm injection; IVF: in vitro fertilization; MDA: multiple displacement amplification; NGS: next-generation sequencing; OI: osteogenesis imperfect; PBS: phosphate buffer saline; PCR: polymerase chain reaction; PGD: preimplantation genetic diagnosis; SNP: single-nucleotide polymorphism; STR

  16. Patterns of linkage disequilibrium and haplotype distribution in disease candidate genes.

    Science.gov (United States)

    Long, Ji-Rong; Zhao, Lan-Juan; Liu, Peng-Yuan; Lu, Yan; Dvornyk, Volodymyr; Shen, Hui; Liu, Yong-Jun; Zhang, Yuan-Yuan; Xiong, Dong-Hai; Xiao, Peng; Deng, Hong-Wen

    2004-05-24

    The adequacy of association studies for complex diseases depends critically on the existence of linkage disequilibrium (LD) between functional alleles and surrounding SNP markers. We examined the patterns of LD and haplotype distribution in eight candidate genes for osteoporosis and/or obesity using 31 SNPs in 1,873 subjects. These eight genes are apolipoprotein E (APOE), type I collagen alpha1 (COL1A1), estrogen receptor-alpha (ER-alpha), leptin receptor (LEPR), parathyroid hormone (PTH)/PTH-related peptide receptor type 1 (PTHR1), transforming growth factor-beta1 (TGF-beta1), uncoupling protein 3 (UCP3), and vitamin D (1,25-dihydroxyvitamin D3) receptor (VDR). Yin yang haplotypes, two high-frequency haplotypes composed of completely mismatching SNP alleles, were examined. To quantify LD patterns, two common measures of LD, D' and r2, were calculated for the SNPs within the genes. The haplotype distribution varied in the different genes. Yin yang haplotypes were observed only in PTHR1 and UCP3. D' ranged from 0.020 to 1.000 with the average of 0.475, whereas the average r2 was 0.158 (ranging from 0.000 to 0.883). A decay of LD was observed as the intermarker distance increased, however, there was a great difference in LD characteristics of different genes or even in different regions within gene. The differences in haplotype distributions and LD patterns among the genes underscore the importance of characterizing genomic regions of interest prior to association studies.

  17. Vitamin K epoxide reductase complex subunit 1 (Vkorc1 haplotype diversity in mouse priority strains

    Directory of Open Access Journals (Sweden)

    Kohn Michael H

    2008-12-01

    Full Text Available Abstract Background Polymorphisms in the vitamin K-epoxide reductase complex subunit 1 gene, Vkorc1, could affect blood coagulation and other vitamin K-dependent proteins, such as osteocalcin (bone Gla protein, BGP. Here we sequenced the Vkorc1 gene in 40 mouse priority strains. We analyzed Vkorc1 haplotypes with respect to prothrombin time (PT and bone mineral density and composition (BMD and BMC; phenotypes expected to be vitamin K-dependent and represented by data in the Mouse Phenome Database (MPD. Findings In the commonly used laboratory strains of Mus musculus domesticus we identified only four haplotypes differing in the intron or 5' region sequence of the Vkorc1. Six haplotypes differing by coding and non-coding polymorphisms were identified in the other subspecies of Mus. We detected no significant association of Vkorc1 haplotypes with PT, BMD and BMC within each subspecies of Mus. Vkorc1 haplotype sequences divergence between subspecies was associated with PT, BMD and BMC. Conclusion Phenotypic variation in PT, BMD and BMC within subspecies of Mus, while substantial, appears to be dominated by genetic variation in genes other than the Vkorc1. This was particularly evident for M. m. domesticus, where a single haplotype was observed in conjunction with virtually the entire range of PT, BMD and BMC values of all 5 subspecies of Mus included in this study. Differences in these phenotypes between subspecies also should not be attributed to Vkorc1 variants, but should be viewed as a result of genome wide genetic divergence.

  18. Class I gene regulation of haplotype preference may influence antiviral immunity in vivo

    DEFF Research Database (Denmark)

    Thomsen, Allan Randrup; Marker, O

    1989-01-01

    targets. In regard to the in vivo significance of haplotype preference it was found that (C X C3) F1 mice expressed an earlier and stronger virus-specific delayed type hypersensitivity response and exerted a more efficient virus control than did (C-H-2dm2 X C3) F1. Taken together these findings suggest...... that haplotype preference reflects a selection process favoring the restriction element associated with the most efficient immune response in vivo. The implications of this are discussed....

  19. Novel harmful recessive haplotypes identified for fertility traits in Nordic Holstein cattle

    DEFF Research Database (Denmark)

    Sahana, Goutam; Nielsen, Ulrik Sander; Aamand, Gert Pedersen

    2013-01-01

    harboring possible recessive lethal alleles. Effects of the identified haplotypes were estimated on two fertility traits: non-return rates and calving interval. Out of the eight identified genomic regions, six regions were confirmed as having an effect on fertility. The information can be used to avoid......Using genomic data, lethal recessives may be discovered from haplotypes that are common in the population but never occur in the homozygote state in live animals. This approach only requires genotype data from phenotypically normal (i.e. live) individuals and not from the affected embryos that die...

  20. HLA Class I and Class II Alleles and Haplotypes Confirm the Berber Origin of the Present Day Tunisian Population.

    Directory of Open Access Journals (Sweden)

    Abdelhafidh Hajjej

    Full Text Available In view of its distinct geographical location and relatively small area, Tunisia witnessed the presence of many civilizations and ethnic groups throughout history, thereby questioning the origin of present-day Tunisian population. We investigated HLA class I and class II gene profiles in Tunisians, and compared this profile with those of Mediterranean and Sub-Sahara African populations. A total of 376 unrelated Tunisian individuals of both genders were genotyped for HLA class I (A, B and class II (DRB1, DQB1, using reverse dot-blot hybridization (PCR-SSO method. Statistical analysis was performed using Arlequin software. Phylogenetic trees were constructed by DISPAN software, and correspondence analysis was carried out by VISTA software. One hundred fifty-three HLA alleles were identified in the studied sample, which comprised 41, 50, 40 and 22 alleles at HLA-A,-B,-DRB1 and -DQB1 loci, respectively. The most frequent alleles were HLA-A*02:01 (16.76%, HLA-B*44:02/03 (17.82%, HLA-DRB1*07:01 (19.02%, and HLA-DQB1*03:01 (17.95%. Four-locus haplotype analysis identified HLA-A*02:01-B*50:01-DRB1*07:01-DQB1*02:02 (2.2% as the common haplotype in Tunisians. Compared to other nearby populations, Tunisians appear to be genetically related to Western Mediterranean population, in particular North Africans and Berbers. In conclusion, HLA genotype results indicate that Tunisians are related to present-day North Africans, Berbers and to Iberians, but not to Eastern Arabs (Palestinians, Jordanians and Lebanese. This suggests that the genetic contribution of Arab invasion of 7th-11th century A.D. had little impact of the North African gene pool.

  1. Defined contribution health benefits.

    Science.gov (United States)

    Fronstin, P

    2001-03-01

    This Issue Brief discusses the emerging issue of "defined contribution" (DC) health benefits. The term "defined contribution" is used to describe a wide variety of approaches to the provision of health benefits, all of which have in common a shift in the responsibility for payment and selection of health care services from employers to employees. DC health benefits often are mentioned in the context of enabling employers to control their outlay for health benefits by avoiding increases in health care costs. DC health benefits may also shift responsibility for choosing a health plan and the associated risks of choosing a plan from employers to employees. There are three primary reasons why some employers currently are considering some sort of DC approach. First, they are once again looking for ways to keep their health care cost increases in line with overall inflation. Second, some employers are concerned that the public "backlash" against managed care will result in new legislation, regulations, and litigation that will further increase their health care costs if they do not distance themselves from health care decisions. Third, employers have modified not only most employee benefit plans, but labor market practices in general, by giving workers more choice, control, and flexibility. DC-type health benefits have existed as cafeteria plans since the 1980s. A cafeteria plan gives each employee the opportunity to determine the allocation of his or her total compensation (within employer-defined limits) among various employee benefits (primarily retirement or health). Most types of DC health benefits currently being discussed could be provided within the existing employment-based health insurance system, with or without the use of cafeteria plans. They could also allow employees to purchase health insurance directly from insurers, or they could drive new technologies and new forms of risk pooling through which health care services are provided and financed. DC health

  2. Haplotype Variation of Flowering Time Genes of Sugar Beet and Its Wild Relatives and the Impact on Life Cycle Regimes

    Directory of Open Access Journals (Sweden)

    Nadine Höft

    2018-01-01

    Full Text Available The species Beta vulgaris encompasses wild and cultivated members with a broad range of phenological development. The annual life cycle is commonly found in sea beets (ssp. maritima from Mediterranean environments which germinate, bolt, and flower within one season under long day conditions. Biennials such as the cultivated sugar beet (B. vulgaris ssp. vulgaris as well as sea beets from northern latitudes require prolonged exposure to cold temperature over winter to acquire floral competence. Sugar beet is mainly cultivated for sugar production in Europe and is likely to have originated from sea beet. Flowering time strongly affects seed yield and yield potential and is thus a trait of high agronomic relevance. Besides environmental cues, there are complex genetic networks known to impact life cycle switch in flowering plants. In sugar beet, BTC1, BvBBX19, BvFT1, and BvFT2 are major flowering time regulators. In this study, we phenotyped plants from a diversity Beta panel encompassing cultivated and wild species from different geographical origin. Plants were grown under different day length regimes with and without vernalization. Haplotype analysis of BTC1, BvBBX19, BvFT1, and BvFT2 was performed to identify natural diversity of these genes and their impact on flowering. We found that accessions from northern latitudes flowered significantly later than those from southern latitudes. Some plants did not flower at all, indicating a strong impact of latitude of origin on life cycle. Haplotype analysis revealed a high conservation of the CCT-, REC-, BBX-, and PEBP-domains with regard to SNP occurrence. We identified sequence variation which may impact life cycle adaptation in beet. Our data endorse the importance of BTC1 in the domestication process of cultivated beets and contribute to the understanding of distribution and adaption of Beta species to different life cycle regimes in response to different environments. Moreover, our data provide a

  3. Strain screen and haplotype association mapping of wheel running in inbred mouse strains.

    Science.gov (United States)

    Lightfoot, J Timothy; Leamy, Larry; Pomp, Daniel; Turner, Michael J; Fodor, Anthony A; Knab, Amy; Bowen, Robert S; Ferguson, David; Moore-Harrison, Trudy; Hamilton, Alicia

    2010-09-01

    Previous genetic association studies of physical activity, in both animal and human models, have been limited in number of subjects and genetically homozygous strains used as well as number of genomic markers available for analysis. Expansion of the available mouse physical activity strain screens and the recently published dense single-nucleotide polymorphism (SNP) map of the mouse genome (approximately 8.3 million SNPs) and associated statistical methods allowed us to construct a more generalizable map of the quantitative trait loci (QTL) associated with physical activity. Specifically, we measured wheel running activity in male and female mice (average age 9 wk) in 41 inbred strains and used activity data from 38 of these strains in a haplotype association mapping analysis to determine QTL associated with activity. As seen previously, there was a large range of activity patterns among the strains, with the highest and lowest strains differing significantly in daily distance run (27.4-fold), duration of activity (23.6-fold), and speed (2.9-fold). On a daily basis, female mice ran further (24%), longer (13%), and faster (11%). Twelve QTL were identified, with three (on Chr. 12, 18, and 19) in both male and female mice, five specific to males, and four specific to females. Eight of the 12 QTL, including the 3 general QTL found for both sexes, fell into intergenic areas. The results of this study further support the findings of a moderate to high heritability of physical activity and add general genomic areas applicable to a large number of mouse strains that can be further mined for candidate genes associated with regulation of physical activity. Additionally, results suggest that potential genetic mechanisms arising from traditional noncoding regions of the genome may be involved in regulation of physical activity.

  4. On Defining Mass

    Science.gov (United States)

    Hecht, Eugene

    2011-01-01

    Though central to any pedagogical development of physics, the concept of mass is still not well understood. Properly defining mass has proven to be far more daunting than contemporary textbooks would have us believe. And yet today the origin of mass is one of the most aggressively pursued areas of research in all of physics. Much of the excitement surrounding the Large Hadron Collider at CERN is associated with discovering the mechanism responsible for the masses of the elementary particles. This paper will first briefly examine the leading definitions, pointing out their shortcomings. Then, utilizing relativity theory, it will propose—for consideration by the community of physicists—a conceptual definition of mass predicated on the more fundamental concept of energy, more fundamental in that everything that has mass has energy, yet not everything that has energy has mass.

  5. Implementing Software Defined Radio

    CERN Document Server

    Grayver, Eugene

    2013-01-01

    Software Defined Radio makes wireless communications easier, more efficient, and more reliable. This book bridges the gap between academic research and practical implementation. When beginning a project, practicing engineers, technical managers, and graduate students can save countless hours by considering the concepts presented in these pages. The author covers the myriad options and trade-offs available when selecting an appropriate hardware architecture. As demonstrated here, the choice between hardware- and software-centric architecture can mean the difference between meeting an aggressive schedule and bogging down in endless design iterations. Because of the author’s experience overseeing dozens of failed and successful developments, he is able to present many real-life examples. Some of the key concepts covered are: Choosing the right architecture for the market – laboratory, military, or commercial Hardware platforms – FPGAs, GPPs, specialized and hybrid devices Standardization efforts to ens...

  6. Defining the mobilome.

    Science.gov (United States)

    Siefert, Janet L

    2009-01-01

    This chapter defines the agents that provide for the movement of genetic material which fuels the adaptive potential of life on our planet. The chapter has been structured to be broadly comprehensive, arbitrarily categorizing the mobilome into four classes: (1) transposons, (2) plasmids, (3) bacteriophage, and (4) self-splicing molecular parasites.Our increasing understanding of the mobilome is as dynamic as the mobilome itself. With continuing discovery, it is clear that nature has not confined these genomic agents of change to neat categories, but rather the classification categories overlap and intertwine. Massive sequencing efforts and their published analyses are continuing to refine our understanding of the extent of the mobilome. This chapter provides a framework to describe our current understanding of the mobilome and a foundation on which appreciation of its impact on genome evolution can be understood.

  7. Software Defined Networking

    DEFF Research Database (Denmark)

    Caba, Cosmin Marius

    Network Service Providers (NSP) often choose to overprovision their networks instead of deploying proper Quality of Services (QoS) mechanisms that allow for traffic differentiation and predictable quality. This tendency of overprovisioning is not sustainable for the simple reason that network...... resources are limited. Hence, to counteract this trend, current QoS mechanisms must become simpler to deploy and operate, in order to motivate NSPs to employ QoS techniques instead of overprovisioning. Software Defined Networking (SDN) represents a paradigm shift in the way telecommunication and data...... generic perspective (e.g. service provisioning speed, resources availability). As a result, new mechanisms for providing QoS are proposed, solutions for SDN-specific QoS challenges are designed and tested, and new network management concepts are prototyped, all aiming to improve QoS for network services...

  8. Occurrence of the Southeast Asian/South American SVMNT haplotype of the chloroquine-resistance transporter gene in Plasmodium falciparum in Tanzania

    DEFF Research Database (Denmark)

    Alifrangis, Michael; Dalgaard, Michael B; Lusingu, John P

    2006-01-01

    Two main haplotypes, CVIET and SVMNT, of the Plasmodium falciparum chloroquine-resistance transporter gene (Pfcrt) are linked to 4-aminoquinoline resistance. The CVIET haplotype has been reported in most malaria-endemic regions, whereas the SVMNT haplotype has only been found outside Africa. We...... investigated Pfcrt haplotype frequencies in Korogwe District, Tanzania, in 2003 and 2004. The SVMNT haplotype was not detected in 2003 but was found in 19% of infected individuals in 2004. Amodiaquine use has increased in the region. The introduction and high prevalence of the SVMNT haplotype may reflect...... this and may raise concern regarding the use of amodiaquine in artemisinin-based combination therapies in Africa....

  9. Haplotype Diversity and Reconstruction of Ancestral Haplotype Associated with the c.35delG Mutation in the GJB2 (Cx26) Gene among the Volgo-Ural Populations of Russia.

    Science.gov (United States)

    Dzhemileva, L U; Posukh, O L; Barashkov, N A; Fedorova, S A; Teryutin, F M; Akhmetova, V L; Khidiyatova, I M; Khusainova, R I; Lobov, S L; Khusnutdinova, E K

    2011-07-01

    The mutations in theGJB2(Сх26) gene make the biggest contribution to hereditary hearing loss. The spectrum and prevalence of theGJB2gene mutations are specific to populations of different ethnic origins. For severalGJB2 mutations, their origin from appropriate ancestral founder chromosome was shown, approximate estimations of "age" obtained, and presumable regions of their origin outlined. This work presents the results of the carrier frequencies' analysis of the major (for European countries) mutation c.35delG (GJB2gene) among 2,308 healthy individuals from 18 Eurasian populations of different ethnic origins: Bashkirs, Tatars, Chuvashs, Udmurts, Komi-Permyaks, Mordvins, and Russians (the Volga-Ural region of Russia); Byelorussians, Ukrainians (Eastern Europe); Abkhazians, Avars, Cherkessians, and Ingushes (Caucasus); Kazakhs, Uzbeks, Uighurs (Central Asia); and Yakuts, and Altaians (Siberia). The prevalence of the c.35delG mutation in the studied ethnic groups may act as additional evidence for a prospective role of the founder effect in the origin and distribution of this mutation in various populations worldwide. The haplotype analysis of chromosomes with the c.35delG mutation in patients with nonsyndromic sensorineural hearing loss (N=112) and in population samples (N =358) permitted the reconstruction of an ancestral haplotype with this mutation, established the common origin of the majority of the studied mutant chromosomes, and provided the estimated time of the c.35delG mutation carriers expansion (11,800 years) on the territory of the Volga-Ural region.

  10. Genetic Diversity, Natural Selection and Haplotype Grouping of Plasmodium knowlesi Gamma Protein Region II (PkγRII): Comparison with the Duffy Binding Protein (PkDBPαRII).

    Science.gov (United States)

    Fong, Mun Yik; Rashdi, Sarah A A; Yusof, Ruhani; Lau, Yee Ling

    2016-01-01

    Plasmodium knowlesi is a simian malaria parasite that has been reported to cause malaria in humans in Southeast Asia. This parasite invades the erythrocytes of humans and of its natural host, the macaque Macaca fascicularis, via interaction between the Duffy binding protein region II (PkDBPαRII) and the Duffy antigen receptor on the host erythrocytes. In contrast, the P. knowlesi gamma protein region II (PkγRII) is not involved in the invasion of P. knowlesi into humans. PkγRII, however, mediates the invasion of P. knowlesi into the erythrocytes of M. mulata, a non-natural host of P. knowlesi via a hitherto unknown receptor. The haplotypes of PkDBPαRII in P. knowlesi isolates from Peninsular Malaysia and North Borneo have been shown to be genetically distinct and geographically clustered. Also, the PkDBPαRII was observed to be undergoing purifying (negative) selection. The present study aimed to determine whether similar phenomena occur in PkγRII. Blood samples from 78 knowlesi malaria patients were used. Forty-eight of the samples were from Peninsular Malaysia, and 30 were from Malaysia Borneo. The genomic DNA of the samples was extracted and used as template for the PCR amplification of the PkγRII. The PCR product was cloned and sequenced. The sequences obtained were analysed for genetic diversity and natural selection using MEGA6 and DnaSP (version 5.10.00) programmes. Genetic differentiation between the PkγRII of Peninsular Malaysia and North Borneo isolates was estimated using the Wright's FST fixation index in DnaSP (version 5.10.00). Haplotype analysis was carried out using the Median-Joining approach in NETWORK (version 4.6.1.3). A total of 78 PkγRII sequences was obtained. Comparative analysis showed that the PkγRII have similar range of haplotype (Hd) and nucleotide diversity (π) with that of PkDBPαRII. Other similarities between PkγRII and PkDBPαRII include undergoing purifying (negative) selection, geographical clustering of haplotypes

  11. Genetic Diversity, Natural Selection and Haplotype Grouping of Plasmodium knowlesi Gamma Protein Region II (PkγRII: Comparison with the Duffy Binding Protein (PkDBPαRII.

    Directory of Open Access Journals (Sweden)

    Mun Yik Fong

    Full Text Available Plasmodium knowlesi is a simian malaria parasite that has been reported to cause malaria in humans in Southeast Asia. This parasite invades the erythrocytes of humans and of its natural host, the macaque Macaca fascicularis, via interaction between the Duffy binding protein region II (PkDBPαRII and the Duffy antigen receptor on the host erythrocytes. In contrast, the P. knowlesi gamma protein region II (PkγRII is not involved in the invasion of P. knowlesi into humans. PkγRII, however, mediates the invasion of P. knowlesi into the erythrocytes of M. mulata, a non-natural host of P. knowlesi via a hitherto unknown receptor. The haplotypes of PkDBPαRII in P. knowlesi isolates from Peninsular Malaysia and North Borneo have been shown to be genetically distinct and geographically clustered. Also, the PkDBPαRII was observed to be undergoing purifying (negative selection. The present study aimed to determine whether similar phenomena occur in PkγRII.Blood samples from 78 knowlesi malaria patients were used. Forty-eight of the samples were from Peninsular Malaysia, and 30 were from Malaysia Borneo. The genomic DNA of the samples was extracted and used as template for the PCR amplification of the PkγRII. The PCR product was cloned and sequenced. The sequences obtained were analysed for genetic diversity and natural selection using MEGA6 and DnaSP (version 5.10.00 programmes. Genetic differentiation between the PkγRII of Peninsular Malaysia and North Borneo isolates was estimated using the Wright's FST fixation index in DnaSP (version 5.10.00. Haplotype analysis was carried out using the Median-Joining approach in NETWORK (version 4.6.1.3.A total of 78 PkγRII sequences was obtained. Comparative analysis showed that the PkγRII have similar range of haplotype (Hd and nucleotide diversity (π with that of PkDBPαRII. Other similarities between PkγRII and PkDBPαRII include undergoing purifying (negative selection, geographical clustering of

  12. Defining the Anthropocene

    Science.gov (United States)

    Lewis, Simon; Maslin, Mark

    2016-04-01

    Time is divided by geologists according to marked shifts in Earth's state. Recent global environmental changes suggest that Earth may have entered a new human-dominated geological epoch, the Anthropocene. Should the Anthropocene - the idea that human activity is a force acting upon the Earth system in ways that mean that Earth will be altered for millions of years - be defined as a geological time-unit at the level of an Epoch? Here we appraise the data to assess such claims, first in terms of changes to the Earth system, with particular focus on very long-lived impacts, as Epochs typically last millions of years. Can Earth really be said to be in transition from one state to another? Secondly, we then consider the formal criteria used to define geological time-units and move forward through time examining whether currently available evidence passes typical geological time-unit evidence thresholds. We suggest two time periods likely fit the criteria (1) the aftermath of the interlinking of the Old and New Worlds, which moved species across continents and ocean basins worldwide, a geologically unprecedented and permanent change, which is also the globally synchronous coolest part of the Little Ice Age (in Earth system terms), and the beginning of global trade and a new socio-economic "world system" (in historical terms), marked as a golden spike by a temporary drop in atmospheric CO2, centred on 1610 CE; and (2) the aftermath of the Second World War, when many global environmental changes accelerated and novel long-lived materials were increasingly manufactured, known as the Great Acceleration (in Earth system terms) and the beginning of the Cold War (in historical terms), marked as a golden spike by the peak in radionuclide fallout in 1964. We finish by noting that the Anthropocene debate is politically loaded, thus transparency in the presentation of evidence is essential if a formal definition of the Anthropocene is to avoid becoming a debate about bias. The

  13. Association of RET Genetic Polymorphisms and Haplotypes with Papillary Thyroid Carcinoma in the Portuguese Population: A Case-Control Study

    Science.gov (United States)

    Santos, Marina; Azevedo, Teresa; Martins, Teresa; Rodrigues, Fernando J.; Lemos, Manuel C.

    2014-01-01

    Thyroid cancer has a multifactorial aetiology resulting from the interaction of genetic and environmental factors. Several low penetrance susceptibility genes have been identified but their effects often vary between different populations. Somatic point mutations and translocations of the REarranged during Transfection (RET) proto-oncogene are frequently found in thyroid cancer. The aim of this case-control study was to determine the effect of four well known RET single nucleotide polymorphisms (SNPs) on the risk for differentiated thyroid carcinoma. A total of 545 Portuguese patients and 543 controls were genotyped by PCR and restriction enzyme analysis, for the following SNPs: G691S (exon 11, rs1799939 G/A), L769L (exon 13, rs1800861 T/G), S836S (exon 14, rs1800862 C/T), and S904S (exon 15, rs1800863 C/G). The minor allele of S836S was overrepresented in patients with papillary thyroid carcinoma (PTC) when compared to controls (OR 1.57; 95% CI 1.05–2.35; p = 0.026). The GGTC haplotype was also overrepresented in PTC (OR 2.51; 95% CI 1.07–5.91; p = 0.029). No associations were found in follicular thyroid carcinoma (FTC). Multivariate logistic regression analysis showed no differences regarding gender, age at diagnosis, lymph node or distant metastasis. However, a near significant overrepresentation of the minor alleles of G691S and S904S was found in patients with tumours greater than 10 mm of diameter at diagnosis. These data suggest that the RET S836S polymorphism in exon 14 and the GGTC haplotype are risk factors for PTC, but not FTC, and that the G691S/S904S polymorphisms might be associated with tumour behaviour. PMID:25330015

  14. Haplotype CGC from XPD, hOGG1 and ITGA2 polymorphisms increases the risk of nasopharyngeal carcinoma in Malaysia.

    Directory of Open Access Journals (Sweden)

    Eng-Zhuan Ban

    Full Text Available 8-oxoG, a common DNA lesion resulting from reactive oxygen species (ROS, has been shown to be associated with cancer initiation. hOGG1 DNA glycosylase is the primary enzyme responsible for excision of 8-oxoG through base excision repair (BER. Integrins are members of a family of cell surface receptors that mediate the cell-cell and extracellular matrix (ECM interactions. Integrins are involved in almost every aspect of carcinogenesis, from cell differentiation, cell proliferation, metastasis to angiogenesis. Loss of ITGA2 expression was associated with enhanced tumor intravasation and metastasis of breast and colon cancer. XPD gene encodes DNA helicase enzyme that is involved in nucleotide excision repair (NER. It is shown in previous research that XPD homozygous wildtype Lys/Lys genotype was associated with higher odds of NPC.We conducted a 1 to N case-control study involving 300 nasopharyngeal carcinoma (NPC cases and 533 controls matched by age, gender and ethnicity to investigate the effect of hOGG1 Ser326Cys, ITGA2 C807T and XPD Lys751Gln polymorphisms on NPC risk. Linkage disequilibrium and haplotype analysis were conducted to explore the association of allele combinations with NPC risk. Restriction fragment length polymorphism (RFLP-PCR was used for DNA genotyping.No significant association was observed between hOGG1 Ser326Cys and ITGA2 C807T polymorphisms with NPC risk after adjustment for age, gender, ethnicity, cigarette smoking, alcohol and salted fish consumption. Lys/Lys genotype of XPD Lys751Gln polymorphism was associated with increased NPC risk (OR = 1.60, 95% CI = 1.06-2.43. Subjects with history of smoking (OR = 1.81, 95% CI = 1.26-2.60, and salted fish consumption before age of 10 (OR = 1.77, 95% CI = 1.30-2.42 were observed to have increased odds of NPC. The odds of developing NPC of CGC haplotype was significantly higher compared to reference AGC haplotype (OR = 2.20, 95% CI = 1.06-4.58.The allele combination of CGC from h

  15. Haplotype CGC from XPD, hOGG1 and ITGA2 polymorphisms increases the risk of nasopharyngeal carcinoma in Malaysia.

    Science.gov (United States)

    Ban, Eng-Zhuan; Lye, Munn-Sann; Chong, Pei Pei; Yap, Yoke-Yeow; Lim, Siew Ying Crystale; Abdul Rahman, Hejar

    2017-01-01

    8-oxoG, a common DNA lesion resulting from reactive oxygen species (ROS), has been shown to be associated with cancer initiation. hOGG1 DNA glycosylase is the primary enzyme responsible for excision of 8-oxoG through base excision repair (BER). Integrins are members of a family of cell surface receptors that mediate the cell-cell and extracellular matrix (ECM) interactions. Integrins are involved in almost every aspect of carcinogenesis, from cell differentiation, cell proliferation, metastasis to angiogenesis. Loss of ITGA2 expression was associated with enhanced tumor intravasation and metastasis of breast and colon cancer. XPD gene encodes DNA helicase enzyme that is involved in nucleotide excision repair (NER). It is shown in previous research that XPD homozygous wildtype Lys/Lys genotype was associated with higher odds of NPC. We conducted a 1 to N case-control study involving 300 nasopharyngeal carcinoma (NPC) cases and 533 controls matched by age, gender and ethnicity to investigate the effect of hOGG1 Ser326Cys, ITGA2 C807T and XPD Lys751Gln polymorphisms on NPC risk. Linkage disequilibrium and haplotype analysis were conducted to explore the association of allele combinations with NPC risk. Restriction fragment length polymorphism (RFLP-PCR) was used for DNA genotyping. No significant association was observed between hOGG1 Ser326Cys and ITGA2 C807T polymorphisms with NPC risk after adjustment for age, gender, ethnicity, cigarette smoking, alcohol and salted fish consumption. Lys/Lys genotype of XPD Lys751Gln polymorphism was associated with increased NPC risk (OR = 1.60, 95% CI = 1.06-2.43). Subjects with history of smoking (OR = 1.81, 95% CI = 1.26-2.60), and salted fish consumption before age of 10 (OR = 1.77, 95% CI = 1.30-2.42) were observed to have increased odds of NPC. The odds of developing NPC of CGC haplotype was significantly higher compared to reference AGC haplotype (OR = 2.20, 95% CI = 1.06-4.58). The allele combination of CGC from hOGG1

  16. Echinococcus equinus and Echinococcus granulosus sensu stricto from the United Kingdom: genetic diversity and haplotypic variation.

    Science.gov (United States)

    Boufana, Belgees; Lett, Wai San; Lahmar, Samia; Buishi, Imad; Bodell, Anthony J; Varcasia, Antonio; Casulli, Adriano; Beeching, Nicholas J; Campbell, Fiona; Terlizzo, Monica; McManus, Donald P; Craig, Philip S

    2015-02-01

    Cystic echinococcosis is endemic in Europe including the United Kingdom. However, information on the molecular epidemiology of Echinococcus spp. from the United Kingdom is limited. Echinococcus isolates from intermediate and definitive animal hosts as well as from human cystic echinococcosis cases were analysed to determine species and genotypes within these hosts. Echinococcus equinus was identified from horse hydatid isolates, cysts retrieved from captive UK mammals and copro-DNA of foxhounds and farm dogs. Echinococcus granulosus sensu stricto (s.s.) was identified from hydatid cysts of sheep and cattle as well as in DNA extracted from farm dog and foxhound faecal samples, and from four human cystic echinococcosis isolates, including the first known molecular confirmation of E. granulosus s.s. infection in a Welsh sheep farmer. Low genetic variability for E. equinus from various hosts and from different geographical locations was detected using the mitochondrial cytochrome c oxidase subunit 1 gene (cox1), indicating the presence of a dominant haplotype (EQUK01). In contrast, greater haplotypic variation was observed for E. granulosus s.s. cox1 sequences. The haplotype network showed a star-shaped network with a centrally placed main haplotype (EgUK01) that had been reported from other world regions. Copyright © 2014 Australian Society for Parasitology Inc. Published by Elsevier Ltd. All rights reserved.

  17. MtDNA haplotype identification of aurochs remains originating from the Czech Republic (Central Europe)

    Czech Academy of Sciences Publication Activity Database

    Kyselý, René; Hájek, M.

    2012-01-01

    Roč. 17, č. 2 (2012), s. 118-125 ISSN 1461-4103 Institutional research plan: CEZ:AV0Z80020508 Institutional support: RVO:67985912 Keywords : wild cattle (Bos primigenius) * aDNA * haplotype P * domestication Subject RIV: AC - Archeology, Anthropology, Ethnology

  18. Using haplotypes to unravel the inheritance of Holstein coat color for a larger audience

    Science.gov (United States)

    Haplotype testing identifies single-nucleotide polymorphisms that bracket a group of alleles from several different genes located on a specific chromosomal section of DNA. For a trait with a limited number of genotypes and phenotypes, the rules of inheritance can be determined by matching up certain...

  19. Population Structure of Pseudocercospora fijiensis in Costa Rica Reveals Shared Haplotype Diversity with Southeast Asian Populations.

    Science.gov (United States)

    Saville, Amanda; Charles, Melodi; Chavan, Suchitra; Muñoz, Miguel; Gómez-Alpizar, Luis; Ristaino, Jean Beagle

    2017-12-01

    Pseudocercospora fijiensis is the causal pathogen of black Sigatoka, a devastating disease of banana that can cause 20 to 80% yield loss in the absence of fungicides in banana crops. The genetic structure of populations of P. fijiensis in Costa Rica was examined and compared with Honduran and global populations to better understand migration patterns and inform management strategies. In total, 118 isolates of P. fijiensis collected from Costa Rica and Honduras from 2010 to 2014 were analyzed using multilocus genotyping of six loci and compared with a previously published global dataset of populations of P. fijiensis. The Costa Rican and Honduran populations shared haplotype diversity with haplotypes from Southeast Asia, Oceania, and the Americas but not Africa for all but one of the six loci studied. Gene flow and shared haplotype diversity was found in Honduran and Costa Rican populations of the pathogen. The data indicate that the haplotypic diversity observed in Costa Rican populations of P. fijiensis is derived from dispersal from initial outbreak sources in Honduras and admixtures between genetically differentiated sources from Southeast Asia, Oceania, and the Americas.

  20. Evidence of a Native Northwest Atlantic COI Haplotype Clade in the Cryptogenic Colonial Ascidian Botryllus schlosseri.

    Science.gov (United States)

    Yund, Philip O; Collins, Catherine; Johnson, Sheri L

    2015-06-01

    The colonial ascidian Botryllus schlosseri should be considered cryptogenic (i.e., not definitively classified as either native or introduced) in the Northwest Atlantic. Although all the evidence is quite circumstantial, over the last 15 years most research groups have accepted the scenario of human-mediated dispersal and classified B. schlosseri as introduced; others have continued to consider it native or cryptogenic. We address the invasion status of this species by adding 174 sequences to the growing worldwide database for the mitochondrial gene cytochrome c oxidase subunit I (COI) and analyzing 1077 sequences to compare genetic diversity of one clade of haplotypes in the Northwest Atlantic with two hypothesized source regions (the Northeast Atlantic and Mediterranean). Our results lead us to reject the prevailing view of the directionality of transport across the Atlantic. We argue that the genetic diversity patterns at COI are far more consistent with the existence of at least one haplotype clade in the Northwest Atlantic (and possibly a second) that substantially pre-dates human colonization from Europe, with this native North American clade subsequently introduced to three sites in Northeast Atlantic and Mediterranean waters. However, we agree with past researchers that some sites in the Northwest Atlantic have more recently been invaded by alien haplotypes, so that some populations are currently composed of a mixture of native and invader haplotypes. © 2015 Marine Biological Laboratory.

  1. WhatsHap: Haplotype Assembly for Future-Generation Sequencing Reads

    NARCIS (Netherlands)

    M.D. Patterson (Murray); T. Marschall (Tobias); N. Pisanti (Nadia); L.J.J. van Iersel (Leo); L. Stougie (Leen); G.W. Klau (Gunnar); A. Schönhuth (Alexander)

    2014-01-01

    htmlabstractThe human genome is diploid, that is each of its chromosomes comes in two copies. This requires to phase the single nucleotide polymorphisms (SNPs), that is, to assign them to the two copies, beyond just detecting them. The resulting haplotypes, lists of SNPs belonging to each copy, are

  2. WhatsHap: Haplotype Assembly for Future-Generation Sequencing Reads

    NARCIS (Netherlands)

    Patterson, M.; Marschall, T.; Pisanti, N.; van Iersel, L.J.J.; Stougie, L.; Klau, G.W.; Schoenhuth, A.

    2014-01-01

    The human genome is diploid, that is each of its chromosomes comes in two copies. This requires to phase the single nucleotide polymorphisms (SNPs), that is, to assign them to the two copies, beyond just detecting them. The resulting haplotypes, lists of SNPs belonging to each copy, are crucial for

  3. De novo assembly of a haplotype-resolved human genome

    DEFF Research Database (Denmark)

    Cao, Hongzhi; Wu, Honglong; Luo, Ruibang

    2015-01-01

    The human genome is diploid, and knowledge of the variants on each chromosome is important for the interpretation of genomic information. Here we report the assembly of a haplotype-resolved diploid genome without using a reference genome. Our pipeline relies on fosmid pooling together with whole-...

  4. Endothelial Nitric Oxide Synthase Haplotypes Are Associated with Preeclampsia in Maya Mestizo Women

    Directory of Open Access Journals (Sweden)

    Lizbeth Díaz-Olguín

    2011-01-01

    Full Text Available Preeclampsia is a specific disease of pregnancy and believed to have a genetic component. The aim of this study was to investigate if three polymorphisms in eNOS or their haplotypes are associated with preeclampsia in Maya mestizo women.

  5. HLA class II linkage disequilibrium and haplotype evolution in the Cayapa Indians of Ecuador

    Energy Technology Data Exchange (ETDEWEB)

    Trachtenberg, E.A.; Erlich, H.A. [Roche Molecular Systems, Alameda, CA (United States); Klitz, W. [Univ. of California, Berkeley, CA (United States)] [and others

    1995-08-01

    DNA-based typing of the HLA class II loci in a sample of the Cayapa Indians of Ecuador reveals several lines of evidence that selection has operated to maintain and to diversify the existing level of polymorphism in the class II region. As has been noticed for other Native American groups, the overall level of polymorphism at the DRB1, DQA1, DQB1, and DPB1 loci is reduced relative to that found in other human populations. Nonetheless, the relative eveness in the distribution of allele frequencies at each of the four loci points to the role of balancing selection in the maintenance of the polymorphism. The DQA1 and DQB1 loci, in particular, have near-maximum departures from the neutrality model, which suggests that balancing selection has been especially strong in these cases. Several novel DQA1-DQB1 haplotypes and the discovery of a new DRB1 allele demonstrate an evolutionary tendency favoring the diversification of class II alleles and haplotypes. The recombination interval between the centromeric DPB1 locus and the other class II loci will, in the absence of other forces such as selection, reduce disequilibrium across this region. However, nearly all common alleles were found to be part of DR-DP haplotypes in strong disequilibrium, consistent with the recent action of selection acting on these haplotypes in the Cayapa. 50 refs., 3 figs., 3 tabs.

  6. Novel Harmful Recessive Haplotypes Identified for Fertility Traits in Nordic Holstein Cattle

    Science.gov (United States)

    Sahana, Goutam; Nielsen, Ulrik Sander; Aamand, Gert Pedersen; Lund, Mogens Sandø; Guldbrandtsen, Bernt

    2013-01-01

    Using genomic data, lethal recessives may be discovered from haplotypes that are common in the population but never occur in the homozygote state in live animals. This approach only requires genotype data from phenotypically normal (i.e. live) individuals and not from the affected embryos that die. A total of 7,937 Nordic Holstein animals wer